Inflammation,epigenetics,and metabolism converge to cell senescence and ageing:the regulation and intervention

Remarkable progress in ageing research has been achieved over the past decades.General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing.Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli,representing current hotspots as they not only(re-)shape the individual cell identity,but also involve in cell fate decision.This review focuses on the present findings and emerging concepts in epigenetic,inflammatory,and metabolic regulations and the consequences of the ageing process.Potential therapeutic interventions targeting cell senescence and regulatory mechanisms,using state-of-the-art techniques are also discussed.

Nicotinamide adenine dinucleotide replenishment rescues colon degeneration in aged mice

Susceptibility of gastrointestinal dysmotility increases with age-associated colonic degeneration.A paucity of remedies reversing colonic degeneration per se hinders the fundamental relief of symptoms.Here we discovered the correlation between colon degeneration and altered nicotinamide adenine dinucleotide(NAD)level in aged mice.Compared to 3-month-old young controls,2-year-old mice showed a spectrum of degenerative colonic phenotypes and exhibited a significant elongated transit time and slowed stool frequency in the context of Lomotil-induced slow-transit constipation.Despite upregulated colonic tryptophan hydroxylases expression,serotonin release and expression of colon-predominant type IV serotonin receptor,reduced viability of interstitial cells of Cajal while enhanced aquaporins(Aqp1,3 and 11)led to a less colonic motility and increased luminal dehydration in aged mice.Notably,this colonic degeneration was accompanied with reduced key NAD^(+)-generating enzyme expression and lowered NAD^(+)/NADH ratio in aged colon.Three-month continuous administration of beta nicotinamide mononucleotide,a NAD^(+)precursor,elevated colonic NAD^(+)level and improved defecation in aged mice.In contrast,pharmacological inhibition of nicotinamide phosphoribosyltransferase,the rate-limiting enzyme for NAD^(+)biosynthesis,induced a reduction in colonic NAD content and impaired gastrointestinal function in young mice.Taken together,these findings suggest the beneficial effect of NAD^(+)in maintaining colonic homoeostasis and reactivating NAD^(+)biosynthesis may represent a promising strategy to counteract age-related gastrointestinal degeneration.