David A. Raichlen and Gene E. Alexander

Trends in Neurosciences. 2014, May; 37(5): 247–255. Article Access - doi:10.1016/j.tins.2014.03.001Journal Impact Factor: 13.555

Akansha GangulyMBT 0415

Department of BiotechnologyGoa University

25th January 2016

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

Contents The human lifespan: an evolutionary

perspective APOE functions and risks APOE evolution Interaction between physical activity and

APOE genotype The evolutionary history of human exercise

and longevity Implications for research on cognitive

ageing, longevity and health Conclusion References

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The human lifespan: an evolutionary perspective

Average adult life span: ~72 years (range 68-78); longer than any other primate.

Unique post-reproductive life span.

‘Grandmother hypothesis’APOE gene: lipid transport.

ε4 carriers afflicted with higher levels of total cholesterol and accumulation of atherosclerotic plaques in arteries; increased risks of cardiovascular disease (CVD) and stroke, as well as dementia and Alzheimer’s disease (AD).

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ε2, ε3 alleles: reduced risks relative to ε4 allele, evolved

around 200,000 years ago.

Frequency of alleles globally: ε3 (78.3%), ε4 (14.5%) and

ε2 (6.4%).

Exceptionally long life span partly due to evolution of ε3

allele because diet modified to include meat, dietary fats

and cholesterol.

Variation in human aging: ranges from successful aging

and a long lifespan (high levels of cognitive and physical

function) to pathological aging (impaired cognition and

diminished physical capacities ,lead to dementia and

relatively increased mortality).4

APOE functions and risks

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APOE protein: circulates in plasma, present in CNS; helps regulate

cholesterol and lipid metabolism, aids cell repair.

APOE gene: on chromosome 19, polymorphic, differential binding of

isoforms to lipoproteins and to LDL receptors.

Nearby SNPs contribute to disease states.

ε4 allele tends to increase total cholesterol compared to homozygous

ε3, ε2 carriers have reduced cholesterol levels due to low affinity

binding to LDL.

ε4- established susceptibility gene to late-onset AD, carriers have

known risk of developing AD, dementia with cognitive decline.

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Exceptions in Nigerian and Kenyan populations, high ε4

frequencies have no strong relation with AD or CAD -

environment/behaviour/diet?

Suggested ε4 impacts on amyloid deposition, mitochondrial

function, synaptogenesis, τ phosphorylation, increased

accumulation and reduced clearance of amyloid β-peptide

(extracellular neuritic plaques, key marker of AD).

PET, MRI imaging show reduced cerebral glucose metabolism,

decline in gray matter volume and thickness in asymptomatic ε4

carriers as compared to noncarriers.

Presence of the ε4 allele should affect the ability of individuals late

in life to contribute to the health and well being of their offspring

and grandchildren.

APOE evolutionε4: ancestral APOE allele in humans; ε2, ε3 alleles evolved

200,000-300,000 years ago.

Chimpanzee monomorphic APOE gene: similar to human ε3 allele.

ε4 allele was evolutionarily novel in human evolution. Possible evolution to protect against Vit. D deficiency.

Lifespan evolved BEFORE ε2/ε3 came into existence.

How did selection generate longer human lifespans when all individuals had two copies of the deleterious ε4 allele?

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Interaction between physical activity and APOE genotype

Exercise and physical activity interact with the APOE genotype to mediate

the effects of the ε4 allele on CAD.

Cross-sectional studies show protective effect of high-intensity activity on

lipid profiles of ε4 carriers, similar to ε2 and ε3 profiles.

Sedentary/inactive ε4 carriers had elevated CAD risk factors compared to

physically active carriers and to ε3 carriers (regardless of aerobic

activity).

Longitudinal studies suggest physical inactivity leads to increased risk of

developing dementia or AD in APOE ε4 carriers; mid-life exercise reduced

dementia risk in all genotypes, reduced risks of cognitive decline and AD

in ε4 carriers.

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APOE ε4 carriers showed greater glucose uptake in temporal lobe

(PET imaging) when engaged in high aerobic activity.

Aerobic exercise and physical activity associated with reduced

amyloid deposition in brain, high structural white matter integrity,

larger gray matter and whole-brain volume.

Physical activity, exercise, and aerobic fitness significantly reduce

CAD risk and improve cognitive aging and biomarkers of AD

pathology in APOE ε4 carriers.

Early or lifelong physical activity increases clearance of Aβ

potentially through improved sleep or other mechanisms, and

enhances brain resilience through neuroprotective processes, such

as increased perfusion and neurogenesis.

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The evolutionary history of human exercise and longevity

Aerobic exercise became part of human lifespan nearly 1.8 mya.

Australopithecus hominids had sedentary ape-like lifestyles

compared to foraging Homo erectus ancestors.

High levels of cardiovascular endurance required for long-distance

hunting, gathering as compared to other primates.

Change in skeleton shape, joint surface area, neurobiological traits

consistent with improvement in endurance running in H. erectus.

Higher levels of physical activity during human evolutionary history

relaxed APOE-related constraints on lifespan as far back as 1.8

million years ago.10

Paleodemographic studies of life-history of fossil taxa show shift to presence of large numbers of older individuals in H.erectus and even more in H.sapiens.

Early evolution of longevity (approximately 1.8 million years ago) with H. erectus most consistent with hypotheses for the evolution of the post-reproductive lifespan that link successful aging to the origins of hunting and gathering.

Long post-reproductive lifespan of humans evolved in concert with the shift towards higher aerobic activity in H. erectus, when the only available APOE allele was ε4.

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Implications for research on cognitive ageing, longevity and health

Understanding lifespan evolution within the constraints of

the deleterious ε4 allele gives impetus for research focused

on enhancing cognitive aging, longevity, and the prevention

of neurodegenerative disease in older populations.

Changes due to modern-day environmental constraints and

human behaviour may have led to greater vulnerability to

the effects of APOE ε4 in subgroups of elderly in which high

levels of physical activity throughout life are no longer

required.

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Conclusion Hypothesis: increase in aerobic activity during transition from

a sedentary, apelike lifestyle, to a hunter-gather lifestyle

relaxed constraints on aging imposed by the homozygous

APOE ε4 genotype.

Increased lifespan, high levels of function in the elderly,

enabled older adults to assist younger kin, reinforcing the

selective benefits of old age.

Diseases such as CAD, AD and other age-related dementias,

may be due, in part, to the mismatch between our genetic

heritage and our modern environment.

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