{"publication_id":"82831700-7ed3-4b2a-87cf-b14d27b3ea02","traces":[{"claim_id":"claim_1","claim":"This paper synthesizes evidence on Mitochondrial DNA damage across 15 accepted source papers and 387 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 4 mechanistic or model-system sources, with no load-bearing cross-study disagreements across the evidence base. No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence and mechanism outcome classes, and negative signals cluster in the cardiometabolic and muscle function outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Mitochondrial DNA damage remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"This paper synthesizes evidence on Mitochondrial DNA damage across 15 accepted source papers and 387 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 4 mechanistic or model-system sources, with no load-bearing cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence and mechanism outcome classes, and negative signals cluster in the cardiometabolic and muscle function outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The conclusion is that Mitochondrial DNA damage remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-mitochondrial_dna_damage-v06-DAILY-2026-06-28T20-23-21Z-R2`.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, deficiency prevalence, longevity, mechanism, muscle function); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"The principal limitation is evidence-role imbalance. The retained corpus contains no sources classified primarily as direct interventional hard-endpoint evidence, 11 adjacent clinical sources, and 4 mechanistic or model-system sources, which means causal interpretation depends on how much weight is assigned to each evidence tier.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"A second limitation is endpoint heterogeneity. Study-level signals span no dominant outcome class, the contextual adjacent evidence and mechanism outcome classes, the cardiometabolic and muscle function outcome classes, and no dominant outcome class; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"For Mitochondrial DNA damage, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. Pending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"Tension-accounting note: disagreement counts are claim-level. Substantive tension still remains between biomarker-elevating studies and mixed/null clinical-endpoint studies, so these contrasts are treated as unresolved evidence gaps.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"Additional corpus sources included animal/preclinical evidence; findings Map completeness note: all 15 admitted manifest rows are surfaced below (Ng 2019, Pena 2024, Gureev 2022, Hsiao 2026, Reid 2023, Kennedy 2025, Shimizu 2026, Liang 2022, Chan 2012, Picca 2019, Chakraborty 2026, Roca-Bayerri 2020, Perez-Perez 2025, Picca 2020, Luo 2024).","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"In animal/preclinical evidence, Ng 2019: Mitochondrial DNA Damage Does Not Determine C. elegans Lifespan: outcome=Mechanism/Longevity (C. elegans); direction=null; directness=mechanistic; tier=C1; finding=representative statistic p < 0.0001; source-level statistic reported.","citation_support":[{"source_id":"source_13","study":"Mitochondrial DNA Damage Does Not Determine C. elegans Lifespan","doi":"10.3389/fgene.2019.00311","url":"https://doi.org/10.3389/fgene.2019.00311","support_kind":"cited_as_match","cited_as":"Ng 2019","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage. Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in ROS detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan."}],"candidate_sources":[]},{"claim_id":"claim_17","claim":"Pena 2024: G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage: outcome=Biomarker/Adjacent Evidence; direction=mixed; directness=indirect; tier=B2; finding=representative non-significant statistic p = 0.92; not treated as positive or negative directional support unless source direction is coded.","citation_support":[{"source_id":"source_1","study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","support_kind":"cited_as_match","cited_as":"Pena 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis."}],"candidate_sources":[]},{"claim_id":"claim_18","claim":"In animal/preclinical evidence, Gureev 2022: Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments: outcome=Biomarker/Adjacent Evidence; direction=negative; directness=indirect; tier=B2; finding=representative statistic p < 0.01; source-level statistic reported.","citation_support":[{"source_id":"source_2","study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","support_kind":"cited_as_match","cited_as":"Gureev 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test."