Discovering Biological Mechanisms of Exceptional Human Health Span and Life Span

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 bio-markers, including low-circulating insulin-like growth factor 1 (IGF-1) and elevated high-density 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 methodol-ogies. 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.