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
