The difference between the sexes in the matter of aging can be summarized crudely as being that women live longer but in worse physical condition than male survivors of an equivalent age. How and why this is the case is the subject of a great deal of research, but the research community has yet to reach a good conclusion on the biochemistry involved. Yet this may well be irrelevant to the future of therapies aimed at repairing the cell and tissue damage that causes aging, as that underlying damage is the same for both sexes. To the degree that medical science can produce rejuvenation, the details of how uncontrolled aging progresses differently in different people becomes a matter of curiosity only, not a priority.
Men typically have shorter lifespans than women in most modern societies and face a higher risk of lethal age-related diseases, such as cardiovascular disease. Despite numerous intrinsic and extrinsic factors (e.g., sex chromosome, sex hormone, gene expression, lifestyle, etc.) being linked to sex-biased lifespan and morbidity, the biological foundation for men achieving longevity has yet to be investigated thoroughly. Notably, epidemiological data disclose a paradoxical phenomenon: the number of long-lived men (LLMs) is significantly lower than that of long-lived women (LLWs), yet LLMs generally exhibit better health status, including good physical performance and decreased cancer risk, suggesting a potential male-specific longevity strategy in humans. These findings emphasize the importance of studying LLMs to uncover the biological basis enabling men to achieve healthy aging and longevity.
In this study, we conducted whole-genome bisulfite sequencing (WGBS) to analyze the methylomes of LLMs and LLWs as well as younger men (YMs) and younger women (YWs). Despite the observed accelerated epigenetic aging in LLMs compared to LLWs, through thorough comparisons with LLWs, YMs, and YWs, we identified thousands of differentially methylated genomic units (DMUs) in LLMs, some of which exhibit potential as methylation markers for LLM discrimination. Contrary to the notion of accelerated epigenetic aging, we suggest that these identified DMUs may play roles in promoting longevity or suppressing age-related diseases, including cancer, through the regulation of target gene transcription. Taken together, our study provides evidence suggesting that LLMs possess distinctive methylation characteristics, underscoring their potential relevance to healthy aging and longevity in men.
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