Approved Research

Mutation load and evolution of ageing in humans

Lay summary

Background & Scientific Rationale:

Ageing is a time-dependent process that causes a decline in biological functions and an increased risk of death in individuals of advanced age. Since virtually all organisms undergo ageing, it is important to ask why species failed to get rid of this process.

There are hundreds of theories postulated to the date to explain why and how ageing occurs and why it is complicated to avoid it. The "non-programmed" evolutionary genetic theories suggest ageing is the result of the decline of natural selection with age as organisms pass sexual maturity. In other words, if an individual has a mutation whose effect occurs at late ages, i.e. later than reproductive age, this mutation will be passed on to the next generation, since it does not impact survival or reproductive success. Over generations, these late-acting deleterious alleles would accumulate in the genomes despite their adverse effects in late-life. This is known as the "mutation accumulation" theory of ageing. Overall, this theory suggests not a few specific variants in the genome, but rather a very high number of mutations whose cumulative effect (mutation load or burden) is related with ageing and lifespan.

Previous studies investigated the link between specific genetic variants and lifespan. However, the functional contribution of the genome-wide or regional mutational burden, rather than specific genetic variants, on ageing and lifespan has not been studied in human populations.

Aim: In this study, using the extensive health and genetic information available in the UK Biobank, we will test the predictions of evolutionary theories of ageing and study the evolution of ageing in humans.

Public health impact: This study will investigate the link between mutation burden and ageing-related traits and lifespan. Understanding of evolution of ageing will help understand the mechanisms and genes relevant to ageing and ageing-related diseases. Specifically,

1. i) we will study the genomic regions that have a stronger association with lifespan,
2. ii) we will investigate the potential compensatory mechanisms that can counteract the effects of mutational load, i.e. genetic factors associated with an unexpectedly longer lifespan for their given mutation load.

Overall, this study will help discover new mechanisms, genes, and interventions that can regulate lifespan and health.

Project duration: 3 years