The process of biological aging or senescence refers to the gradual loss of homeostasis and subsequent loss of function - leading to higher chances of mortality. Many mechanisms and driving forces have been suggested to facilitate the evolution of a molecular circuit acting as a trade-off between survival and proliferation, resulting in senescence. A major observation on biological aging and longevity in humans and model organisms is the prevalence of significant sexual divergence in the onset, mechanisms and effects of aging associated processes. In the current account, we describe possible mechanisms by which aging, sex and reproduction are evolutionarily intertwined in order to maintain systemic energy homeostasis. We also interrogate existing literature on the sexual dimorphism of genetic, cellular, metabolic, endocrine and epigenetic processes driving cellular and systemic aging. Subsequently, based on available evidence, we propose a hypothetic model of sex-limited decoupling of female longevity from sirtuins, a major family of regulator proteins of the survival-proliferation trade-off. We also provide necessary considerations to be made in order to test the hypothesis and explore the physiological and therapeutic implications of this decoupling event in male and female longevity after reaching reproductive maturity. HYPOTHESIS STATEMENT: Sirtuins provide survival benefits in a sex-nonspecific manner but the dependency on sirtuins in driving metabolic networks after reaching reproductive maturity is evolutionarily decoupled from female longevity.
Keywords: Energy Homeostasis; Epigenetic regulation; Senescence; Sexual dimorphism; Sirtuins; Systemic aging.
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