Genetic Determinants of Human Health Span and Life Span: Progress and New Opportunities

Abstract

We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome.

Association of the K153R polymorphism in the myostatin gene and extreme longevity

“…Human lifespan is a partly heritable phenotype, with some alleles contributing to 'longevity assurance', because they enhance the structure and function of the organism (Martin et al 2007). As we age, we inevitably experience age-associated declines in the systems and organs that determine physical fitness, notably in the skeletal muscle tissue, i.e.…”

“…Identifying candidate gene variants associated with longevity is possible by studying the genotype of centenarians (Martin et al 2007). This group of people are the survival tail of population, with a lifespan of at least 15-20 years higher than the average westerner.…”

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

“…Both protective alleles and a benevolent environment contribute to excess physiological capacity, which in turn indirectly determines an individual's healthy life span and longevity (Martin et al 2007). The wellrecognized increase in variability with aging reflects the precarious balance between the stochastic destruction, environmental influences, and correcting effect of genes responsible for repair.…”

Geriatrics: Gateway to Next Medicine§

“…Notably, identification of "the aging" gene has proven to be futile. Martin estimates that 6000 genes are involved in human aging [3]. It, like virtually all human ailments, is polygenic.…”