As geneticists, we take for granted that mutating a single gene can extend C. elegans lifespan way beyond that experienced by WT animals. Thus, the genetic approach to longevity research has revealed several important molecular pathways regulating lifespan, including insulin signalling and oxidative stress. This is very striking, given the inherent complexity of ageing phenotypes, which involve changes in many different biological and physiological processes. It seems likely that traditional genetic screens for lifespan mutants are at, or nearing, saturation, and yet our understanding of the biology of ageing is far from complete. Does this mean that longevity is controlled by just a few “master” regulators, or that complex genetic interactions are important in determining robust longevity outcomes, such that rather few single mutants display profoundly altered rates of ageing? Here, we have modeled the human monogenic premature ageing disorder Werner syndrome (WS) using mutation of wrn-1, homologous to the WS associated WRN gene. WS recapitulates many features of the normal ageing process, but these manifest at an early age. Furthermore, cells from WS patients are characterized by genomic instability. Although a growing body of research can explain how WRN maintains genome stability, it is not clear why functional WRN is so important for longevity, or whether the observed genomic instability in WS contributes to premature ageing. We have demonstrated the progeroid nature of C. elegans wrn-1 mutants, but, unexpectedly, we find that combining short-lived wrn-1 mutants with short lived p53/cep-1 mutants results in a very striking daf-16-dependent improvement in both lifespan and healthspan, greatly beyond that of WT worms – a phenomenon we call synthetic superviability (SSV). Furthermore, we show that genomic instability per se does not drive ageing, since these long-lived double mutants display high levels of genomic instability. Rather, it appears that the ability to sense and respond to stresses such as DNA damage (mediated by factors like p53) limits lifespan. Remove the stress responder (which normally perhaps “overreacts” to particular stresses, thus limiting lifespan), and the intrinsic stress pushes the physiological outcome into an enhanced longevity mode, akin to hormesis. Investigations are now underway to discover other genetic combinations which also induce SSV; the cep-1;wrn-1 double mutant may turn out to be the prototype of a new class of combinatorial mutant with improved longevity, despite the fact that each single mutant displays progeria. This completely novel type of genetic interaction may provide rich resources for a deeper understanding of the biology of ageing.
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