Aging Cell最新文献

{"title":"Age-related dysregulation of the retinal transcriptome in African turquoise killifish","authors":"Steven Bergmans,&nbsp;Nicole C. L. Noel,&nbsp;Luca Masin,&nbsp;Ellen G. Harding,&nbsp;Aleksandra M. Krzywańska,&nbsp;Julie D. De Schutter,&nbsp;Rajagopal Ayana,&nbsp;Chi-Kuo Hu,&nbsp;Lut Arckens,&nbsp;Philip A. Ruzycki,&nbsp;Ryan B. MacDonald,&nbsp;Brian S. Clark,&nbsp;Lieve Moons","doi":"10.1111/acel.14192","DOIUrl":"10.1111/acel.14192","url":null,"abstract":"<p>Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNAseq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in the ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterized, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNAseq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasizes the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of sarcopenia with the long-term risk of atrial fibrillation: A prospective cohort study","authors":"Yiyang Tang,&nbsp;Zhenghui Liu,&nbsp;Qin Chen,&nbsp;Mukamengjiang Juaiti,&nbsp;Zaixin Yu,&nbsp;Benhui Liang,&nbsp;Lihuang Zha","doi":"10.1111/acel.14198","DOIUrl":"10.1111/acel.14198","url":null,"abstract":"<p>The relationship between sarcopenia and the long-term risk of atrial fibrillation (AF) remains unclear. This study recruited a large prospective Caucasian cohort from the UK Biobank. Participants were assessed at baseline with handgrip strength and muscle mass and were categorized into groups of non-sarcopenia, probable sarcopenia, and confirmed sarcopenia. Kaplan–Meier method and Cox proportional hazards model were used to explore the association between sarcopenia and the incidence of AF. The genetic predisposition of AF was assessed by polygenic risk score. Sensitivity analyses were performed to validate the results. A total of 384,433 participants with a median age of 58 years and 54.3% women were enrolled in this study. There were 24,007 cases of new-onset AF over a median follow-up of 12.56 years. The groups of non-sarcopenia, probable sarcopenia, and confirmed sarcopenia accounted for 22,290 (6.1%), 1665 (9.2%), and 52 (11.9%) cases, respectively. Compared with the non-sarcopenia group, participants with probable sarcopenia or confirmed sarcopenia had an 8% (95% CI, 1.03–1.14) or 61% (95% CI, 1.23–2.12) higher risk of AF incidence. The findings remained robust in multiple sensitivity analyses, such as subgroup analysis and further adjustment of genetic predisposition. Notably, the association between sarcopenia and a high AF risk was more pronounced in younger participants, women, and those with valvular heart disease. In conclusion, sarcopenia was associated with a high long-term risk of AF in Caucasians, supporting sarcopenia as a new independent risk factor of AF.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy”","authors":"","doi":"10.1111/acel.14183","DOIUrl":"10.1111/acel.14183","url":null,"abstract":"<p>Liu, H., Xu, Q., Wufuer, H., Li, Z., Sun, R., Jiang, Z., Dou, X., Fu, Q., Campisi, J., Sun, Y. 2024. Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy. <i>Aging Cell</i> 23(1): e13921; https://doi.org/10.1111/acel.13921</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14183","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation","authors":"Maria Elisa Caetano-Silva,&nbsp;Akriti Shrestha,&nbsp;Audrey F. Duff,&nbsp;Danica Kontic,&nbsp;Patricia C. Brewster,&nbsp;Mikaela C. Kasperek,&nbsp;Chia-Hao Lin,&nbsp;Derek A. Wainwright,&nbsp;Diego Hernandez-Saavedra,&nbsp;Jeffrey A. Woods,&nbsp;Michael T. Bailey,&nbsp;Thomas W. Buford,&nbsp;Jacob M. Allen","doi":"10.1111/acel.14190","DOIUrl":"10.1111/acel.14190","url":null,"abstract":"<p>Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin. Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic <i>Il6</i>, <i>Tnf</i>, and <i>Tlr4</i>) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge (Abx), with sustained elevation in <i>Escherichia</i> (Proteobacteria) and altered TLR5 immunogenicity 7 days post-Abx cessation. Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14190","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-pituitary growth hormone enables colon cell senescence evasion","authors":"Vera Chesnokova,&nbsp;Svetlana Zonis,&nbsp;Tugce Apaydin,&nbsp;Robert Barrett,&nbsp;Shlomo Melmed","doi":"10.1111/acel.14193","DOIUrl":"10.1111/acel.14193","url":null,"abstract":"<p>DNA damage-induced senescence is initially sustained by p53. Senescent cells produce a senescence-associated secretory phenotype (SASP) that impacts the aging microenvironment, often promoting cell transformation. Employing normal non-tumorous human colon cells (hNCC) derived from surgical biopsies and three-dimensional human intestinal organoids, we show that local non-pituitary growth hormone (npGH) induced in senescent cells is a SASP component acting to suppress p53. npGH autocrine/paracrine suppression of p53 results in senescence evasion and cell-cycle reentry, as evidenced by increased Ki67 and BrdU incorporation. Post-senescent cells exhibit activated epithelial-to-mesenchymal transition (EMT), and increased cell motility. Nu/J mice harboring GH-secreting HCT116 xenografts with resultant high GH levels and injected intrasplenic with post-senescent hNCC developed fourfold more metastases than did mice harboring control xenografts, suggesting that paracrine npGH enables post-senescent cell transformation. By contrast, senescent cells with suppressed npGH exhibit downregulated Ki67 and decreased soft agar colony formation. Mechanisms underlying these observations include npGH induction by the SASP chemokine CXCL1, which attracts immune effectors to eliminate senescent cells; GH, in turn, suppresses CXCL1, likely by inhibiting phospho-NFκB, resulting in SASP cytokine downregulation. Consistent with these findings, GH-receptor knockout mice exhibited increased colon phospho-NFκB and CXCL1, while GH excess decreased colon CXCL1. The results elucidate mechanisms for local hormonal regulation of microenvironmental changes in DNA-damaged non-tumorous epithelial cells and portray a heretofore unappreciated GH action favoring age-associated epithelial cell transformation.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative stress-related cellular aging causes dysfunction of the Kv3.1/KCNC1 channel reverted by melatonin","authors":"Sara Spinelli,&nbsp;Alessia Remigante,&nbsp;Raffaella Liuni,&nbsp;Gianluca Mantegna,&nbsp;Giuseppe Legname,&nbsp;Angela Marino,&nbsp;Rossana Morabito,&nbsp;Silvia Dossena","doi":"10.1111/acel.14185","DOIUrl":"10.1111/acel.14185","url":null,"abstract":"<p>The voltage-gated Kv3.1/KCNC1 channel is abundantly expressed in fast-spiking principal neurons and GABAergic inhibitory interneurons throughout the ascending auditory pathway and in various brain regions. Inactivating mutations in the <i>KCNC1</i> gene lead to forms of epilepsy and a decline in the expression of the Kv3.1 channel is involved in age-related hearing loss. As oxidative stress plays a fundamental role in the pathogenesis of epilepsy and age-related hearing loss, we hypothesized that an oxidative insult might affect the function of this channel. To verify this hypothesis, the activity and expression of endogenous and ectopic Kv3.1 were measured in models of oxidative stress-related aging represented by cell lines exposed to 100 mM d-galactose. In these models, intracellular reactive oxygen species, thiobarbituric acid reactive substances, sulfhydryl groups of cellular proteins, and the activity of catalase and superoxide dismutase were dysregulated, while the current density of Kv3.1 was significantly reduced. Importantly, the antioxidant melatonin reverted all these effects. The reduction of function of Kv3.1 was not determined by direct oxidation of amino acid side chains of the protein channel or reduction of transcript or total protein levels but was linked to reduced trafficking to the cell surface associated with Src phosphorylation as well as metabolic and endoplasmic reticulum stress. The data presented here specify Kv3.1 as a novel target of oxidative stress and suggest that Kv3.1 dysfunction might contribute to age-related hearing loss and increased prevalence of epilepsy during aging. The pharmacological use of the antioxidant melatonin can be protective in this setting.