Reduced insulin/IGF-1 signalling upregulates two anti-viral immune pathways, decreases viral load and increases survival under viral infection in C. elegans.

Reduced insulin/IGF-1 signalling (rIIS) improves survival across diverse taxa and there is a growing interest in its role in regulating immune function. Whilst rIIS can improve anti-bacterial resistance, the consequences for anti-viral immunity are yet to be systematically examined. Here, we show that rIIS in adult Caenorhabditis elegans increases the expression of key genes in two different anti-viral immunity pathways, whilst reducing viral load in old age, increasing survival and reducing rate-of-senescence under infection by naturally occurring positive-sense single-stranded RNA Orsay virus. We found that both drh-1 in the anti-viral RNA interference (RNAi) pathway and cde-1 in the terminal uridylation-based degradation of viral RNA pathway were upregulated in early adulthood under rIIS and increased anti-viral resistance was not associated with reproductive costs. Remarkably, rIIS increased anti-viral gene expression only in infected worms, potentially to curb the costs of constitutively upregulated immunity. RNA viruses are found across taxa from plants to mammals and we demonstrate a novel role for rIIS in regulating resistance to viral infection. We therefore highlight this evolutionarily conserved signalling pathway as a promising therapeutic target to improve anti-viral immunity.

Multigenerational downregulation of insulin/IGF-1 signaling in adulthood improves lineage survival, reproduction, and fitness in Caenorhabditis elegans supporting the developmental theory of ageing.

Adulthood-only downregulation of insulin/IGF-1 signaling (IIS), an evolutionarily conserved pathway regulating resource allocation between somatic maintenance and reproduction, increases life span without fecundity cost in the nematode, Caenorhabditis elegans. However, long-term multigenerational effects of reduced IIS remain unexplored and are proposed to carry costs for offspring quality. To test this hypothesis, we ran a mutation accumulation (MA) experiment and downregulated IIS in half of the 400 MA lines by silencing daf-2 gene expression using RNA interference (RNAi) across 40 generations. Contrary to the prediction, adulthood-only daf-2 RNAi reduced extinction of MA lines both under UV-induced and spontaneous MA. Fitness of the surviving UV-induced MA lines was higher under daf-2 RNAi. Reduced IIS increased intergenerational F1 offspring fitness under UV stress but had no quantifiable transgenerational effects. Functional hrde-1 was required for the benefits of multigenerational daf-2 RNAi. Overall, we found net benefit to fitness from multigenerational reduction of IIS and the benefits became more apparent under stress. Because reduced daf-2 expression during development carries fitness costs, we suggest that our findings are best explained by the developmental theory of ageing, which maintains that the decline in the force of selection with age results in poorly regulated gene expression in adulthood.

Ageing as "early-life inertia": Disentangling life-history trade-offs along a lifetime of an individual.

The theory that ageing evolves because of competitive resource allocation between the soma and the germline has been challenged by studies showing that somatic maintenance can be improved without impairing reproduction. However, it has been suggested that cost-free improvement in somatic maintenance is possible only under a narrow range of benign conditions. Here, we show that experimental downregulation of insulin/IGF-1 signaling (IIS) in C. elegans nematodes, a robustly reproducible life span- and health span-extending treatment, reduces fitness in a complex variable environment when initiated during development but does not reduce fitness when initiated in adulthood. Thus, our results show that the costs and benefits of reduced IIS can be uncoupled when organisms inhabit variable environments, and, therefore, do not provide support for the resource allocation theory. Our findings support the theory that the force of natural selection on gene expression in evolutionarily conserved signaling pathways that shape life-history traits declines after the onset of reproduction resulting in organismal senescence.

Cost-free lifespan extension via optimization of gene expression in adulthood aligns with the developmental theory of ageing.

Ageing evolves because the force of selection on traits declines with age but the proximate causes of ageing are incompletely understood. The 'disposable soma' theory of ageing (DST) upholds that competitive resource allocation between reproduction and somatic maintenance underpins the evolution of ageing and lifespan. In contrast, the developmental theory of ageing (DTA) suggests that organismal senescence is caused by suboptimal gene expression in adulthood. While the DST predicts the trade-off between reproduction and lifespan, the DTA predicts that age-specific optimization of gene expression can increase lifespan without reproduction costs. Here we investigated the consequences for lifespan, reproduction, egg size and individual fitness of early-life, adulthood and post-reproductive onset of RNAi knockdown of five 'longevity' genes involved in key biological processes in Caenorhabditis elegans. Downregulation of these genes in adulthood and/or during post-reproductive period increases lifespan, while we found limited evidence for a link between impaired reproduction and extended lifespan. Our findings demonstrate that suboptimal gene expression in adulthood often contributes to reduced lifespan directly rather than through competitive resource allocation between reproduction and somatic maintenance. Therefore, age-specific optimization of gene expression in evolutionarily conserved signalling pathways that regulate organismal life histories can increase lifespan without fitness costs.

