Genetics of Human Aging

Human genetics has provided a framework for understanding the biology of the human species and is a rapidly growing field of aging research. The genetic analysis of human aging is aimed at identifying genetic variants that reflect the biological age of individuals and predict long-term morbidity and/or mortality, and ultimately revealing the genetic determinants of aging in humans. By associating genetic variants with human age-related phenotypes, including exceptional longevity, vast numbers of candidate genetic variants can be obtained and tested in cell culture or animal models for their functional impact on aging-related molecular, cellular, and organismal phenotypic endpoints. While there have been numerous genetic variants found to be associated with a range of age-related traits and diseases, a substantial proportion of the causality remains unexplained, and fundamental questions remain regarding genes and their variants influencing aging and longevity in humans. Further studies need to be performed in order to understand the genetic determinants of healthspan and lifespan. Hopefully, human genetics-based elucidation of molecular pathways will provide a rational basis for targeted intervention strategies to slow aging and delay the onset and progression of age-related diseases. In this chapter, we will review what is known about the bewildering genetic variation in human populations and how this variation has been used as the workhorse of human genetics as markers in linkage and association studies of the biology and pathophysiology of aging. We will then review study designs and methods for discovery and validation of genetic variants for age-related phenotypes, and discuss what ultimately needs to be done to develop genetics-based intervention and therapeutic strategies against aging in humans.