山田 宏哉

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.

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.

Regulatory T (Treg) cells, which play an important role in maintaining self-tolerance, are present in the thyroid-infiltrating lymphocytes of patients with autoimmune thyroid disease (AITD). We examined the expression of membrane-bound transforming growth factor-β1 (mTGF-β1), which mediates regulatory function and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). The protein in turn may inhibit regulatory function on Treg cells and TGF-β1 receptor II (TGF-βRII) and GITR expression. We also evaluated GITR ligand (GITRL) localization in thyroid tissues. mTGF-β1+ cells proportion in Treg cells was higher in the thyroid of patients with AITD than in their peripheral blood. GITR+ cells proportion among Tregs and Teff cells was also higher in the thyroid than in peripheral blood. GITRL expression in thyrocytes was higher in AITD patients than in healthy subjects. The interaction and balance of mTGF-β1, GITR, TGF-βRII, and GITRL especially thyrocyte GITRL expression, could be critical in AITD pathogenesis.

BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of death in Japan. Although several CVD risk scores tailored for Japanese individuals have been developed, no tools are available to estimate these scores at the population level. We developed the "Jcvrisk" R package, which integrates four major Japanese CVD risk models recommended by the clinical guideline. As a showcase, we applied the Jcvrisk package to longitudinal population-based study to evaluate trends in estimated different risk scores. METHODS: We used longitudinal data from the Yakumo Study, an annual health checkup for residents in Yakumo, Hokkaido. This package includes four risk models with 14 risk scores from representative cardiovascular cohort studies, including three EPOCH scores, one Hisayama score, two Suita scores, and eight JALS scores. For temporal comparisons of CVD risk scores, we summarized scores from 2000 to 2020 every five years. RESULTS: The mean age of participants throughout all study years was around 60 years old. Most risk factors did not change remarkably over the 20 years, with only a decrease in smoking prevalence and an increase in high density lipoprotein cholesterol (HDL-C). However, all CVD risk scores consistently indicated an upward trend in 10-year CVD risk. CONCLUSIONS: Jcvrisk package includes functions to calculate CVD risk scores for Japanese adults. The package serves as a valuable tool for researchers and policymakers aiming to assess and monitor cardiovascular risk at both individual and population levels in Japan.