The genetic basis of human lifespan

Background: Ageing is predicted to be the next global public health challenge, mainly due to the proportion of elderly people in populations increasing rapidly. While people are living longer, they are not healthier - most people develop one or multiple chronic diseases as they age - and as a result almost a quarter of the global burden of illness is now attributed to people aged 60 years and older (Suzman et al. 2015). The loss of physiological integrity associated with ageing has been studied extensively in model organisms, leading to the discovery of longevity genes and the characterisation of molecular ageing pathways (Lopez-Otin et al. 2013). Many of these pathways are shared with higher eukaryotes, but our understanding of human ageing is still within its infancy. The complex interactions between genes, environment, and behaviour are much harder to tease apart in observational studies on human populations than in controlled experiments on model organisms in the lab. This is especially true when human-specific environmental factors such as educational attainment and social status come into play. Recently, genome-wide association studies (GWAS) have reached the sample sizes and study designs necessary to overcome these difficulties and robustly identify human longevity genes (Deelen et al. 2014; Joshi et al. 2016). Now the statistical power is available, we can attempt to elucidate the genetic basis of human ageing.

Project: This project will use a quantitative genetic approach to investigate the heritable components of human lifespan and longevity traits using data from multiple databases, including the Orkney/Shetland population isolates and UK Biobank. Investigating the genetic components of age-related disease susceptibility, longevity-associated behaviour, and age-specific phenotypes will provide further insights into the biology of human ageing. The effects of all putative longevity genes on gene expression will be reviewed and where appropriate, modelled in vivo using tissue cultures and CRISPR-Cas9 transgenic mice.

Aims:
1. Identify human SNPs associating with a variety of ageing phenotypes
2. Explore how those variants regulate gene expression.
3. Characterise the effect on metabolism & longevity when manipulating the genes in vivo

References:

Deelen, J. et al., 2014. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Human Molecular Genetics, 23(16), pp.4420-4432.
Joshi, P.K. et al., 2016. Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan. Nature Communications, 7, p.11174.
Lopez-Otin, C. et al., 2013. The hallmarks of aging. Cell, 153(6), pp.1194-217.
Suzman, R. et al., 2015. Health in an ageing world - what do we know? The Lancet, 385, pp.484-486.