Genetic, environmental, and pharmacological determinants of telomere attrition rates: Implications for the prevention of age-related multimorbidity

The UK Office for National Statistics estimates that in 50 years' time, there will be an additional 8.6 million people aged 65 years and over. Longer lifespan has clear benefits, but when it is associated with an increased proportion of the population suffering from age-related diseases, it can pose a burden to individual sufferers and to the economy.

Telomeres are 'DNA tails' at the end of chromosomes that shorten as we age. Premature telomere shortening is hypothesized to predispose individuals to multiple age-related diseases, including coronary artery disease and rheumatoid arthritis. This is because cells with very short telomere lengths are less able to divide and replace old, damaged or unhealthy cells within tissues. Interestingly, there is evidence that the rate of telomere shortening can be affected by genetic, environmental and pharmacological factors. A deeper understanding of which specific factors affect rates of telomere shortening might allow us to pinpoint individuals at high risk of specific age-related diseases or clusters of age-related diseases, and identify new ways of preventing or delaying their onset.

Within this grant, I will make use of telomere length data generated from half a million adults in the UK, to determine: (a) which genetic factors affect the rate at which our telomeres shorten, (b) how faster telomere shortening impacts on risk for different types of diseases, (c) whether specific environmental or lifestyle factors (e.g. exercise, diet) can protect from faster telomere shortening and diseases in late adulthood, (d) whether existing drugs might slow telomere shortening and be repurposed as anti-ageing compounds.

Exploring ways in which we can extend the human healthspan and prevent multimorbidity is of fundamental importance to our ageing society. Telomeres are TTAGGG nucleotide repeats at the end of chromosomes that progressively shorten in accordance with age and the number of cell divisions. Short telomere lengths trigger cell senescence, tissue-level pathology and are associated with an increased risk of multiple age-related diseases.

This New Investigator Research Grant will investigate genetic, environmental and pharmacological factors that affect the rate of telomere attrition and define how faster telomere attrition impacts on disease-related traits.

Specifically, I will:

(A) Perform the first genome-wide and transcriptome-wide association study of telomere attrition rates, utilising data collected from half a million UK adults. Polygenic risk scoring will also be used to determine if we can predict who in an independent population are most susceptible to faster telomere attrition based on their genetic profile.

(B) Use Mendelian randomisation to infer the impact faster telomere attrition exerts on ~1,400 disease related traits.

(C) Determine environmental factors in adulthood that are associated with reduced rates of telomere attrition 3+ years later, in >11,000 adults. This will be achieved by quantifying telomere length, or accessing existing data, from longitudinal cohorts with deep phenotyping.

(D) Use large cohort data, longitudinal samples, and a genetically-informed drug repurposing strategy to identify existing compounds that could slow the rate of telomere attrition, and test whether the use of these compounds is associated with lower risk of age-related disease.