Yamazaki Mirai

Epigenetic aging biomarkers are promising novel biological age indicators derived from algorithms based on DNA methylation patterns. Since epigenetic age was first described over a decade ago, it has been used as an exposure or an outcome in biomedical research to address the fundamental question of "aging". Yet, a critical question remains unresolved: how epigenetic age mediates the effects of exposures on health outcomes. Mediation analysis provides a rigorous statistical framework for decomposing total effects into direct and indirect pathways, thereby testing the extent to which epigenetic age deviation explains exposure-outcome relationships. Meanwhile, the reporting quality using mediation analysis varied across studies. This scoping review provides a methodological primer on causal mediation analysis and a literature review using epigenetic age as a mediator with quality assessment. We conducted an initial literature search through four online databases (PubMed, Embase, MEDLINE, and CINAHL) at the beginning of September 2025. We identified 22 studies (published since 2022) examining epigenetic aging as a mediator between environmental/lifestyle exposures and health outcomes. Most studies used blood-based DNA methylation and applied causal mediation frameworks. GrimAge, PhenoAge, and DunedinPACE were more frequently used. Outcomes primarily included mortality and cardiovascular disease, while exposures covered smoking, diet, socioeconomic factors, clinical biomarkers, and environmental pollutants. Although causal mediation analysis suggested that epigenetic aging could be a possible mechanistic mediator linking exposures to disease risk, many studies lacked methodological rigor. To enhance epigenetic evaluation in broad settings, further work should apply causal mediation analysis to epigenetic aging markers with a rigorous methodology.

OBJECTIVES: Mitochondrial dysfunction has been implicated in neurodegenerative diseases, but evidence regarding its association with cognitive performance in the general population remains limited. This study aimed to examine the association between peripheral blood mitochondrial DNA copy number (mtDNA-CN) and cognitive function in the general Japanese population. METHODS: We conducted a cross-sectional analysis of 282 participants (134 men and 148 women) from the Yakumo Study, a population-based health examination in Hokkaido, Japan. Peripheral blood mtDNA-CN was measured by quantitative real-time PCR and categorized into tertiles. Cognitive function was assessed using the short version of the Mini-Mental State Examination (SMMSE), the Logical Memory Test (LMT), and the Digit Cancellation Test (D-CAT). Logistic regression analyses were performed to evaluate the association between mtDNA-CN levels and cognitive performance, with adjustments for relevant demographic and clinical factors. RESULTS: Lower mtDNA-CN was significantly associated with poorer SMMSE scores in women and with reduced D-CAT3 performance-reflecting attention and executive function-in men. No significant associations were observed for LMT scores in either sex. These domain- and sex-specific associations remained consistent after adjustment for potential confounders. CONCLUSIONS: Lower mtDNA-CN was associated with poorer cognitive performance in the general Japanese population, in a cognitive domain- and sex-specific manner. mtDNA-CN thus has potential as a non-invasive biomarker for the early identification of individuals at increased risk of cognitive decline. Longitudinal studies are necessary to evaluate its predictive utility and potential application in dementia prevention strategies.

Abstract Epidemiological and experimental studies have shown that low methylmercury (MeHg) exposure causes cytotoxic effects. As to such cytotoxic effects, we have supposed that not only MeHg itself but also MeHg interacting with living environmental factors may cause cytotoxic effects. MeHg exposure is known to induce oxidative stress and cell death via ferroptosis in hepatocytes. In this study, we examined whether MeHg exposure followed by palmitic acid (PA) exposure at low non-toxic concentrations cause oxidative stress and cell death in HepG2 cells. In HepG2 cells combinedly exposed to MeHg and PA at low non-toxic concentrations, cell viability and glutathione peroxidase 4 expression levels were significantly decreased, while reactive oxygen species level was significantly increased. Ferrostatin-1 pretreatment suppressed oxidative stress and cell death found in the HepG2 cells. These results indicate that combined exposure to MeHg and PA at low non-toxic concentrations induces oxidative stress associated cell death in HepG2 cells.

BACKGROUND: Current evidence suggested an increased risk for cancer mortality in those with low AHRR DNAm levels. Therefore, AHRR DNAm could identify a more "fragile" group at risk for cancer mortality than questionnaire-based evaluations. Given this, the aim was to identify "fragile" groups at risk of cancer mortality by integrating questionnaire-based smoking indices and leukocyte AHRR DNAm levels in the Japanese population. METHODS: The target population was 795 participants without a clinical history who underwent a health check-up in 1990. They were followed for up to 30 years for mortality. The AHRR DNAm levels in leukocytes were measured by the pyrosequencing method. Hazard ratios (HRs) for cancer mortality were calculated using a Cox proportional hazards model. RESULTS: Significantly higher HRs for all-cancer mortality were observed in low AHRR DNAm groups regardless of smoking intensity (Pack-years<20: 3.69 [1.46-9.37], Pack-years≥20: 2.13 [1.11-4.09]). Compared to current smokers, significantly lower HRs for all-cancer mortality were observed in the group with high AHRR DNAm regardless of years since quitting (YSQ) (YSQ≤10: 0.13 [0.02-0.96], YSQ>10: 0.28 [0.08-0.98]). Even for YSQ greater than 10, there was no significant mortality risk reduction in the low AHRR DNAm group. CONCLUSIONS: The population with low AHRR DNAm levels had a higher risk of cancer mortality even with low smoking exposure. Furthermore, no significant risk reduction was observed in former smokers with low AHRR DNAm levels. IMPACT: AHRR DNAm levels in leukocytes may help identify groups at risk for cancer mortality overlooked by questionnaire-based smoking indices.