It is well established that females and males in mammalian (and many other) species exhibit meaningfully different trajectories of health and mortality in later life. It is also well established, at least in mice, that many of the interventions demonstrated to modestly slow aging have meaningfully different outcomes in males versus females. The question of why these differences exist has no satisfactory answer at the present time, however. There are a great many theories and potential contributions, but no data that concretely establishes the important mechanisms and relative sizes of these contributions to the overall effect.
The burden of aging is not shared equally between the sexes, as lifespan and healthspan differ between males and females. Lifespan, the length of time in which an organism is alive, is related to but distinct from healthspan, which is the length of time an organism is free of disease and disability. Women live longer than men in most countries, but women also experience more disease and disability than men.
While scientists seek interventions to increase both healthspan and lifespan, considering sex as a biological variable is imperative to ensure treatments will work optimally in both men and women, or to develop sex-specific interventions. Here, we review dietary, genetic, environmental, behavioral, and pharmacological interventions that increase lifespan in a sexually dimorphic manner in laboratory rodents, including the mouse which is the is most widely used mammalian model system in the aging field.
While sex differences in life history traits have long been of interest to evolutionary biologists, a cellular and molecular understanding of how these traits influence lifespan remains understudied. Starting from fertilization, differences in chromosome complement and hormone levels drive further morphological and behavioral differences. Crucial aspects of female biology, including the role of X chromosome regulation, the role of gonadal hormones, and the role of ovarian health, remain understudied in the context of aging interventions. Whether differences in response to interventions is due sex-specific differences in baseline lifespan, or differences in sexually dimorphic characteristics such as body size, adiposity, metabolism, or even gonadal hormone or chromosome status remains unknown.
Link: https://doi.org/10.1016/j.arr.2026.103123
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