Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy.

The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side effects from continuous dosing. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice. In Drosophila, a brief, early rapamycin treatment of adults extended lifespan and attenuated age-related decline in the intestine to the same degree as lifelong dosing. Lasting memory of earlier treatment was mediated by elevated autophagy in intestinal enterocytes, accompanied by increased levels of intestinal LManV and lysozyme. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a 3-month, early treatment also induced a memory effect, with maintenance similar to chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn.

Social environment drives sex and age-specific variation in Drosophila melanogaster microbiome composition and predicted function.

Social environments influence multiple traits of individuals including immunity, stress and ageing, often in sex-specific ways. The composition of the microbiome (the assemblage of symbiotic microorganisms within a host) is determined by environmental factors and the host's immune, endocrine and neural systems. The social environment could alter host microbiomes extrinsically by affecting transmission between individuals, probably promoting homogeneity in the microbiome of social partners. Alternatively, intrinsic effects arising from interactions between the microbiome and host physiology (the microbiota-gut-brain axis) could translate social stress into dysbiotic microbiomes, with consequences for host health. We investigated how manipulating social environments during larval and adult life-stages altered the microbiome composition of Drosophila melanogaster fruit flies. We used social contexts that particularly alter the development and lifespan of males, predicting that any intrinsic social effects on the microbiome would therefore be sex-specific. The presence of adult males during the larval stage significantly altered the microbiome of pupae of both sexes. In adults, same-sex grouping increased bacterial diversity in both sexes. Importantly, the microbiome community structure of males was more sensitive to social contact at older ages, an effect partially mitigated by housing focal males with young rather than coaged groups. Functional analyses suggest that these microbiome changes impact ageing and immune responses. This is consistent with the hypothesis that the substantial effects of the social environment on individual health are mediated through intrinsic effects on the microbiome, and provides a model for understanding the mechanistic basis of the microbiota-gut-brain axis.

Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila.

Reduced activity of the insulin/IGF signalling network increases health during ageing in multiple species. Diverse and tissue-specific mechanisms drive the health improvement. Here, we performed tissue-specific transcriptional and proteomic profiling of long-lived Drosophila dilp2-3,5 mutants, and identified tissue-specific regulation of >3600 transcripts and >3700 proteins. Most expression changes were regulated post-transcriptionally in the fat body, and only in mutants infected with the endosymbiotic bacteria, Wolbachia pipientis, which increases their lifespan. Bioinformatic analysis identified reduced co-translational ER targeting of secreted and membrane-associated proteins and increased DNA damage/repair response proteins. Accordingly, age-related DNA damage and genome instability were lower in fat body of the mutant, and overexpression of a minichromosome maintenance protein subunit extended lifespan. Proteins involved in carbohydrate metabolism showed altered expression in the mutant intestine, and gut-specific overexpression of a lysosomal mannosidase increased autophagy, gut homeostasis, and lifespan. These processes are candidates for combatting ageing-related decline in other organisms.

Interactive effects of social environment, age and sex on immune responses in Drosophila melanogaster.

Social environments have been shown to have multiple effects on individual immune responses. For example, increased social contact might signal greater infection risk and prompt a prophylactic upregulation of immunity. This differential investment of resources may in part explain why social environments affect ageing and lifespan. Our previous work using Drosophila melanogaster showed that single-sex social contact reduced lifespan for both sexes. Here, we assess how social interactions (isolation or contact) affect susceptibility to infection, phagocytotic activity and expression of a subset of immune- and stress-related genes in young and old flies of both sexes. Social contact had a neutral, or even improved, effect on post-infection lifespan in older flies and reduced the expression of stress response genes in females; however, it reduced phagocytotic activity. Overall, the effects of social environment were complex and largely subtle and do not indicate a consistent effect. Together, these findings indicate that social contact in D. melanogaster does not have a predictable impact on immune responses and does not simply trade-off immune investment with lifespan.

Sex-specific effects of social isolation on ageing in Drosophila melanogaster.

Social environments can have a major impact on ageing profiles in many animals. However, such patterns in variation in ageing and their underlying mechanisms are not well understood, particularly because both social contact and isolation can be stressful. Here, we use Drosophila melanogaster fruitflies to examine sex-specific effects of social contact. We kept flies in isolation versus same-sex pairing throughout life, and measured actuarial (lifespan) and functional senescence (declines in climbing ability). To investigate underlying mechanisms, we determined whether an immune stress (wounding) interacted with effects of social contact, and assessed behaviours that could contribute to differences in ageing rates. Pairing reduced lifespan for both sexes, but the effect was greater for males. In contrast, pairing reduced the rate of decline in climbing ability for females, whereas for males, pairing caused more rapid declines with age. Wounding reduced lifespan for both sexes, but doubled the negative effect of pairing on male lifespan. We found no evidence that these effects are driven by behavioural interactions. These findings suggest that males and females are differentially sensitive to social contact, that environmental stressors can impact actuarial and functional senescence differently, and that these effects can interact with environmental stressors, such as immune challenges.