Experimentally reduced insulin/IGF-1 signaling in adulthood extends lifespan of parents and improves Darwinian fitness of their offspring

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

ALDH1 bio-activates nifuroxazide to eradicate ALDH^High melanoma-initiating cells

5-Nitrofurans are antibiotic pro-drugs that have potential as cancer therapeutics. Here, we show that 5-nitrofurans can be bio-activated by aldehyde dehydrogenase (ALDH) 1A1/1A3 enzymes that are highly expressed in a subpopulation of cancer-initiating (stem) cells. We discover that the 5-nitrofuran, nifuroxazide, is selective for bio-activation by ALDH1 isoforms over ALDH2, whereby it both oxidizes ALDH1 and is converted to cytotoxic metabolites in a two-hit pro-drug mechanism. We show that ALDH1High melanoma cells are sensitive to nifuroxazide, while ALDH1A3 loss-of-function mutations confer drug resistance. In tumors, nifuroxazide targets ALDH1High melanoma subpopulations with the subsequent loss of melanoma-initiating cell potential. BRAF and MEK inhibitor therapy increases ALDH1 expression in patient melanomas, and effectively combines with nifuroxazide in melanoma cell models. The selective eradication of ALDH1High cells by nifuroxazide-ALDH1 activation goes beyond current strategies based on inhibiting ALDH1 and provides a rational basis for the nifuroxazide mechanism of action in cancer

The discovery, distribution and diversity of DNA viruses associated with Drosophila melanogaster in Europe

International audienceDrosophila melanogaster is an important model for antiviral immunity in arthropods, but very few DNA viruses have been described from the family Drosophilidae. This deficiency limits our opportunity to use natural host-pathogen combinations in experimental studies, and may bias our understanding of the Drosophila virome. Here we report fourteen DNA viruses detected in a metagenomic analysis of approximately 6500 pool-sequenced Drosophila, sampled from 47 European locations between 2014 and 2016. These include three new nudiviruses, a new and divergent entomopoxvirus, a virus related to Leptopilina boulardi filamentous virus, and a virus related to Musca domestica salivary gland hypertrophy virus. We also find an endogenous genomic copy of galbut virus, a dsRNA partitivirus, segregating at very low frequency. Remarkably, we find that Drosophila Vesanto virus, a small DNA virus previously described as a bidnavirus, may be composed of up to 12 segments and thus represent a new lineage of segmented DNA viruses. Two of the DNA viruses, Drosophila Kallithea nudivirus and Drosophila Vesanto virus are relatively common, found in 2% or more of wild flies. The others are rare, with many likely to be represented by a single infected fly. We find that virus prevalence in Europe reflects the prevalence seen in publicly-available datasets, with Drosophila Kallithea nudivirus and Drosophila Vesanto virus the only ones commonly detectable in public data from wild-caught flies and large population cages, and the other viruses being rare or absent. These analyses suggest that DNA viruses are at lower prevalence than RNA viruses in D. melanogaster, and may be less likely to persist in laboratory cultures. Our findings go some way to redressing an earlier bias toward RNA virus studies in Drosophila, and lay the foundation needed to harness the power of Drosophila as a model system for the study of DNA viruses

The evolutionary ecology of ageing in a wild Soay sheep population

Senescence, declining physiological function resulting in reduced survival and fertility with increasing age is a widely observed natural phenomena. Many studies of senescence in natural populations have found actuarial and reproductive senescence in wild vertebrates. More recently, evidence of ageing in diverse phenotypic traits has been reported. This has revealed the complex nature of senescence with huge variation in ageing patterns across vital rates and phenotypic traits within a population. Understanding how variation in ageing patterns is generated and maintained is important to understand the evolution of senescence in the wild. Many factors are likely to contribute to variation in ageing patterns observed in the wild and recent studies have highlighted the role of some processes such as – a) tradeoffs between life-history traits underpinning ageing and how molecular markers may behave as a mediator of these tradeoffs; b) the influence of parental age on offspring performance and ageing; c) the role of potential declines in selection with increasing age driving the ageing process across phenotypes in the wild. In this thesis, I set out to investigate some of the proximate and ultimate drivers of variation in senescence in a natural Soay sheep population. In Chapters 2 and 3, I examined the role of a molecular marker, telomere length in mediating tradeoffs between different life-history traits by investigating whether costs of maternal reproductive investment, infection and immunity influence TL. In Chapter 4, I investigated the short- and long-term impact of parental age effects on offspring traits examining the effect of both maternal and paternal age on four offspring traits – a) first-year survival, b) offspring adult lifespan, c) offspring lifetime breeding success and d) offspring lifetime recruitment success. In Chapter 5, I jointly developed evolutionary theory to explain variation in ageing patterns across phenotypic traits within a population (also known as asynchronous ageing) and proposed a methodological framework to estimate age-specific phenotypic selection in natural populations. In Chapter 6, I implemented the methods outlined in Chapter 5 to estimate age-dependent phenotypic selection across six traits in female Soay sheep

reproduction mated parents N2

Daily reproduction of mated parents (N2) subjected to daf-2 RNAi or empty vector

lifespan unmated parents N2

Lifespan of unmated parents (N2) subjected to daf-2 RNAi or empty vector. If they died of matricide it is coded as 1 in matricide column

lifespan parents mutants for Dryad

Lifespan of parents (N2,rrf-1,ppw-1) subjected to daf-2 RNAi or empty vector. If they died of matricide it is coded as 1 in matricide column