}],"candidate_sources":[]},{"claim_id":"claim_19","claim":"Hsiao 2026: Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia: outcome=Biomarker/Adjacent Evidence; direction=negative; directness=indirect; tier=B2; finding=representative statistic p<0.05; source-level statistic reported.","citation_support":[{"source_id":"source_3","study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","support_kind":"cited_as_match","cited_as":"Hsiao 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering."}],"candidate_sources":[]},{"claim_id":"claim_20","claim":"Reid 2023: Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease: outcome=Biomarker/Adjacent Cognitive; direction=negative; directness=indirect; tier=B2; finding=representative statistic P = 0.0007; source-level statistic reported.","citation_support":[{"source_id":"source_5","study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","support_kind":"cited_as_match","cited_as":"Reid 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk."}],"candidate_sources":[]},{"claim_id":"claim_21","claim":"Kennedy 2025: Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells: outcome=Mechanism/Contextual Adjacent Evidence (cell/in vitro); direction=unclear; directness=indirect; tier=B2; finding=representative statistic p < 0.0001; source-level statistic reported.","citation_support":[{"source_id":"source_4","study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","support_kind":"cited_as_match","cited_as":"Kennedy 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction."}],"candidate_sources":[]},{"claim_id":"claim_22","claim":"Shimizu 2026: A PUFA-rich diet increases endogenous genotoxic stress and mitochondrial DNA damage in mice: outcome=Mechanism/Cardiometabolic (mouse); direction=negative; directness=mechanistic; tier=C1; finding=representative statistic P < 0.05; source-level statistic reported.","citation_support":[],"candidate_sources":[{"study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","year":2024,"doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Pena 2024","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","year":2022,"doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Gureev 2022","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","year":2026,"doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Hsiao 2026","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","year":2025,"doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Kennedy 2025","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","year":2023,"doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Reid 2023","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"Liang 2022: Effects of Treadmill Exercise on Mitochondrial DNA Damage and Cardiomyocyte Telomerase Activity in Aging Model Rats Based on Classical Apoptosis Signaling Pathway: outcome=Mechanism (rodent); direction=null; directness=mechanistic; tier=C1; finding=representative statistic P < 0.05; source-level statistic reported.","citation_support":[{"source_id":"source_7","study":"Effects of Treadmill Exercise on Mitochondrial DNA Damage and Cardiomyocyte Telomerase Activity in Aging Model Rats Based on Classical Apoptosis Signaling Pathway","doi":"10.1155/2022/3529499","url":"https://doi.org/10.1155/2022/3529499","support_kind":"cited_as_match","cited_as":"Liang 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"In order to explore the effect of treadmill exercise on mitochondrial DNA damage and myocardial telomerase activity in aging model rats based on the classical apoptosis signaling pathway, a total of 36 clean-grade male SD rats are selected. After modeling, the rats are randomly divided into groups, namely, control and 3 times/w and 6 times/w exercise rats, with 12 rats in each group. After the rats of each group are modeled, the myocardial tissue and cells are collected, the apoptosis of myocardial cells is detected by TUNEL method, and the protein expressions of Bax and Bcl-2 in myocardial tissue are detected by western blotting. The mtDNA content of the control rats is the highest, which is significantly higher than that of the exercise group ( P < 0.05); the expression of mtDNA content in the heart of the rats exercising 3 times/w is significantly higher than that of the rats exercising 6 times/w ( P < 0.05); cardiomyocyte apoptosis AI value, Bcl-2, and Bax expressions of the control rats is the highest and significantly higher than those in the exercise group ( P < 0."