The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified many loci that influence key human ageing traits, including lifespan. Multi-trait loci have been linked with several age-related diseases, suggesting shared ageing influences. Mutations that drive accelerated ageing in prototypical progeria syndromes in humans point to an important role for genome maintenance and stability. Together, these different strands of genetic research are highlighting pathways for the discovery of anti-ageing interventions that may be applicable in humans.
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D.M. and L.C.P. are supported by the University of Exeter Medical School and additionally by the University of Connecticut School of Medicine. This work is supported in part by the UK Medical Research Council (grants MR/M023095/1 and MRS009892/1). This work was supported in part by the Intramural Research Program at the National Institute on Aging.
The authors declare no competing interests.
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Circos Table Viewer: http://mkweb.bcgsc.ca/tableviewer/visualize/
GWAS Catalog: https://www.ebi.ac.uk/gwas/
Online Mendelian Inheritance of Man (OMIM): https://www.omim.org
- Genome-wide association studies
(GWAS). A study that involves genotyping large numbers of participants to identify statistical associations between genetic variants and traits of interest.
- Somatic mutations
Changes to the genetic code arising from errors during DNA damage repair, DNA replication or mitosis, occurring in somatic (non-germline) tissues.
The proportion of variance in a phenotype that can be attributed to genetic differences among individuals in a given population. Narrow-sense heritability estimates additive genetic effects. Broad-sense heritability includes both additive and dominance effects.
- Polygenic risk score
Individual-level scores that summarize genetic risk (or protection) for a given phenotype. For each person, a score is computed by counting the number of effect alleles (genetic variants, weighted by their effect) that the person carries. A polygenic score is computed by summing scores from a large number, potentially all, of the variants in the genome.
- Linkage disequilibrium
(LD). Non-random associations between alleles at different loci.
- Mendelian randomization
A method that uses single-nucleotide polymorphisms associated with an exposure as instruments to probe the causal nature of the relationship between this exposure and an outcome of interest.
- Antagonistic pleiotropy
Theory arguing that some mutations are selected because they are beneficial to early-life fitness but become harmful later in life, thus causing ageing.
- Clonal expansion
The production of daughter cells from a single parent cell, all sharing a particular characteristic or trait.
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Melzer, D., Pilling, L.C. & Ferrucci, L. The genetics of human ageing. Nat Rev Genet 21, 88–101 (2020). https://doi.org/10.1038/s41576-019-0183-6
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