Discovering Biological Mechanisms of Exceptional Human Health Span and Life Span

Abstract

Humans age at different rates and families with exceptional longevity provide an opportunity to understand why some people age slower than others. Unique features exhibited by centenarians include a family history of extended life span, compression of morbidity with resultant extension of health span, and longevity-associated biomarker profiles. These biomarkers, including low-circulating insulin-like growth factor 1 (IGF-1) and elevated highdensity lipoprotein (HDL) cholesterol levels, are associated with functional genotypes that are enriched in centenarians, suggesting that they may be causative for longevity. While not all genetic discoveries from centenarians have been validated, in part due to exceptional life span being a rare phenotype in the general population, the APOE2 and FOXO3a genotypes have been confirmed in a number of populations with exceptional longevity. However, life span is now recognized as a complex trait and genetic research methods to study longevity are rapidly extending beyond classical Mendelian genetics to polygenic inheritance methodologies. Moreover, newer approaches are suggesting that pathways that have been recognized for decades to control life span in animals may also regulate life span in humans. These discoveries led to strategic development of therapeutics that may delay aging and prolong health span.

Suppressing APOE4-induced mortality and cellular damage by targeting VHL

“…APOE4 proteins differ in cholesterol transport capabilities compared to its allelic counterparts and, contrary to its heightened association with AD risk, it is linked to decreased susceptibility to age-related macular degeneration [8][9][10] . Genetic variations including non-APOE4 variant alleles of APOE have also been shown to be associated with reduced mortality in rare long-lived human centenarians 11 . These studies have provided intriguing cases of how genetic variations may link to mortality and age-related diseases in humans.…”