}],"candidate_sources":[]},{"claim_id":"claim_24","claim":"Chan 2012: Simultaneous Quantification of Mitochondrial DNA Damage and Copy Number in Circulating Blood: A Sensitive Approach to Systemic Oxidative Stress: outcome=Biomarker/Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic P < 0.01; source-level statistic reported.","citation_support":[{"source_id":"source_14","study":"Simultaneous Quantification of Mitochondrial DNA Damage and Copy Number in Circulating Blood: A Sensitive Approach to Systemic Oxidative Stress","doi":"10.1155/2013/157547","url":"https://doi.org/10.1155/2013/157547","support_kind":"cited_as_match","cited_as":"Chan 2012","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Systemic oxidative stress is associated with a wide range of pathological conditions. Oxidative DNA damage is frequently measured in circulating lymphocytes. Mitochondrial DNA (mtDNA) is known to be more sensitive to oxidative damage than nuclear DNA but is rarely used for direct measurement of DNA damage in clinical studies. Based on the supercoiling-sensitive real-time PCR method, we propose a new approach for the noninvasive monitoring of systemic oxidative stress by quantifying the mtDNA structural damage and copy number change in isolated lymphocytes in a single test. We show that lymphocytes have significantly less mtDNA content and relatively lower baseline levels of damage than cancer cell lines. In an ex vivo challenge experiment, we demonstrate, for the first time, that exogenous H2O2 induces a significant increase in mtDNA damage in lymphocytes from healthy individuals, but no repair activity is observed after 1 h recovery. We further demonstrate that whole blood may serve as a convenient alternative to the isolated lymphocytes in mtDNA analysis."}],"candidate_sources":[]},{"claim_id":"claim_25","claim":"Chakraborty 2026: F2,6BP restores mitochondrial genome integrity in Huntington’s disease: outcome=Contextual Adjacent Evidence; direction=positive; directness=indirect; tier=B2; finding=representative statistic p < 0.005; source-level statistic reported.","citation_support":[{"source_id":"source_8","study":"F2,6BP restores mitochondrial genome integrity in Huntington’s disease","doi":"10.1016/j.jbc.2026.111156","url":"https://doi.org/10.1016/j.jbc.2026.111156","support_kind":"cited_as_match","cited_as":"Chakraborty 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks, is a potential cause for its compromised functionality. Here we show that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly decreased in the mitochondrial extract of brains of patients with HD due to a lower level of fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Such decrease in PNKP activity leads to persistent DNA strand breaks that are refractory to subsequent steps for repair completion. Both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria, and PFKFB3 is part of a mitochondrial DNA repair complex containing HTT, PNKP, DNA Pol γ (POLG), and Lig IIIα. Notably, PNKP binds F2,6BP (Kd = 525 ± 25 nM) and utilizes it as a cofactor. The levels of both F2,6BP and PFKFB3 are significantly decreased in the mitochondrial extract of HD mouse striatal neuronal cells and patients' brain."}],"candidate_sources":[]},{"claim_id":"claim_26","claim":"Substantive evidence synthesis: The manifest includes 15 retained sources, 0 direct-source row(s), and receipt-level directional coding across negative=2, null=2, unclear=11. Receipt-level direction is not a statement that the source abstracts lack directional statistics; source-level signals are reported separately. Full source-level signals are: Pena 2024: outcome=Biomarker/Adjacent Evidence; direction=mixed; directness=indirect; tier=B2; result=G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage; finding=representative non-significant statistic p = 0.92; not treated as positive or negative directional support unless source direction is coded; claims=50; Gureev 2022: outcome=Biomarker/Adjacent Evidence; direction=negative; directness=indirect; tier=B2; result=Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments; finding=representative statistic p < 0.01; source-level statistic reported; claims=48; Hsiao 2026: outcome=Biomarker/Adjacent Evidence; direction=negative; directness=indirect; tier=B2; result=Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia; finding=representative statistic p<0.05; source-level statistic reported; claims=32; Reid 2023: outcome=Biomarker/Adjacent Cognitive; direction=negative; directness=indirect; tier=B2; result=Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s; finding=representative statistic P = 0.0007; source-level statistic reported; claims=27; Kennedy 2025: outcome=Mechanism/Contextual Adjacent Evidence (cell/in