Wilson, James

Joshi, Peter

Timmers, Paul Reimund Hugo Jan

Medical Research Council (MRC)

2021-09-14T15:58:14Z

2021-09-14T15:58:14Z

2020-11-30

Human lifespan is determined by a complex interplay of genetics, environment, lifestyle and chance. In the UK, life expectancy has increased by roughly three years every decade, but despite longer lives, individuals also spend more years living with chronic disease. With populations greying and periods of morbidity becoming more prolonged, the burden of ageing and age-related disease is set to become a major healthcare challenge. Understanding the factors underlying trends in human lifespan could guide policy interventions to mitigate the burden of disease, while an understanding of the genetics of lifespan could provide insight into the ageing process. The latter could in turn reveal potential therapeutic targets to delay age-related disease and inform which individuals to target based on their genetic risk. In this thesis, I explore human lifespan from these two perspectives. First, I examined trends in mortality and morbidity in two million Scots using hospital admission and death records and found recent improvements in lifespan could be largely explained by improvements in the incidence and survival after hospitalisation of cancers and heart disease. However, I also found recent deteriorations in infectious disease, especially for individuals from lower socioeconomic classes, suggesting a need for a renewed public health focus in this area. Next, I performed a genome-wide association study (GWAS) to find genetic determinants of lifespan using DNA from 27 European cohorts and the lifespans of their parents (one million total). I identified 12 genomic regions affecting survival and found genetic variants across the genome, when aggregated into polygenic scores, could distinguish up to five years of survival between score deciles. Combining the lifespan GWAS with two other GWAS of lifespan-related traits, I identified 78 genes—some of which delay ageing in model organisms— which putatively influence both human lifespan and healthy years of life and which are enriched for haem metabolism. These findings present the most promising targets for therapeutic interventions to date, which may help delay the onset of age-related disease and extend the healthy years of life for all.

https://hdl.handle.net/1842/38042

http://dx.doi.org/10.7488/era/1313

en

The University of Edinburgh

Timmers PRHJ, Mounier N, Lall K, et al. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances [dataset]. Elife 2019;8. doi:https://doi.org/10.7488/ds/2463

Timmers PR, Kerssens JJ, Minton JW, et al. Trends in disease incidence and survival and their effect on mortality in Scotland: nationwide cohort study of linked hospital admission and death records 2001–2016. BMJ Open Published Online First: 2020. doi:http://dx.doi.org/10.1136/bmjopen2019-034299

lifespan

healthy years of life

iron processing

morbidity and mortality

genome-wide association study

Human lifespan: recent trends and genetic determinants

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy