Single-nucleus transcriptomic landscape of primate hippocampal aging

The hippocampus plays a crucial role in learning and memory,and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases.Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing.Here,we reported a variety of new aging-associated phenotypic changes of the primate hippocampus.These include,in particular,increased DNA damage and heterochromatin erosion with time,alongside loss of proteostasis and elevated inflammation.To understand their cellular and molecular causes,we established the first single-nucleus transcriptomic atlas of primate hippocampal aging.Among the 12 identified cell types,neural transiently amplifying progenitor cell(TAPC)and microglia were most affected by aging.In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory;additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte,as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis.This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

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).

DJ-1 is dispensable for human stem cell homeostasis

Dear Editor,Safeguard!ng cellular redox homeostasis is crucial for maintaining organism health and preventing diseases.Oxidative stress,often characterized by decreased mitochondrial integrity and increased reactive oxygen species(ROS)product!on,disrupts proteostasis and genomic stability,which may eventually lead to cellular decomposition(Oh et al.,2014).Stem cells(such as mesenchymal stem cells,MSCs,and neural stem cells,NSCs)are susceptible to various external and internal stresses,and their dysfunction con tributes to aging and agin g-related diseases.Thus,it is of importance to elucidate the complex signaling networks regulated by oxidative stress in stem cells.Although redox signaling has been implicated in multiple cellular processes,how the redox system functions in various human stem cells is unclear.

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.