A Genetic View of the Degree to Which Human Longevity is Shaped by Cancer
Cancers are not as high in the list of major causes of death in our species as one might imagine. In this we differ from laboratory mice, which researchers have fondly referred to as "little cancer factories". Nonetheless, when thinking about the evolution of the mechanisms of aging in any mammalian species, one runs into considerations of the risk of cancer again and again. There is a coin, with regeneration and tissue maintenance on one side and risk of cancer on the other. In long-lived species, evolution has come to a balance between these two sides. In our species a lengthening of life span relative to other primates required a suppression of cancer risk that has given rise to a drawn-out decline in function and increasing burden of cellular senescence.
Human lifespan is shaped by both genetic and environmental exposures and their interaction. To enable precision health, it is essential to understand how genetic variants contribute to earlier death or prolonged survival. In this study, we tested the association of common genetic variants and the burden of rare non-synonymous variants in a survival analysis, using age-at-death (N = 35,551, median age-at-death = 72.4), and last-known-age (N = 358,282, median last-known-age = 71.9), in European ancestry participants of the UK Biobank.
The associations we identified seemed predominantly driven by cancer, likely due to the age range of the cohort. Common variant analysis highlighted three longevity-associated loci: APOE, ZSCAN23, and MUC5B. We identified six genes whose burden of loss-of-function variants is significantly associated with reduced lifespan: TET2, ATM, BRCA2, CKMT1B, BRCA1, and ASXL1. Additionally, in eight genes, the burden of pathogenic missense variants was associated with reduced lifespan: DNMT3A, SF3B1, CHL1, TET2, PTEN, SOX21, TP53, and SRSF2. Most of these genes have previously been linked to oncogenic-related pathways and some are linked to and are known to harbor somatic variants that predispose to clonal hematopoiesis. A direction-agnostic approach additionally identified significant associations with C1orf52, TERT, IDH2, and RLIM, highlighting a link between telomerase function and longevity as well as identifying additional oncogenic genes.
Our results emphasize the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.