An evolutionary medicine and life history perspective on aging and disease: Trade-offs, hyperfunction, and mismatch.

The rise in chronic diseases over the last century presents a significant health and economic burden globally. Here, we apply evolutionary medicine and life history theory to better understand their development. We highlight an imbalanced metabolic axis of growth and proliferation (anabolic) versus maintenance and dormancy (catabolic), focusing on major mechanisms including IGF-1, mTOR(definition), AMPK, and Klotho. We also relate this axis to the hyperfunction theory of aging, which similarly implicates anabolic mechanisms such as mTOR in aging and disease. Next, we highlight the Brain-Body Energy Conservation model, which connects the hyperfunction theory with energetic trade-offs that induce hypofunction and catabolic health risks such as impaired immunity. Finally, we discuss how modern environmental mismatches exacerbate this process. Following our review, we discuss future research directions to better understand health risk. This includes studying IGF-1, mTOR, AMPK, and Klotho and how they relate to health and aging in human subsistence populations, including with lifestyle shifts. It also includes understanding their role in the developmental origins of health and disease as well as the social determinants of health disparities. Furthermore, we discuss the need for future studies on exceptionally long-lived species to understand potentially underappreciated trade-offs and costs that come with their longevity. We close with considering possible implications for therapeutics, including (i) compensatory pathways counteracting treatments, (ii) a "Goldilocks zone," in which suppressing anabolic metabolism too far introduces catabolic health risks, and (iii) species constraints, in which therapeutics tested in shorter lived species with greater anabolic imbalance will be less effective in humans.