The Grandmother Hypothesis: A Perspective from Cardiovascular Aging.

Human menopause and the prolonged post-reproductive lifespan (PRLS) are distinctive features of female aging with profound implications for long-term health. Evolutionary theories, such as the Grandmother Hypothesis and other models (e.g., intergenerational reproductive conflict), suggest menopause evolved under ancestral conditions of high extrinsic mortality in early life, short lifespans, and inclusive-fitness benefits derived from kin investment. In such environments, postmenopausal survival was brief, minimizing selective pressure from estrogen deficiency. However, modern advancements in medicine, nutrition, and public health have fundamentally altered this paradigm: women now commonly live three decades or more past reproduction, often within social structures characterized by reduced kin reliance and lower risks associated with late-life childbearing. This extended PRLS exacerbates the effects of estrogen deficiency on cardiovascular, metabolic, skeletal, autonomic, and neurocognitive vulnerabilities that were likely of limited consequence ancestrally. The result is an evolutionary mismatch between historically selected life-history traits and contemporary longevity. The present review synthesizes evolutionary theory with comparative biology, aging research, epidemiology, and clinical evidence related to hormone replacement therapy (HRT) to interrogate how the timing and consequences of ovarian aging shape cardiovascular health and pathogenesis in women. Reframing menopause beyond the end of fertility to include its endocrine and physiological consequences helps explain the rise of postmenopausal cardiovascular risk in modern societies and highlights opportunities to target ovarian-cardiovascular aging, or related pathways, in order to reduce postmenopausal cardiovascular disease risk and better align healthspan with lifespan.