Abstract
The intestine, a high-turnover tissue, plays a critical role in regulating aging and health in both vertebrates and invertebrates. Maintaining the epithelial barrier function of the intestine by preserving innate immune homeostasis significantly delays aging and prevents mortality. In an effort to explore effective chemicals and materials that can improve intestinal integrity, we performed a nonbiased screen utilizing Drosophila as an animal model. We showed that long-term uptake of aspirin markedly prevented age-onset gut leakage, the over-proliferation of intestinal stem cells, and the dysbiosis of commensal microbiota in fruit flies. Mechanistically, aspirin efficiently downregulated chronic activation of intestinal immune deficiency signaling during aging. Furthermore, our in vivo and in vitro biochemical analyses indicated that aspirin is a negative modulator in control of the K63-linked ubiquitination of Imd. Our findings uncover a novel regulatory mechanism by which aspirin positively modulates intestinal homeostasis, thus delaying aging, in Drosophila.
Highlights
Longevity is influenced by a variety of both intrinsic and extrinsic factors, which include heredity, sex, diet, health conditions, living environment, and so on [1,2,3,4,5,6,7,8]
These results suggest that aspirin might play a role in positively regulating the epithelial barrier function of the Drosophila intestine during aging
In Drosophila, the innate immune immune deficiency (Imd) signaling pathway has been shown to be highly correlated with intestinal homeostasis during aging [11, 22, 30]; hyperregulation of Imd signaling normally leads to dysbiosis of the gut microbiota, breakdown of the gut epithelial barrier, aging-related disorders and even death [10, 23]
Summary
Longevity is influenced by a variety of both intrinsic and extrinsic factors, which include heredity, sex, diet, health conditions, living environment, and so on [1,2,3,4,5,6,7,8]. Regulators that control the ubiquitin-related processes of key factors such as Imd [28], Dredd [29], Tak1 [30], or Relish [31] effectively determine the fate of the Imd signaling pathway and related biological activities [22, 32]. Deeper insight into these processes would reveal novel therapeutic options or medicines for the treatment of diseases and pathological conditions in mammalian systems. Our study uncovers a novel Imd-dependent regulatory mechanism by which aspirin modulates Drosophila intestinal homeostasis and the aging process
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