vitro); direction=unclear; directness=indirect; tier=B2; result=Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells; finding=representative statistic p < 0.0001; source-level statistic reported; claims=27; Shimizu 2026: outcome=Mechanism/Cardiometabolic (mouse); direction=negative; directness=mechanistic; tier=C1; result=A PUFA-rich diet increases endogenous genotoxic stress and mitochondrial DNA damage in mice; finding=representative statistic P < 0.05; source-level statistic reported; claims=26; Chan 2012: outcome=Biomarker/Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Simultaneous Quantification of Mitochondrial DNA Damage and Copy Number in Circulating Blood: A Sensitive Approach to; finding=representative statistic P < 0.01; source-level statistic reported; claims=21; Picca 2019: outcome=Biomarker/Adjacent Muscle Function; direction=unclear; directness=indirect; tier=B2; result=Advanced Age Is Associated with Iron Dyshomeostasis and Mitochondrial DNA Damage in Human Skeletal Muscle; finding=representative statistic p = 0.0002; source-level statistic reported; claims=17; Chakraborty 2026: outcome=Contextual Adjacent Evidence; direction=positive; directness=indirect; tier=B2; result=F2,6BP restores mitochondrial genome integrity in Huntington’s disease; finding=representative statistic p < 0.005; source-level statistic reported; claims=14; Roca-Bayerri 2020: outcome=Biomarker/Adjacent Deficiency Prevalence; direction=unclear; directness=indirect; tier=B2; result=Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus; finding=representative statistic P < .05; source-level statistic reported; claims=14; Perez-Perez 2025: outcome=Mechanism (mouse); direction=unclear; directness=mechanistic; tier=C1; result=Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice; finding=representative statistic p = 0.0003; source-level statistic reported; claims=12; Picca 2020: outcome=Biomarker/Adjacent Muscle Function; direction=unclear; directness=indirect; tier=B2; result=Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the; finding=representative statistic p = 0.0002; source-level statistic reported; claims=9; Luo 2024: outcome=Biomarker/Adjacent Muscle Function; direction=negative; directness=indirect; tier=B2; result=Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage; finding=7 extracted claim(s); receipt-level direction is the coded finding; claims=7; Ng 2019: outcome=Mechanism/Longevity (C. elegans); direction=null; directness=mechanistic; tier=C1; result=Mitochondrial DNA Damage Does Not Determine C. elegans Lifespan; finding=representative statistic p < 0.0001; source-level statistic reported; claims=60; Liang 2022: outcome=Mechanism (rodent); direction=null; directness=mechanistic; tier=C1; result=Effects of Treadmill Exercise on Mitochondrial DNA Damage and Cardiomyocyte Telomerase Activity in Aging Model Rats; finding=representative statistic P < 0.05; source-level statistic reported; claims=23. Contextual-adjacent subdomain map:  - biology-mechanism and molecular-context evidence: Pena 2024, Gureev 2022, Hsiao 2026, Kennedy 2025, Chan 2012, Chakraborty 2026  These signals inform the bounded conclusion by separating effect direction from evidence tier/directness; indirect, review-level, mechanistic, or contextual evidence remains hypothesis-generating.","citation_support":[{"source_id":"source_1","study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","support_kind":"cited_as_match","cited_as":"Pena 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis."},{"source_id":"source_2","study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","support_kind":"cited_as_match","cited_as":"Gureev 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test."},{"source_id":"source_3","study":"Airway microbial dysbiosis and oxidative mitochondrial DNA damage in the development of bronchopulmonary dysplasia","doi":"10.1183/23120541.00874-2025","url":"https://doi.org/10.1183/23120541.00874-2025","support_kind":"cited_as_match","cited_as":"Hsiao 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"BACKGROUND: This study investigated the association between airway microbiome composition, oxidative mitochondrial DNA (mtDNA) damage and the development of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: A prospective cohort study enrolled 82 very low birth weight preterm infants (<32 weeks' gestation). Tracheal aspirates (TA) were collected at birth and on postnatal day 28. Airway microbial diversity and composition were assessed using 16S rRNA sequencing. Oxidative mtDNA damage was measured using 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in TA samples. We used PICRUSt2-based metagenome predictions from 16S rRNA gene sequencing of TA samples, with functional pathway annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: Infants who developed BPD (n=25) had lower gestational age, birth weight and prolonged ventilatory support (p<0.05). Oxidative mtDNA damage was significantly higher in infants with BPD, particularly in moderate-to-severe cases (p<0.05). BPD was associated with reduced microbial alpha diversity and distinct beta diversity clustering."