Women live on average longer than men but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the aging gut in Drosophila. The intestinal epithelium of the aging female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in aging females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like aging pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.DOI: http://dx.doi.org/10.7554/eLife.10956.001
SummaryIntermittent fasting (IF) can improve function and health during aging in laboratory model organisms, but the mechanisms at work await elucidation. We subjected fruit flies (Drosophila melanogaster) to varying degrees of IF and found that just one month of a 2-day fed:5-day fasted IF regime at the beginning of adulthood was sufficient to extend lifespan. This long-lasting, beneficial effect of early IF was not due to reduced fecundity. Starvation resistance and resistance to oxidative and xenobiotic stress were increased after IF. Early-life IF also led to higher lipid content in 60-day-old flies, a potential explanation for increased longevity. Guts of flies 40 days post-IF showed a significant reduction in age-related pathologies and improved gut barrier function. Improved gut health was also associated with reduced relative bacterial abundance. Early IF thus induced profound long-term changes. Pharmacological and genetic epistasis analysis showed that IF acted independently of the TOR pathway because rapamycin and IF acted additively to extend lifespan, and global expression of a constitutively active S6K did not attenuate the IF-induced lifespan extension. We conclude that short-term IF during early life can induce long-lasting beneficial effects, with robust increase in lifespan in a TOR-independent manner, probably at least in part by preserving gut health.
Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer’s disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the mechanisms mediating Nrf2 inhibition in neurodegenerative conditions may therefore direct the design of drugs targeted for the prevention of these diseases with minimal side-effects. Our study provides the first in vivo evidence that specific inhibition of Keap1, a negative regulator of Nrf2, can prevent neuronal toxicity in response to the AD-initiating Aβ42 peptide, in correlation with Nrf2 activation. Comparatively, lithium, an inhibitor of the Nrf2 suppressor GSK-3, prevented Aβ42 toxicity by mechanisms independent of Nrf2. A new direct inhibitor of the Keap1-Nrf2 binding domain also prevented synaptotoxicity mediated by naturally-derived Aβ oligomers in mouse cortical neurons. Overall, our findings highlight Keap1 specifically as an efficient target for the re-activation of Nrf2 in AD, and support the further investigation of direct Keap1 inhibitors for the prevention of neurodegeneration in vivo.
The greatest risk factor for Alzheimer's disease (AD) is age, and changes in the ageing nervous system are likely contributors to AD pathology. Amyloid beta (Aβ) accumulation, which occurs as a result of the amyloidogenic processing of amyloid precursor protein (APP), is thought to initiate the pathogenesis of AD, eventually leading to neuronal cell death. Previously, we developed an adult-onset Drosophila model of AD. Mutant Aβ42 accumulation led to increased mortality and neuronal dysfunction in the adult flies. Furthermore, we showed that lithium reduced Aβ42 protein, but not mRNA, and was able to rescue Aβ42-induced toxicity. In the current study, we investigated the mechanism/s by which lithium modulates Aβ42 protein levels and Aβ42 induced toxicity in the fly model. We found that lithium caused a reduction in protein synthesis in Drosophila and hence the level of Aβ42. At both the low and high doses tested, lithium rescued the locomotory defects induced by Aβ42, but it rescued lifespan only at lower doses, suggesting that long-term, high-dose lithium treatment may have induced toxicity. Lithium also down-regulated translation in the fission yeast Schizosaccharomyces pombe associated with increased chronological lifespan. Our data highlight a role for lithium and reduced protein synthesis as potential therapeutic targets for AD pathogenesis.
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