Testing the developmental theory of ageing: from genes to populations

Why do organisms age? The decline in the force of natural selection with age leads to accumulation of late-acting deleterious alleles (‘mutation accumulation’) and selection for alleles whose effects of fitness are beneficial in early-life but detrimental in late-life (‘antagonistic pleiotropy’). However, these population genetic models do not offer insight into the physiological processes that result in trait senescence, and ultimately shape organismal life histories. Two conceptual advances merge an evolutionary approach with proximate physiological mechanisms into an integrated theory of ageing. First, the classical resource allocation-based theory of ageing – i.e., the ‘disposable soma’ (DST) – has been challenged by empirical studies showing that somatic maintenance is not constrained by resource allocation to reproduction. Second, emerging new theory – the developmental theory of ageing (DTA) – argues instead that ageing results from suboptimal regulation of gene expression in adulthood. We recently used age-specific optimality selection approach to show how ageing evolves via the DTA and generated predictions for separating the DST and the DTA in empirical studies. The DTA uniquely predicts that optimisation of age-specific gene expression decelerates ageing and improves fitness. While the new theory successfully explains empirical findings that do not fit the canonical DST, the DTA also faces major challenges. First, it has never been tested experimentally outside Caenorhabditis elegans, a nematode widely used as a model in biology. Thus, the DTA can be challenged on the grounds of generality. Second, the DTA predicts that interfering with gene expression during development to decelerate ageing will be detrimental to fitness. However, our ongoing NERC-funded work challenges this prediction by showing that optimisation of gene expression during development increases performance across the life course from development to adulthood and increases fitness. How can we reconcile empirical discoveries and novel theory? We propose a research programme that combines conceptual and methodological advances to provide the first comprehensive test of DTA across species and environments, to resolve key contradictions between theory and empirical data, and to explicitly link age-specific gene function to population viability. Objective 1 – to establish the generality of DTA beyond the model organism: We will use novel methodological approaches developed in our lab to test the prediction that optimising age-specific gene expression in an environment-sensing molecular signalling pathway reliably decelerates ageing and increases fitness across nine Caenorhabditis species from phylogenetically distant species supergroups. Objective 2 – to identify the nature of the trade-off: We will test the hypothesis that accelerated development, increased reproduction and decelerated ageing come at the cost of compromised environmental sensing. Our enabling research suggests that downregulation of environment-sensing molecular signalling slows down senescence but elicits very costly maladaptive responses to environmental change suggesting a tantalizing possibility of a novel trade-off at the root of ageing. Objective 3 – to link gene function to population viability: Objective 3 capitalises on our recent work that discovered age-specific changes in the expression of immune response gene clusters as candidates for decelerated ageing in C. elegans in response to downregulation of environment-sensing signalling. We will change the expression of key genes within these clusters to test the hypothesis that enhanced immunity improves population viability in stable environments but reduces population viability in changing environments. This programme will test novel theory of ageing across different levels of biological organisation to advance our understanding of how ageing evolves.