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.