Non-human model organisms have provided evidence to suggest that rare protein-coding variants in pathways linked to longevity can guard against common, age-related conditions in long-lived individuals. Now, in a recent study, published in Nature Aging, researchers have analysed the whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine the enrichment of rare coding variants associated with conserved longevity pathways.
The genetics of ageing
Ageing is a multifactorial process accompanied by a decline in tissue function and an increased risk of disease. Ageing is not a passive, entropic process. In fact, it is subject to active modulation by signalling pathways and transcription factors that are conserved across species.
In humans, lifespan is a complex trait affected by a number of factors that vary within human populations. While nongenetic factors, such as diet, are important, human population studies have shown that lifespan also has a genetic component. This genetic component particularly becomes important at ages beyond 100 years (centenarians).
Common variants associated with human survival have been searched for in many recent genome-wide association studies (GWAS). These studies have identified more than 50 longevity-associated genetic loci of genome-wide significance. Several studies have also detected an association of human longevity with variants in several ageing genes, including insulin signalling genes, using candidate gene approaches. Most of these longevity-associated SNPs have small effect sizes, and collectively, only explain a very small proportion of heritability for human longevity. Therefore, recent studies have suggested that rare variants may account for some of this ‘missing’ heritability.
Whole-genome sequence analysis to identify rare variants
The researchers behind this study sequenced the exomes of 515 centenarians of Ashkenazi Jewish ancestry. The team also sequenced the exomes of 496 non-centenarian controls, aged between 70 and 95 years of age. Their analysis uncovered nearly 130,300 rare SNPs or small insertions or deletions that were considered for association studies.
The proportion of rare, pathogenic variants was comparable in the centenarian and non-centenarian participants. However, the researchers noted that the rare variants identified in the centenarian group were overrepresented in specific pathways that have been previously linked to longevity in studies of model organisms. This suggests that these particular variants may contribute to longer lifespan across species.
The researchers also found a higher frequency of rare variants centred on insulin and insulin-like growth factor 1 signalling in the centenarians. The team validated these results using data from thousands of more centenarians and non-centenarians from three more population cohorts.
Interactions of rare variants with pathogenic or common variants
To further delve into their findings, the researchers considered rare variant interactions with potentially pathogenic or common variants. The team then assessed how these interactions contribute to polygenic risk scores for several age-related diseases, such as coronary artery disease.
When the team searched for rare variants that appeared to protect against common age-related diseases, they identified rare Wnt signalling pathway variants in centenarians. These Wnt signalling variants appeared to protect against the negative effects of APOE4 gene alleles. These variants have previously been linked to Alzheimer’s disease, hyperlipidemia and atherosclerosis as well as a shorter life expectancy.
The researchers behind this study suggested that their results may eventually lead to promising drug targets for extending lifespan and tackling some age-related conditions. However, before their results can be used to identify drug target, the team stressed that additional studies, including long-read genome sequencing analyses, are needed to search for potential longevity contributors in the non-coding regions of the genome. Nonetheless, this research opens the door to the development of drugs that can help extend lifespan by treating age-related conditions.
Image credit: kjpargeter – FreePik