},{"source_id":"source_4","study":"Methods for Mitochondrial DNA Damage and Depletion in Immortalized Trabecular Meshwork Cells","doi":"10.3390/ijms26136255","url":"https://doi.org/10.3390/ijms26136255","support_kind":"cited_as_match","cited_as":"Kennedy 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1 rtTAadv-TRE-UNG1Y147A ). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts ( CTGF , FN1 , PAI1 , and SFRP1 ) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1 rtTAadv-TRE-UNG1Y147A cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction."},{"source_id":"source_5","study":"Integrative blood-based characterization of oxidative mitochondrial DNA damage variants implicates Mexican American’s metabolic risk for developing Alzheimer’s disease","doi":"10.1038/s41598-023-41190-6","url":"https://doi.org/10.1038/s41598-023-41190-6","support_kind":"cited_as_match","cited_as":"Reid 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Alzheimer's Disease (AD) continues to be a leading cause of death in the US. As the US aging population (ages 65 +) expands, the impact will disproportionately affect vulnerable populations, e.g., Hispanic/Latino population, due to their AD-related health disparities. Age-related regression in mitochondrial activity and ethnic-specific differences in metabolic burden could potentially explain in part the racial/ethnic distinctions in etiology that exist for AD. Oxidation of guanine (G) to 8-oxo-guanine (8oxoG) is a prevalent lesion and an indicator of oxidative stress and mitochondrial dysfunction. Damaged mtDNA (8oxoG) can serve as an important marker of age-related systemic metabolic dysfunction and upon release into peripheral circulation may exacerbate pathophysiology contributing to AD development and/or progression. Analyzing blood samples from Mexican American (MA) and non-Hispanic White (NHW) participants enrolled in the Texas Alzheimer's Research & Care Consortium, we used blood-based measurements of 8oxoG from both buffy coat PBMCs and plasma to determine associations with population, sex, type-2 diabetes, and AD risk."},{"source_id":"source_6","study":"A PUFA-rich diet increases endogenous genotoxic stress and mitochondrial DNA damage in mice","doi":"10.1186/s41021-026-00360-4","url":"https://doi.org/10.1186/s41021-026-00360-4","support_kind":"cited_as_match","cited_as":"Shimizu 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"BACKGROUND: Substitution of dietary saturated fat with seed oils highly enriched in n-6 polyunsaturated fatty acids (PUFAs) has been advocated as healthy strategy to offset elevated cholesterol levels. However, both n-6 as well as n-3 PUFAs, considered essential because vertebrates lack the enzymatic apparatus for their de novo synthesis, are the main source of endogenous DNA damage during the aging process due to their high oxidizability. The membrane pacemaker theory of aging is an extension to the oxidative theory of aging and postulates that higher PUFA content in membrane lipids determines the lifespan of different species. OBJECTIVE: We have examined whether a saturated fat-rich diet lacking the essential fatty acids versus a PUFA-rich diet differentially affects lipid profiles and membrane fatty-acid composition, as well as markers of oxidative protein and DNA damage and mitochondrial DNA (mtDNA) integrity in vivo. METHODS: Three-week-old male C57BL/6J mice were fed isocaloric, high-fat diets containing either coconut oil (SFA-rich) or soybean oil (PUFA-rich) for 12 weeks."