Unraveling brain aging through the lens of oral microbiota

The oral cavity is a complex physiological community encompassing a wide range of microorganisms.Dysbiosis of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative diseases.Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention strategies.In this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration.We also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized.Here,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells.Upon in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging.In particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular senescence.This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis,a worldwide prevalent inflammatory disease.However,a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still lacking.Here,we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging,by which a panel of cell type-specific signatures were elucidated.Epithelial cells were identified as the most affected cell types by aging in the gingiva.Further analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis,which declined during aging in epithelial cells,especially in basal cells.The decline of YAP activity during aging was confrmed in the human gingival tissues,and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation effects.Our work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases,with the ultimate goal of advancing periodontal health and promoting healthy aging.

Ethical concerns in aging research:perspectives of global frontline researchers

This study investigated the ethical landscape of aging research amid the increasing global focus on extending the human lifespan and health span.Our global survey of 180 researchers across 38 jurisdictions revealed divergent perceptions of aging,a consensus regarding the feasibility of delaying aging,and multiple perspectives regarding lifespan extension.The present findings underscore a paradigm shift toward inclusive and ethically sound research,emphasizing the need for an approach that strikes a balance between basic and clinical research.In addition,this study highlighted key ethical concerns in aging research,including the effects of misleading advertising,potential inequality in access to aging interventions,and risks pertaining to the extrapolation of research findings from lower-model organisms to humans.The insights presented in this paper call for an integrated approach for overcoming the complex ethical and societal challenges in aging research to ensure responsible and equitable advancements in this burgeoning field.

Multimodal Omics Approaches to Aging and Age‑Related Diseases

Aging is associated with a progressive decline in physiological capacities and an increased risk of aging-associated disorders.An increasing body of experimental evidence shows that aging is a complex biological process coordinately regulated by multiple factors at diferent molecular layers.Thus,it is difcult to delineate the overall systematic aging changes based on single-layer data.Instead,multimodal omics approaches,in which data are acquired and analyzed using complementary omics technologies,such as genomics,transcriptomics,and epigenomics,are needed for gaining insights into the precise molecular regulatory mechanisms that trigger aging.In recent years,multimodal omics sequencing technologies that can reveal complex regulatory networks and specifc phenotypic changes have been developed and widely applied to decode aging and age-related diseases.This review summarizes the classifcation and progress of multimodal omics approaches,as well as the rapidly growing number of articles reporting on their application in the feld of aging research,and outlines new developments in the clinical treatment of age-related diseases based on omics technologies.

Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of infertility.However,the molecular basis of ovarian aging in higher vertebrates remains poorly understood.Herein,we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries.From a global view,somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region,likely constituting a hostile microenvironment that facilitates ovarian aging.Further,we uncovered that inflammation,the senescent-associated secretory phenotype,senescence,and fibrosis are the likely primary contributors to ovarian aging(PCOA).Of note,we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2(Metallothionein 2)highly expressing spot(MT2^(high))characterized by high levels of inflammation,potentially serving as an aging hotspot in the primate ovary.Moreover,with advanced age,a subpopulation of MT2^(high)accumulates,likely disseminating and amplifying the senescent signal outward.Our study establishes the first primate spatiotemporal transcriptomic atlas,advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

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.

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.

Single-nucleus transcriptomics reveals a gatekeeper role for FoxP1 in primate cardiac aging

Aging poses a major risk factor for cardiovascular diseases,the leading cause of death in the aged population.However,the cell type-specific changes underlying cardiac aging are far from being clear.Here,we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age.We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profles.Via transcription regulatory network analysis,we identified FOxP1,a core transcription factor in organ development,as a key downregulated factor in aged cardiomyocytes,concomitant with the dysregulation of FoxP1 target genes associated with heart function and cardiac diseases.Consistently,the deficiency of FOxP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes.Altogether,our findings depict the celiular and molecular landscape of ventricular aging at the single-cell resolution,and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.

A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis

The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.Here,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas.Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential continuum.Remarkably,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional profiles.Concomitantly,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for spermatogenesis.Collectively,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.

Single-nucleus profiling unveils a geroprotective role of the Foxo3 in primate skeletal muscle aging

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia,and increases the risk of many aging-related metabolic diseases.Here,we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging.A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types,indicating a higher susceptibility of skeletal muscle fiber to aging.We found a downregulation of Foxo3 in aged primate skeletal muscle,and identi-fied FOxo3 as a hub transcription factor maintaining skeletal muscle homeostasis.Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model,we revealed that silence of Foxo3 accelerates human myotube senescence,whereas genetic activation of endogenous FOxO3 alleviates human myotube aging.Altogether,based on a combination of monkey skeletal muscle and human myotube aging research models,we unraveled the pivotal role of the FOxO3 in safeguarding primate skeletal muscle from aging,providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-relateddisorders.

