The APOE gene has a number of common variants that are known to correlate with differences in human life expectancy, as well as with Alzheimer's disease risk. Researchers here show that there are life expectancy effects distinct from any impact of Alzheimer's disease on life span. If including the whole population, those with and without dementia, there is about a five year difference in the time taken to reach 50% mortality in a cohort between the best (APOE2) and worst (APOE4) variants.
The non-dementia-impacting mechanisms by which this difference in life expectancy manifests are presently unknown. While aging has root causes that are fairly well catalogued at this point, the way in which aging unfolds from those root causes is very complex, and still poorly mapped. This is exactly why more effort should go towards repairing the root causes rather than tinkering with the operation of metabolism later stages of aging. That some gene variants affect the progression of aging is interesting, but largely irrelevant to any meaningful effort to produce rejuvenation, as that effort should focus on first causes rather than downstream processes.
Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models.
Notably, APOE2 was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of APOE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.