Exercise, APOE genotype, and the evolution of the human lifespan

•The long human lifespan evolved when our ancestors were homozygous for APOE ɛ4.•The ɛ4 allele is associated with heart disease, Alzheimer's disease, and reduced lifespan.•High levels of physical activity reduce disease risks in ɛ4 carriers.•We propose that human longevity evolved due to a shift toward high activity levels.•Current lifespan constraints may reflect a mismatch between lifestyle and evolutionary history.

Humans have exceptionally long lifespans compared with other mammals. However, our longevity evolved when our ancestors had two copies of the apolipoprotein E (APOE) ɛ4 allele, a genotype that leads to a high risk of Alzheimer's disease (AD), cardiovascular disease, and increased mortality. How did human aging evolve within this genetic constraint? Drawing from neuroscience, anthropology, and brain-imaging research, we propose the hypothesis that the evolution of increased physical activity approximately 2 million years ago served to reduce the amyloid plaque and vascular burden of APOE ɛ4, relaxing genetic constraints on aging. This multidisciplinary approach links human evolution with health and provides a complementary perspective on aging and neurodegenerative disease that may help identify key mechanisms and targets for intervention.