Single-cell transcriptomic atlas of mouse cochlear aging

Progressive functional deterioration in the cochlea is associated with age-related hearing loss(ARHL).However,the cellular and molecular basis underlying cochlear aging remains largely unknown.Here,we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging,in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points.Overall,our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging,highlights unexpected age-related transcriptional fluctuations in intermediate ceils localized in the stria vascularis(SV)and demonstrates that upregulation of endoplasmic reticulum(ER)chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging.Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related sVatrophyand hencedelay theprogressionofARHL.

The landscape of aging

Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.

Glutathione restoration: a sword to combat skeletal muscle stem cell aging

In a recent study published in Cell Metabolism,Thomas A.Rando and colleagues reported a critical role of dysregulated glutathione(GSH)metabolism in driving the aging process of skeletal muscle stem cells(MuSCs),uncovering a novel mechanism underlying the divergent responses of quiescent stem cells to environmental stressors with age,thus providing a potentially accessible target to alleviate age-associated skeletal muscle degeneration.

Fecal microbiota transplantation:A new strategy to delay aging

The gut microbiota,the community of gut microorganisms that inhabit the gastrointestinal tract,plays a crucial role in modulating host immunity,metabolism,and neurological health,thereby influencing the entire organism.Aging is associated with changes in gut microbiota composition and functionality,often resulting in dysbiosis,an imbalance of gut microbiota and an aging hallmark.Recent studies have suggested that fecal microbiota transplantation(FMT),the transfer of fecal material containing beneficial microbes from a healthy donor to a recipient with a disturbed microbiota,may restore the balance of host gut microbiota and ameliorate some aging-associated impairments in diverse organs.In particular,FMT from young donors has shown more beneficial effects than FMT from aged donors.In this paper,we review recent advances in FMT for its effects on aging and discuss the potential mechanisms and challenges of this novel intervention,highlighting its potential to improve health outcomes in the aging population.

Biomarkers of aging

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.

DNA methylation clocks for estimating biological age in Chinese cohorts

Epigenetic clocks are accurate predictors of human chronological age based on the analysis of DNA methylation(DNAm)at specific CpG sites.However,a systematic comparison between DNA methylation data and other omics datasets has not yet been performed.Moreover,available DNAm age predictors are based on datasets with limited ethnic representation.To address these knowledge gaps,we generated and analyzed DNA methylation datasets from two independent Chinese cohorts,revealing age-related DNAm changes.Additionally,a DNA methylation aging clock(iCAS-DNAmAge)and a group of DNAm-based multi-modal clocks for Chinese individuals were developed,with most of them demonstrating strong predictive capabilities for chronological age.The clocks were further employed to predict factors influencing aging rates.The DNAm aging clock,derived from multi-modal aging features(compositeAge-DNAmAge),exhibited a close association with multi-omics changes,lifestyles,and disease status,underscoring its robust potential for precise biological age assessment.Our findings offer novel insights into the regulatory mechanism of age-related DNAm changes and extend the application of the DNAm clock for measuring biological age and aging pace,providing the basis for evaluating aging intervention strategies.

Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological conditions.However,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive.Here,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(MsCs),as a platform for discovering cell type-specific hypox-ia-induced response mechanisms.Through comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular regeneration.We found human MSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKZF1,an effector of HIF-1a,impaired pro-angiogenic processes.Altogether,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

The synovium,a thin layer of tissue that is adjacent to the joints and secretes synovial fluid,undergoes changes in aging that contribute to intense shoulder pain and other joint diseases.However,the mechanism underlying human synovial aging remains poorly characterized.Here,we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged individuals.By delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks,we identified two subsets of mesenchymal stromal cells(MSCs)in human synovium,which are lining and sublining MSCs,and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged MSCs.Moreover,the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling,including vascular hyperplasia and tissue fibrosis.In particular,we identified forkhead box O1(FOXO1)as one of the major regulons for aging differentially expressed genes(DEGs)in synovial MSCs,and validated its downregulation in both lining and sublining MSC populations of the aged synovium.In human FOXO1-depleted MSCs derived from human embryonic stem cells,we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors.These data indicate an important role of FOXO1 in the regulation of human synovial aging.Overall,our study improves our understanding of synovial aging during joint degeneration,thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

Degeneration Directory:a multi-omics web resource for degenerative diseases

Background of database.Organ degeneration refers to the gradual decline in organ function and structure deterioration that occurs during aging,which represents the greatest risk factor for various degenerative diseases,including cardiovascular diseases,neurodegenerative diseases,and osteoarthritis,etc.(Aging Biomarker et al.,2023;Becker et al.,2018;Cai et al.,2022).