Genetics of healthy aging and longevity
Open accessAbstract
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.
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The APOE ε4 allele is a strong genetic risk factor for Alzheimer disease and is the strongest hit in genome-wide association studies of longevity.
“the ɛ4 allele is a strong genetic risk factor for Alzheimer disease,20 and by far the strongest hit in genome-wide association studies of longevity.21,22”
From Plasma levels of apolipoprotein E, <i>APOE</i> genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort (2019) · cites this paper as [22]
The Genome-wide association studies section says that SNPs in or near APOE were the only genome-wide-significant longevity findings and reports a strong inverse association between APOE4 and longevity. It identifies the genome-wide-significant hits as nearby SNPs, however, rather than establishing that the ε4 allele itself was the strongest GWAS hit. The Linkage studies section describes apoE isoforms as Alzheimer disease risk factors, but does not specifically establish the strength of ε4’s risk. (LLM, conf=0.85)
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- Authors
- Brooks-Wilson, A. R.
- Affiliations
- BC Cancer Agency (CA)
- Corresponding author
- Brooks-Wilson, Angela R.
- Venue
- Human Genetics
- Published
- 2013-08-08
- Volume
- 132
- Issue
- 12
- Pages
- 1323-1338
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- PMC
- PMC3898394
- OpenAlex
- W2072130124
- Cited by
- 380
- References
- 123
- Citations by year
- 2026: 17 · 2025: 31 · 2024: 40 · 2023: 33 · 2022: 34 · 2021: 43 · 2020: 25 · 2019: 26 · 2018: 30 · 2017: 24 · 2016: 23 · 2015: 35 · 2014: 19
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Human Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- healthy aging, longevity, centenarians, apolipoprotein E, FOXO3, chromosome 3, genome-wide association study, candidate genes, gene-environment interaction, rare alleles, epigenetics, DNA methylation, lifestyle factors, age-related diseases, population stratification
- MeSH terms
- Aging, Health, Humans, Life Expectancy, Genetic Linkage, Longevity, Genetic Variation, Epigenesis, Genetic, Genome-Wide Association Study, Gene-Environment Interaction
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