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

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Highlights

  • 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.

Section snippets

The human lifespan from an evolutionary perspective

Humans live longer than any other primate, and are unique in having a prolonged postreproductive lifespan 1, 2, 3, 4. In humans living more traditional lifestyles (e.g., hunter-gatherers), despite having a life expectancy of under 40 (driven mainly by high infant and juvenile mortality), the average modal adult life span is approximately 72 years of age (with a range of 68–78; [5]). By comparison, our closest living relatives, chimpanzees, have a modal lifespan of 15 years and a life expectancy

APOE functions and risks

APOE is a protein that circulates in the plasma and is present in the central nervous system, helping to regulate cholesterol and lipid metabolism, as well as aid cellular reparative processes 19, 20. The APOE gene, located on chromosome 19, is polymorphic, with three isoforms that differentially affect the affinity of the APOE protein for lipoprotein particles and the binding of the protein to low-density lipoprotein (LDL) receptors 11, 21. In addition, nearby single nucleotide polymorphisms

APOE evolution

Based on a comprehensive analysis of haplotype diversity, Fullerton et al. [11] showed that ɛ4 is the ancestral APOE allele in humans, and the divergence of the ɛ4 and the ɛ2 and ɛ3 clades occurred between 200 000 and 300 000 years ago. Even after the evolution of other alleles, ɛ4 remained present in our ancestors, given that McIntosh et al. [67] showed that the Denisovan hominin (30 000–80 000-years old) appears to have had the ɛ4 allele. Although direct measures of lipid binding have not been

Interaction between physical activity and APOE genotype

Recent work suggests that exercise and physical activity interact with the APOE genotype to mediate the effects of the ɛ4 allele on CAD. In a cross-sectional study, ɛ4 carriers showed a significant protective effect of high-intensity activity, with athletic ɛ2, ɛ3, and ɛ4 carriers having similar blood lipid profiles and sedentary ɛ4 carriers showing significantly high levels of lipid risk factors for CAD [69]. A similar result was found in a cross-sectional study of middle-aged highly fit and

The evolutionary history of human exercise and longevity

There is a great deal of evidence suggesting that aerobic exercise became an increasingly important element of the human lifestyle beginning approximately 1.8 million years ago. With the evolution of Homo erectus, our ancestors began a new lifestyle oriented around a combination of meat eating and gathering 95, 96. This lifestyle contrasts with the more sedentary ape-like lifestyles of the earlier hominin genus, Australopithecus, who are reconstructed to have ranged much shorter distances than

Implications for research on cognitive aging, longevity, and health

Understanding how the long human lifespan evolved in the context of the deleterious effects of the APOE homozygous ɛ4 genotype may have important implications for current research efforts focused on enhancing cognitive aging, longevity, and the prevention of neurodegenerative disease in older populations. It is well established that human aging today is characterized by substantial heterogeneity, often expressed as a continuum that can extend from successful to pathological aging 14, 15. Such

Concluding remarks

Here, we have developed a hypothesis for the evolution of the human lifespan that shows how increases in aerobic activity during our transition from a low-activity, sedentary, ape-like lifestyle, to a high-activity hunter- gather lifestyle served to relax constraints on aging imposed by the deleterious homozygous APOE ɛ4 genotype. This increased lifespan, and high levels of function in the elderly, would have enabled older adults to assist younger kin, reinforcing the selective benefits of old

Acknowledgments

The authors would like to acknowledge support from the National Institute on Aging (AG025526 and AG19610), the National Science Foundation (NSF BCS 0820270), the Wenner Gren Foundation, the state of Arizona and Arizona Department of Health Services, Arizona Advanced Research Institute for Biomedical Imaging, and the Evelyn F. McKnight Brain Institute.

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