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

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

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

Host-pathogen coevolution increases genetic variation in susceptibility to infection

It is common to find considerable genetic variation in susceptibility to infection in natural populations. We have investigated whether natural selection increases this variation by testing whether host populations show more genetic variation in susceptibility to pathogens that they naturally encounter than novel pathogens. In a large cross-infection experiment involving four species of Drosophila and four host-specific viruses, we always found greater genetic variation in susceptibility to viruses that had coevolved with their host. We went on to examine the genetic architecture of resistance in one host species, finding that there are more major-effect genetic variants in coevolved host-pathogen interactions. We conclude that selection by pathogens has increased genetic variation in host susceptibility, and much of this effect is caused by the occurrence of major-effect resistance polymorphisms within populations

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

1. 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. But, how they do this is largely unknown. 2. Here, we have investigated the temperature preference of the fruit fly, Drosophila melanogaster, during infection with the fungal pathogen, Metarhizium robertsii, and the consequences of temperature preference on life history traits. We have used multiple measurements to assess the fitness consequences of temperature including age-specific changes in mortality rate and reproduction, providing more sensitive measures of accounting for variation in fitness with age. 3. We report that D. melanogaster optimizes its life history by exploiting thermal variation. Fungus-infected fruit flies seek out cooler temperatures, which immediately reduces their fecundity but, ultimately, increases their lifetime reproductive success. Colder temperatures reduced fungal growth rates both in vivo and in vitro, indicating that cooler temperatures increased resistance to the infection. 4. By comparing life history responses in infected and control animals, we found that cold seeking in infected animals facilitates a trade off between early- and late-age reproduction, but does not otherwise provide life history benefits that are specific to infected animals. These results indicate that cold-seeking is a mechanism for reducing the reproductive costs of infection. In contrast, uninfected control flies prefer warmer temperatures that optimise reproductive success via a rapid propagation strategy. 5. These findings help explain how life history trade-offs are mediated and how animals cope with infection, which will be increasingly important given the recent emergence of fungal pathogens and global climate change

Combined file of Figs S1-S6 and Table S1 from Manipulation of feeding regime alters sexual dimorphism for lifespan and reduces sexual conflict in <i>Drosophila melanogaster</i>

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, <i>Drosophila melanogaster</i>, 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

Hunt_et_al_2015_Dryad_data_sheets

Raw data collected from laboratory experiments used for the following analyses: sheet 1. Age-specific fecundity, sheet 2. In vivo fungal growth, sheet 3. Tolerance (Mortality vs. CFUs), sheet 4. Intrinsic rate of increase, sheet 5. Lifetime reproductive success, sheet 6. Survival (individual vials), sheet7. Mortality (population cages), sheet 8. Temperature preference. Key: NT - no treatment, HT - heat-killed fungal treatment, MR - Live fungal treatment

Phase I/IIa Trial of Atorvastatin in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysm

ObjectivesTo determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA).Study designThis was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75&nbsp;mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17&nbsp;years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6&nbsp;weeks after initiation of atorvastatin treatment.ResultsA 6-week course of up to 0.75&nbsp;mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3&nbsp;years; IQR, 2.6-6.4&nbsp;years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls.ConclusionsAtorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug