Aging weakens Th17 cell pathogenicity and ameliorates experimental autoimmune uveitis in mice

Aging-induced changes in the immune system are associated with a higher incidence of infection and vaccination failure.Lymph nodes,which filter the lymph to identify and fight infections,play a central role in this process.However,careful characterization of the impact of aging on lymph nodes and associated autoimmune diseases is lacking.We combined single-cell RNA sequencing(scRNA-seq)with flow cytometry to delineate the immune cell atlas of cervical draining lymph nodes(CDLNs)of both young and old mice with or without experimental autoimmune uveitis(EAU).We found extensive and complicated changes in the cellular constituents of CDLNs during aging.When confronted with autoimmune challenges,old mice developed milder EAU compared to young mice.Within this EAU process,we highlighted that the pathogenicity of T helper 17 cells(Th17)was dampened,as shown by reduced GM-CSF secretion in old mice.The mitigated secretion of GMCSF contributed to alleviation of IL-23 secretion by antigen-presenting cells(APCs)and may,in turn,weaken APCs’effects on facilitating the pathogenicity of Th17 cells.Meanwhile,our study further unveiled that aging downregulated GM-CSF secretion through reducing both the transcript and protein levels of IL-23R in Th17 cells from CDLNs.Overall,aging altered immune cell responses,especially through toning down Th17 cells,counteracting EAU challenge in old mice.

FTO stabilizes MIS12 and counteracts senescence

Dear Editor, N6-methyladenosine(m6A)is an abundant epitranscriptomic modification that regulates messenger RNA(mRNA)biology.The m6A modification regulates mRNA splicing,transport,stability,and translation through coordinated activities by methyltransferases(writers),binding proteins(readers),and demethylases(erasers)(Huang et al.,2020;Wu et al.,2020).Among m6A regulators,fat mass of obesity-associ-ated protein(FTO),is the first discovered eraser with RNA m6A demethylation activity(Jia et al.,2011).Since then,FTO has been reported to play m6A-dependent roles in a variety of physiological processes including adipogenesis,neuro-genesis and tumorigenesis(Fischer et al.,2009;Li et al.,2017;Huang et al.,2020).Consequently,FTO deficiency in mice leads to dramatic phenotypes,such as decreased fat mass and impaired brain development(Fischer et al.,2009;Li et al.,2017).Similarly,inhibition of FTO reduces tumori-genesis in multiple types of cancer models,while FTO is highly expressed in many cancers(Huang et al.,2020).

Low-dose chloroquine treatment extends the lifespan of aged rats

Dear Editor,Chloroquine(CQ)has long been used as an anti-malarial agent(Wellems and Plowe,2001).Recently,CQ has also been applied to treat viral infection and related diseases(Wellems and Plowe,2001;Huang et al.,2020).However,the safety and efficacy of its applications are still under extensive debate(Solomon and Lee,2009).Here,we discovered that low-dose CQ has a geroprotective effect on physiologically aged rats.Low-dose CQ prolonged lifespan,repressed systemic inflammation,and inhibited fibrosis across multiple tissue types in aged rats.Furthermore,we constructed transcriptomic maps for 6 tissues(kidney,small intestine,liver,heart,lung,and aorta)upon CQ treatment,thus revealing the effects of CQ at a systemic level.CQ treatment mitigated age-related molecular changes and repressed genes linked to fibrosis and the inflammatory response.Altogether,our data provide a valuable resource for investigating the impact of CQ on multiple aged tissues,which may facilitate the development of clinical applications that mitigate age-related changes in the elderly.

mTORC2/RICTOR exerts differential levels of metabolic control in human embryonic,mesenchymal and neural stem cells

Dear Editor,Stem cells,including pluripotent stem cells and adult stem cells,possess the remarkable capability of being able to selfrenew while at the same time having potential to differentiate into different cell lineages and functionally distinct cell types.Human embryonic stem cells(hESCs)can differentiate into all adult stem cell types,including human mesenchymal stem cells(hMSCs)and human neural stem cells(hNSCs),but can also give rise to all terminally differentiated cell types(Wang et al.,2021a).Through the continuous replenishment of differentiated cells,stem cells support tissue homeostasis and respond to tissue injuries.Given the promising applications of stem cells in cell therapy and regenerative medicine,insights into molecular events underlying stem cell maintenance,self-renewal ability and pluripotency,continue to garner strong interest(Shan et al.,2021).Although metabolic pathways have been implicated in the reciprocal regulations of stem cell self-renewal and differentiation as well as organ homeostatic maintenance(Garcia-Prat et al.,2017),central aspects of how metabolic requirements differ and are regulated across the various types of human stem cells in our body remain enigmatic.