Sex-Specific Responses of Life Span and Fitness to Variation in Developmental Versus Adult Diets in Drosophila melanogaster.

Nutritional variation across the lifetime can have significant and sex-specific impacts on fitness. Using Drosophila melanogaster, we measured these impacts by testing the effects on life span and reproductive success of high or low yeast content in developmental versus adult diets, separately for each sex. We tested two hypotheses: that dietary mismatches between development and adulthood are costly and that any such costs are sex-specific. Overall, the results revealed the rich and complex responses of each sex to dietary variation across the lifetime. Contrary to the first hypothesis, dietary mismatches between developmental and adult life stages were not universally costly. Where costs of nutritional variation across the life course did occur, they were sex-, context-, and trait-specific, consistent with hypothesis 2. We found effects of mismatches between developmental and adult diets on reproductive success in females but not males. Adult diet was the main determinant of survival, and life span was significantly longer on high yeast adult food, in comparison to low, in both sexes. Developing on a high yeast diet also benefited adult female life span and reproductive success, regardless of adult diet. In contrast, a high yeast developmental diet was only beneficial for male life span when it was followed by low yeast adult food. Adult diet affected mating frequency in opposing directions, with males having higher mating frequency on high and females on low, with no interaction with developmental diet for either sex. The results emphasize the importance of sex differences and of the directionality of dietary mismatches in the responses to nutritional variation.

Manipulation of feeding regime alters sexual dimorphism for lifespan and reduces sexual conflict in Drosophila melanogaster.

Sexual dimorphism for lifespan (SDL) is widespread, but poorly understood. A leading hypothesis, which we test here, is that strong SDL can reduce sexual conflict by allowing each sex to maximize its sex-specific fitness. We used replicated experimental evolution lines of the fruit fly, Drosophila melanogaster, which had been maintained for over 360 generations on either unpredictable 'Random' or predictable 'Regular' feeding regimes. This evolutionary manipulation of feeding regime led to robust, enhanced SDL in Random over control, Regular lines. Enhanced SDL was associated with a significant increase in the fitness of focal males, tested with wild-type (WT) females. This was due to sex-specific changes to male life history, manifested as increased early reproductive output and reduced survival. In contrast, focal female fitness, tested with WT males, did not differ across regimes. Hence increased SDL was associated with a reduction in sexual conflict, which increased male fitness and maintained fitness in females. Differences in SDL were not associated with developmental time or developmental survival. Overall, the results showed that the expression of enhanced SDL, resulting from experimental evolution of feeding regimes, was associated with male-specific changes in life history, leading to increased fitness and reduced sexual conflict.

Cold-seeking behaviour mitigates reproductive losses from fungal infection in Drosophila.

Animals must tailor their life-history strategies to suit the prevailing conditions and respond to hazards in the environment. Animals with lethal infections are faced with a difficult choice: to allocate more resources to reproduction and suffer higher mortality or to reduce reproduction with the expectation of enhanced immunity and late-age reproduction. However, the strategies employed to mediate shifts in life-history traits are largely unknown. Here, we investigate the temperature preference of the fruit fly, Drosophila melanogaster, during infection with the fungal pathogen, Metarhizium robertsii, and the consequence of temperature preference on life-history traits. We have measured the temperature preference of fruit flies under different pathogen conditions. We conducted multiple fitness assays of the host and the pathogen under different thermal conditions. From these data, we estimated standard measures of fitness and used age-specific methodologies to test for the fitness trade-offs that are thought to underlie differences in life-history strategy. We found that fungus-infected fruit flies seek out cooler temperatures, which facilitates an adaptive shift in their life-history strategy. The colder temperatures preferred by infected animals were detrimental to the pathogen because it increased resistance to infection. But, it did not provide net benefits that were specific to infected animals, as cooler temperatures increased lifetime reproductive success and survival whether or not the animals were infected. Instead, we find that cold-seeking benefits infected animals by increasing their late-age reproductive output, at a cost to their early-age reproductive output. In contrast, naive control flies prefer warmer temperatures that optimize early-age reproductive, at a cost to reproductive output at late ages. These findings show that infected animals exhibit fundamentally different reproductive strategies than their healthy counterparts. Temperature preference can facilitate shifts in strategy, but not without inevitable trade-offs.