Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada,
Hum Genet. 2013 Dec;132(12):1323-38. doi: 10.1007/s00439-013-1342-z. Epub 2013 Aug 8.
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.
长寿和健康衰老都是迄今为止研究最为复杂的表型之一。成年人死亡年龄的遗传性约为 25%。对异常长寿个体的研究表明，遗传性在最老的年龄最大。对异常长寿家族的连锁研究现在支持 3 号染色体上的长寿基因座；其他假定的长寿基因座在不同的研究中存在差异。候选基因研究已经确定了与长寿相关的 APOE 和 FOXO3A 变体；其他基因的结果不一致。对百岁老人与年轻对照的全基因组关联扫描（GWAS）仅发现 APOE 达到全基因组显著水平（GWS）；然而，对未达到 GWS 的关联中代表的 SNPs 或基因组合的分析，已经确定了与衰老相关的基因和生物学过程的途径和特征。这些 SNP 的影响，可能会产生共同的影响，可能会被基因-环境相互作用或种族间差异所掩盖。GWAS 和全基因组测序数据都表明，通过 GWAS 定义的常见复杂疾病的风险等位基因，也许令人惊讶的是，在长寿个体中也存在，他们可能通过保护性遗传因素来耐受它们。这种保护性因素可能“缓冲”特定风险等位基因的作用。罕见等位基因也可能有助于健康衰老和长寿。表观遗传学正在迅速成为衰老和长寿的一个关键方面。百岁老人延迟与年龄相关的甲基化变化，并且他们可以将这种甲基化保存能力传递给他们的后代。非遗传因素，特别是生活方式，显然会影响与年龄相关的疾病的发展，并影响普通人群的健康和寿命。为了充分了解健康衰老和长寿的理想表型，有必要从大量健康长寿个体中检查全基因组数据，同时研究常见和罕见等位基因，对人群分层进行无可挑剔的控制，并考虑环境等非遗传因素。
