Classical theory maintains that ageing evolves via energy trade‐offs between reproduction and survival leading to accumulation of unrepaired cellular damage with age. In contrast, the emerging new theory postulates that ageing evolves because of deleterious late‐life hyper‐function of reproduction‐promoting genes leading to excessive biosynthesis in late‐life. The hyper‐function theory uniquely predicts that optimizing nutrient‐sensing molecular signaling in adulthood can simultaneously postpone ageing and increase Darwinian fitness. Here, we show that reducing evolutionarily conserved insulin/IGF‐1 nutrient‐sensing signaling via daf‐2 RNA interference (RNAi) fulfils this prediction in Caenorhabditis elegans nematodes. Long‐lived daf‐2 RNAi parents showed normal fecundity as self‐fertilizing hermaphrodites and improved late‐life reproduction when mated to males. Remarkably, the offspring of daf‐2 RNAi parents had higher Darwinian fitness across three different genotypes. Thus, reduced nutrient‐sensing signaling in adulthood improves both parental longevity and offspring fitness supporting the emerging view that suboptimal gene expression in late‐life lies at the heart of ageing.

Theory maintains that when future environment is predictable, parents should adjust the phenotype of their offspring to match the anticipated environment. The plausibility of positive anticipatory parental effects is hotly debated and the experimental evidence for the evolution of such effects is currently lacking. We experimentally investigated the evolution of anticipatory maternal effects in a range of environments that differ drastically in how predictable they are. Populations of the nematode Caenorhabditis remanei, adapted to 20°C, were exposed to a novel temperature (25°C) for 30 generations with either positive or zero correlation between parent and offspring environment. We found that populations evolving in novel environments that were predictable across generations evolved a positive anticipatory maternal effect, because they required maternal exposure to 25°C to achieve maximum reproduction in that temperature. In contrast, populations evolving under zero environmental correlation had lost this anticipatory maternal effect. Similar but weaker patterns were found if instead rate-sensitive population growth was used as a fitness measure. These findings demonstrate that anticipatory parental effects evolve in response to environmental change so that ill-fitting parental effects can be rapidly lost. Evolution of positive anticipatory parental effects can aid population viability in rapidly changing but predictable environments.

23Classical theory maintains that ageing evolves via energy trade-offs between reproduction 24 and survival leading to accumulation of unrepaired cellular damage with age. In contrast, the 25 emerging new theory postulates that ageing evolves because of deleterious late-life hyper-26 function of reproduction-promoting genes leading to excessive biosynthesis in late-life. The 27 hyper-function theory uniquely predicts that optimizing nutrient-sensing molecular signalling 28 in adulthood can simultaneously postpone ageing and increase Darwinian fitness. Here we 29 show that reducing evolutionarily conserved insulin/IGF-1 nutrient-sensing signalling via 30 daf-2 RNA interference (RNAi) fulfils this prediction in Caenorhabditis elegans nematodes.31 Long-lived daf-2 RNAi parents showed normal fecundity as self-fertilizing hermaphrodites 32 and improved late-life reproduction when mated to males. Remarkably, the offspring of daf-2 33 RNAi parents had higher Darwinian fitness across three different genotypes. Thus, reduced 34 nutrient-sensing signalling in adulthood improves both parental longevity and offspring 35 fitness supporting the emerging view that sub-optimal gene expression in late-life lies at the 36 heart of ageing. 37 38 39 4 Impact Statement 40 Understanding mechanisms underpinning ageing is fundamental to improving quality of life 41 in an increasingly long-lived society. Recent breakthroughs have challenged the long-42 standing paradigm that the energy trade-off between reproduction and somatic maintenance 43 causes organismal senescence via slow accumulation of unrepaired cellular damage with age. 44 The emerging new theory of ageing provides a conceptually novel framework by proposing 45 that ageing is a direct consequence of physiological processes optimized for early-life 46 function, such as growth and early-life reproduction, that are running 'too high' (i.e. at 47 hyperfunction) in late adulthood. Contrary to the classic view based on damage accumulation, 48 the hyperfunction theory proposes that suboptimal gene expression in late-life causes ageing 49 via excessive biosynthesis. Thus, the hyperfunction theory uniquely predicts that longevity 50 and Darwinian fitness can be simultaneously increased by reducing unnecessarily high levels 51of nutrient-sensing signalling in adulthood. Here we show that reducing evolutionarily 52 conserved nutrient-sensing signalling pathway fulfils this prediction in Caenorhabditis 53 elegans nematodes. We found that downregulation of the insulin/IGF-1 signalling in adult C. 54 elegans nematodes not only improves longevity but, most intriguingly, increases fitness of 55 the resulting offspring in the next generation. We found support for increase in offspring 56 fitness across different genetic backgrounds. Our findings contradict the theoretical 57 conjecture that energy trade-offs between growth, reproduction and longevity is the universal 58 cause of senescence and provide strong experimental support for the emerging hyperfunction 59 theory of ageing.60 61 62 U...

Rapamycin inhibits the nutrient-sensing TOR pathway and extends life span in a wide range of organisms. Although life-span extension usually differs between the sexes, the reason for this is poorly understood. Because TOR influences growth, rapamycin likely affects life-history traits such as growth and reproduction. Sexes have different life-history strategies, and theory predicts that they will resolve the tradeoffs between growth, reproduction, and life span differently. Specifically, in taxa with female-biased sexual size dimorphism, reduced growth may have smaller effects on male fitness. We investigated the effects of juvenile, adult, or life-long rapamycin treatment on growth, reproduction, life span, and individual fitness in the outcrossing nematode Caenorhabditis remanei Life-long exposure to rapamycin always resulted in the strongest response, whereas postreproductive exposure did not affect life span. Although rapamycin resulted in longer life span and smaller size in males, male individual fitness was not affected. In contrast, size and fitness were negatively affected in females, whereas life span was only extended under high rapamycin concentrations. Our results support the hypothesis that rapamycin affects key life-history traits in a sex-specific manner. We argue that the fitness cost of life-span extension will be sex specific and propose that the smaller sex generally pay less while enjoying stronger life-span increase.