Abstract
Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.
Highlights
The basis of human longevity and healthy aging, and how to achieve these desirable phenotypes, remain among the principal challenges of biology and medicine
Epigenetics is quickly emerging as a critical aspect of aging and longevity
The chromosome 14 linkage is at a different site from that observed in the Amish study; the large chromosome 17 region overlaps the 17q21 locus observed by Kerber et al Fine mapping of these linkage regions using genome-wide association scans (GWAS) data in a subset of 1228 unrelated nonagenarians and 1907 controls identified a SNP near APOE at the 19q locus as significantly associated with longevity
Summary
The basis of human longevity and healthy aging, and how to achieve these desirable phenotypes, remain among the principal challenges of biology and medicine. This review was intended to summarize our current understanding of genetic factors affecting the phenotypes of longevity and healthy aging in humans, including the definition and heritability of these traits, and linkage, association, and sequencing studies. This delay in disease development and postponement of cognitive and physical decline in the oldest group amounted to a compression of morbidity (Fries 1980) Based on these findings, Andersen et al (2012) suggest that a realistic and practical limit of human lifespan is 110–115 years, close to that of the oldest documented person in the world to date, who lived to 122 (Robine and Allard 1998). Potential explanations for this difference include hormonal and immune differences, hemizygosity of the X-chromosome in men (which may allow manifestation of unfavorable sex-linked variants), and unrecognized confounders [reviewed in Newman and Murabito (2013)]
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