},{"source_id":"source_7","study":"Effects of Treadmill Exercise on Mitochondrial DNA Damage and Cardiomyocyte Telomerase Activity in Aging Model Rats Based on Classical Apoptosis Signaling Pathway","doi":"10.1155/2022/3529499","url":"https://doi.org/10.1155/2022/3529499","support_kind":"cited_as_match","cited_as":"Liang 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"In order to explore the effect of treadmill exercise on mitochondrial DNA damage and myocardial telomerase activity in aging model rats based on the classical apoptosis signaling pathway, a total of 36 clean-grade male SD rats are selected. After modeling, the rats are randomly divided into groups, namely, control and 3 times/w and 6 times/w exercise rats, with 12 rats in each group. After the rats of each group are modeled, the myocardial tissue and cells are collected, the apoptosis of myocardial cells is detected by TUNEL method, and the protein expressions of Bax and Bcl-2 in myocardial tissue are detected by western blotting. The mtDNA content of the control rats is the highest, which is significantly higher than that of the exercise group ( P < 0.05); the expression of mtDNA content in the heart of the rats exercising 3 times/w is significantly higher than that of the rats exercising 6 times/w ( P < 0.05); cardiomyocyte apoptosis AI value, Bcl-2, and Bax expressions of the control rats is the highest and significantly higher than those in the exercise group ( P < 0."},{"source_id":"source_8","study":"F2,6BP restores mitochondrial genome integrity in Huntington’s disease","doi":"10.1016/j.jbc.2026.111156","url":"https://doi.org/10.1016/j.jbc.2026.111156","support_kind":"cited_as_match","cited_as":"Chakraborty 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks, is a potential cause for its compromised functionality. Here we show that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly decreased in the mitochondrial extract of brains of patients with HD due to a lower level of fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Such decrease in PNKP activity leads to persistent DNA strand breaks that are refractory to subsequent steps for repair completion. Both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria, and PFKFB3 is part of a mitochondrial DNA repair complex containing HTT, PNKP, DNA Pol γ (POLG), and Lig IIIα. Notably, PNKP binds F2,6BP (Kd = 525 ± 25 nM) and utilizes it as a cofactor. The levels of both F2,6BP and PFKFB3 are significantly decreased in the mitochondrial extract of HD mouse striatal neuronal cells and patients' brain."},{"source_id":"source_9","study":"Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus","doi":"10.1093/cid/ciaa984","url":"https://doi.org/10.1093/cid/ciaa984","support_kind":"cited_as_match","cited_as":"Roca-Bayerri 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"BACKGROUND: Neurocognitive impairment (NCI) remains common in people living with human immunodeficiency virus (PLWH), despite suppressive antiretroviral therapy (ART), but the reasons remain incompletely understood. Mitochondrial dysfunction is a hallmark of aging and of neurodegenerative diseases. We hypothesized that human immunodeficiency virus (HIV) or ART may lead to mitochondrial abnormalities in the brain, thus contributing to NCI. METHODS: We studied postmortem frozen brain samples from 52 PLWH and 40 HIV-negative controls. Cellular mitochondrial DNA (mtDNA) content and levels of large-scale mtDNA deletions were measured by real-time polymerase chain reaction. Heteroplasmic mtDNA point mutations were quantified by deep sequencing (Illumina). Neurocognitive data were taken within 48 months antemortem. RESULTS: We observed a decrease in mtDNA content, an increase in the mtDNA \"common deletion,\" and an increase in mtDNA point mutations with age (all P < .05). Each of these changes was exacerbated in HIV-positive cases compared with HIV-negative controls (all P < .05)."},{"source_id":"source_10","study":"Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice","doi":"10.3390/biom15121706","url":"https://doi.org/10.3390/biom15121706","support_kind":"cited_as_match","cited_as":"Perez-Perez 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"Mitochondrial dysfunction and loss of mitochondrial DNA (mtDNA) integrity are increasingly recognized as key contributors to liver diseases such as cirrhosis and hepatocellular carcinoma. However, the role of mtDNA repair in maintaining mitochondrial homeostasis during liver injury remains poorly understood. Apurinic/apyrimidinic endonuclease 1 (APE1), encoded by the Apex1 gene, is the primary endonuclease mediating base excision repair of mtDNA. We hypothesize that APE1 is required to preserve mtDNA integrity in response to genotoxic stress in the liver. To test this, wild-type (WT) and Apex1 haploinsufficient mice ( Apex1 +/- ) were treated with the alkylating agent azoxymethane (AOM), a carcinogen bioactivated in the liver, and tissues were collected 20 weeks after the last exposure. Apex1 +/- mice exhibited a 3.2-fold increase in mtDNA lesions and a 55% reduction in mtDNA abundance, changes not observed in WT mice. Bioenergetics profiling revealed a 1.5-fold increase in the ATP5β/GAPDH ratio in WT mice and a 2.5-fold increase in Apex1 +/- mice, indicating a more pronounced shift toward oxidative phosphorylation in the absence of full APE1 function."