Yamazaki Mirai

Chronic metabolic stress is increasingly recognized as a driver of aging-like tissue dysfunction, but whether it durably reprograms liver regenerative cells, potentially compromising tissue maintenance and repair, remains unknown. Here, we show that high-fat diet (HFD)-induced metabolic stress promotes a persistent senescence-like state in the liver regenerative compartment. In male rats, chronic HFD feeding induced hepatic steatosis together with oxidative stress, inflammatory responses, and senescence-associated changes. Following carbon tetrachloride-induced liver injury, HFD-fed animals exhibited reduced proliferative responses. To determine whether these abnormalities were durably retained within regenerative cell populations, we established liver organoids from control and HFD-fed rats. HF-derived organoids showed reduced formation efficiency and impaired serial propagation capacity outside the original metabolic environment. Senescence-associated abnormalities, including increased senescence-associated β-galactosidase staining, reduced Lamin B1 staining, and decreased Ki67 positivity, remained detectable through Passage 3. Transcriptomic and functional analyses revealed mitochondrial dysfunction and enhanced oxidative and inflammatory responses. These organoids also exhibited enhanced lipid accumulation and inflammatory secretion following fatty acid challenge. Treatment with the mitochondria-targeted antioxidant MitoQ reduced oxidative stress and inflammatory secretion, improved oxygen consumption, and partially restored organoid formation efficiency, supporting a functional contribution of mitochondrial dysfunction to regenerative impairment. Together, these findings support a model in which chronic metabolic stress leaves persistent senescence-like dysfunction within the liver regenerative compartment, extending its consequences beyond abnormalities in mature liver tissue.

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.

The developmental origins of health and disease (DOHaD) hypothesis suggests that environmental exposures during development can induce long-term health effects, yet the cellular origin of such persistence remains unclear. Here, we suggest that neural stem cells (NSCs) may develop aberrant properties that persist with possible involvement of epigenetic mechanisms linking maternal dietary stress to neurocognitive impairments. In a rat model of maternal high-fructose corn syrup intake, offspring showed hippocampus-dependent memory deficits and reduced neurogenesis. NSCs from fetal and adolescent hippocampi exhibited persistent dysfunction with transcriptomic dysregulation. Mechanistically, transient downregulation of DNA methyltransferase 3A in fetal NSCs was associated with sustained repression of secreted phosphoprotein 1, encoding intracellular osteopontin (iOPN). iOPN overexpression partially restored NSC function, supporting a potential causal link. Our study proposes a DOHaD framework in which stem cells with lasting alterations may retain epigenetic traces of early life stress, with implications for organ systems and disease risk.

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.