Harnessing variation in Drosophila melanogaster reveals different routes to increased infection susceptibility over age and sex-dependent association with lifespan

Abstract Background It is widely accepted that susceptibility to infection increases with age, usually attributed to immune system dysregulation. However, factors beyond decreased resistance mechanisms may increase susceptibility, such as changes to physiological or metabolic processes determining overall tolerance, and this may differ between individuals. We hypothesised that age-related increases in susceptibility reflect changes in both immune system function and disease tolerance, with their relative importance varying by population and sex. Results We assessed age-related susceptibility to bacterial pathogens in an outbred Drosophila melanogaster population and 22 isolines. We leveraged this variation to investigate age-related infection susceptibility and lifespan and to estimate frequencies of declines in resistance or tolerance mechanisms. Susceptibility increased early in life and was widespread across infections and populations. Despite strong correlation between the sexes in baseline susceptibility and its decrease over age, susceptibility at old age did not correlate. Increased susceptibility was associated with impaired resistance ( bona fide immunosenescence), but more frequently with reduced tolerance, which could be detected early in life, and remained low. We find susceptibility at old age predicts lifespan in males only. Conclusions Increased infection susceptibility is an early-arising ageing phenotype occurring in both sexes and driving male mortality. Infection susceptibility followed a power-law (Weibull) rather than the exponential (Gompertz) pattern typical of mortality, with each doubling of age approximately doubling susceptibility. We argue that the term “immunosenescence” should be limited to dysregulation of resistance mechanisms, and consideration of population variation, sex, and ageing of non-immune functions is critical to fully understand age-related loss of pathogen control.