},{"source_id":"source_11","study":"Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults","doi":"10.3390/cells9122579","url":"https://doi.org/10.3390/cells9122579","support_kind":"cited_as_match","cited_as":"Picca 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial-iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA 4977 ) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope ( 56 Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA 4977 relative abundance was greater in old than in young participants, regardless of SPPB category."},{"source_id":"source_12","study":"Cancerous Conditions Accelerate the Aging of Skeletal Muscle via Mitochondrial DNA Damage","doi":"10.3390/ijms25137060","url":"https://doi.org/10.3390/ijms25137060","support_kind":"cited_as_match","cited_as":"Luo 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Skeletal muscle aging and sarcopenia result in similar changes in the levels of aging markers. However, few studies have examined cancer sarcopenia from the perspective of aging. Therefore, this study investigated aging in cancer sarcopenia and explored its causes in vitro and in vivo. In mouse aging, in vitro cachexia, and mouse cachexia models, skeletal muscles showed similar changes in aging markers including oxidative stress, fibrosis, reduced muscle differentiation potential, and telomere shortening. Furthermore, examination of mitochondrial DNA from skeletal muscle revealed a 5 kb deletion in the major arc; truncation of complexes I, IV, and V in the electron transport chain; and reduced oxidative phosphorylation (OXPHOS). The mouse cachexia model demonstrated high levels of high-mobility group box-1 (HMGB1) and tumor necrosis factor-α (TNFα) in cancer ascites. Continuous administration of neutralizing antibodies against HMGB1 and TNFα in this model reduced oxidative stress and abrogated mitochondrial DNA deletion."},{"source_id":"source_13","study":"Mitochondrial DNA Damage Does Not Determine C. elegans Lifespan","doi":"10.3389/fgene.2019.00311","url":"https://doi.org/10.3389/fgene.2019.00311","support_kind":"cited_as_match","cited_as":"Ng 2019","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage. Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in ROS detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan."},{"source_id":"source_14","study":"Simultaneous Quantification of Mitochondrial DNA Damage and Copy Number in Circulating Blood: A Sensitive Approach to Systemic Oxidative Stress","doi":"10.1155/2013/157547","url":"https://doi.org/10.1155/2013/157547","support_kind":"cited_as_match","cited_as":"Chan 2012","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Systemic oxidative stress is associated with a wide range of pathological conditions. Oxidative DNA damage is frequently measured in circulating lymphocytes. Mitochondrial DNA (mtDNA) is known to be more sensitive to oxidative damage than nuclear DNA but is rarely used for direct measurement of DNA damage in clinical studies. Based on the supercoiling-sensitive real-time PCR method, we propose a new approach for the noninvasive monitoring of systemic oxidative stress by quantifying the mtDNA structural damage and copy number change in isolated lymphocytes in a single test. We show that lymphocytes have significantly less mtDNA content and relatively lower baseline levels of damage than cancer cell lines. In an ex vivo challenge experiment, we demonstrate, for the first time, that exogenous H2O2 induces a significant increase in mtDNA damage in lymphocytes from healthy individuals, but no repair activity is observed after 1 h recovery. We further demonstrate that whole blood may serve as a convenient alternative to the isolated lymphocytes in mtDNA analysis."},{"source_id":"source_15","study":"Advanced Age Is Associated with Iron Dyshomeostasis and Mitochondrial DNA Damage in Human Skeletal Muscle","doi":"10.3390/cells8121525","url":"https://doi.org/10.3390/cells8121525","support_kind":"cited_as_match","cited_as":"Picca 2019","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants."}],"candidate_sources":[]},{"claim_id":"claim_27","claim":"Additional corpus sources included animal/preclinical evidence; manifest outcome-class count summary: Contextual Adjacent Evidence: admitted n=6 (mixed=1, negative=2, positive=1, unclear=2); leading sources: Pena 2024, Gureev 2022, Hsiao 2026; Muscle Function: admitted n=3 (negative=1, unclear=2); leading sources: Picca 2019, Picca 2020, Luo 2024; Mechanism: admitted n=2 (null=1, unclear=1); leading sources: Liang 2022, Perez-Perez 2025; Cardiometabolic: admitted n=1 (negative=1); leading sources: Shimizu 2026; Cognitive: admitted n=1 (negative=1); leading sources: Reid 2023.","citation_support":[{"source_id":"source_15","study":"Advanced Age Is Associated with Iron Dyshomeostasis and Mitochondrial DNA Damage in Human Skeletal Muscle","doi":"10.3390/cells8121525","url":"https://doi.org/10.3390/cells8121525","support_kind":"cited_as_match","cited_as":"Picca 2019","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants."}],"candidate_sources":[]},{"claim_id":"claim_28","claim":"Ng 2019: Mitochondrial DNA Damage Does Not Determine C. elegans Lifespan; representative statistic p < 0.0001; source-level statistic reported; outcome=Mechanism/Longevity (C. elegans); direction=null; directness=mechanistic; tier=C1.","citation_support":[{"source_id":"source_13","study":"Mitochondrial DNA Damage Does Not Determine C. elegans Lifespan","doi":"10.3389/fgene.2019.00311","url":"https://doi.org/10.3389/fgene.2019.00311","support_kind":"cited_as_match","cited_as":"Ng 2019","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"mechanistic","excerpt":"The mitochondrial free radical theory of aging (mFRTA) proposes that accumulation of oxidative damage to macromolecules in mitochondria is a causative mechanism for aging. Accumulation of mitochondrial DNA (mtDNA) damage may be of particular interest in this context. While there is evidence for age-dependent accumulation of mtDNA damage, there have been only a limited number of investigations into mtDNA damage as a determinant of longevity. This lack of quantitative data regarding mtDNA damage is predominantly due to a lack of reliable assays to measure mtDNA damage. Here, we report adaptation of a quantitative real-time polymerase chain reaction (qRT-PCR) assay for the detection of sequence-specific mtDNA damage in C. elegans and apply this method to investigate the role of mtDNA damage in the aging of nematodes. We compare damage levels in old and young animals and also between wild-type animals and long-lived mutant strains or strains with modifications in ROS detoxification or production rates. We confirm an age-dependent increase in mtDNA damage levels in C. elegans but found that there is no simple relationship between mtDNA damage and lifespan."}],"candidate_sources":[]},{"claim_id":"claim_29","claim":"Pena 2024: G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage; representative non-significant statistic p = 0.92; not treated as positive or negative directional support unless source direction is coded; outcome=Biomarker/Adjacent Evidence; direction=mixed; directness=indirect; tier=B2.","citation_support":[{"source_id":"source_1","study":"G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage","doi":"10.1038/s41531-024-00660-y","url":"https://doi.org/10.1038/s41531-024-00660-y","support_kind":"cited_as_match","cited_as":"Pena 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"Pathogenic mutations in LRRK2 cause Parkinson's disease (PD). The G2019S variant is the most common, which results in abnormally high kinase activity. Compounds that target LRRK2 kinase activity are currently being developed and tested in clinical trials. We recently found that G2019S LRRK2 causes mitochondrial DNA (mtDNA) damage and treatment with multiple classes of LRRK2 kinase inhibitors at concentrations associated with dephosphorylation of LRRK2 reversed mtDNA damage to healthy control levels. Because maintaining the normal function of LRRK2 in heterozygous G2019S LRRK2 carriers while specifically targeting the G2019S LRRK2 activity could have an advantageous safety profile, we explored the efficacy of a G2019S mutant selective LRRK2 inhibitor to reverse mtDNA damage in G2019S LRRK2 models and patient cells relative to non-selective LRRK2 inhibitors. Potency of LRRK2 kinase inhibition by EB-42168, a G2019S mutant LRRK2 kinase inhibitor, and MLi-2, a non-selective inhibitor, was determined by measuring phosphorylation of LRRK2 at Ser935 and/or Ser1292 using quantitative western immunoblot analysis."}],"candidate_sources":[]},{"claim_id":"claim_30","claim":"Gureev 2022: Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments; representative statistic p < 0.01; source-level statistic reported; outcome=Biomarker/Adjacent Evidence; direction=negative; directness=indirect; tier=B2.","citation_support":[{"source_id":"source_2","study":"Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments","doi":"10.3390/ijms232315197","url":"https://doi.org/10.3390/ijms232315197","support_kind":"cited_as_match","cited_as":"Gureev 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"indirect","excerpt":"In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test."}],"candidate_sources":[]}]}