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetically determined blood pressure, antihypertensive drug classes, and frailty: A Mendelian randomization study","authors":"Zhenhuang Zhuang,&nbsp;Yueying Li,&nbsp;Yimin Zhao,&nbsp;Ninghao Huang,&nbsp;Wenxiu Wang,&nbsp;Wendi Xiao,&nbsp;Jie Du,&nbsp;Xue Dong,&nbsp;Zimin Song,&nbsp;Jinzhu Jia,&nbsp;Zhonghua Liu,&nbsp;Robert Clarke,&nbsp;Lu Qi,&nbsp;Tao Huang","doi":"10.1111/acel.14173","DOIUrl":"10.1111/acel.14173","url":null,"abstract":"<p>Observational studies have suggested that the use of antihypertensive drugs was associated with the risk of frailty; however, these findings may be biased by confounding and reverse causality. This study aimed to explore the effect of genetically predicted lifelong lowering blood pressure (BP) through different antihypertensive medications on frailty. One-sample Mendelian randomization (MR) and summary data-based MR (SMR) were applied. We utilized two kinds of genetic instruments to proxy the antihypertensive medications, including genetic variants within or nearby drugs target genes associated with systolic/diastolic BP, and expression level of the corresponding gene. Among 298,618 UK Biobank participants, one-sample MR analysis observed that genetically proxied BB use (relative risk ratios, 0.76; 95% CI, 0.65–0.90; <i>p</i> = 0.001) and CCB use (0.83; 0.72–0.95; <i>p</i> = 0.007), equivalent to a 10-mm Hg reduction in systolic BP, was significantly associated with lower risk of pre-frailty. In addition, although not statistically significant, the effect directions of systolic BP through ACEi variants (0.72; 0.39–1.33; <i>p</i> = 0.296) or thiazides variants (0.74; 0.53–1.03; <i>p</i> = 0.072) on pre-frailty were also protective. Similar results were obtained in analyses for diastolic BP. SMR of expression in artery showed that decreased expression level of KCNH2, a target gene of BBs, was associated with lower frailty index (beta −0.02, <i>p</i> = 2.87 × 10⁻⁴). This MR analysis found evidence that the use of BBs and CCBs was potentially associated with reduced frailty risk in the general population, and identified KCNH2 as a promising target for further clinical trials to prevent manifestations of frailty.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease","authors":"Xin-Rong Wu,&nbsp;Xiao-Na Zhu,&nbsp;Yuan-Bo Pan,&nbsp;Xue Gu,&nbsp;Xian-Dong Liu,&nbsp;Si Chen,&nbsp;Yu Zhang,&nbsp;Tian-Le Xu,&nbsp;Nan-Jie Xu,&nbsp;Suya Sun","doi":"10.1111/acel.14187","DOIUrl":"10.1111/acel.14187","url":null,"abstract":"<p>Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT_1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT_2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist β-amyloid peptides (Aβ) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical validation of C12FDG as a marker associated with senescence and osteoarthritic phenotypes","authors":"William S. Hambright,&nbsp;Victoria R. Duke,&nbsp;Adam D. Goff,&nbsp;Alex W. Goff,&nbsp;Lucas T. Minas,&nbsp;Heidi Kloser,&nbsp;Xueqin Gao,&nbsp;Charles Huard,&nbsp;Ping Guo,&nbsp;Aiping Lu,&nbsp;John Mitchell,&nbsp;Michael Mullen,&nbsp;Charles Su,&nbsp;Tamara Tchkonia,&nbsp;Jair M. Espindola Netto,&nbsp;Paul D. Robbins,&nbsp;Laura J. Niedernhofer,&nbsp;James L. Kirkland,&nbsp;Chelsea S. Bahney,&nbsp;Marc Philippon,&nbsp;Johnny Huard","doi":"10.1111/acel.14113","DOIUrl":"10.1111/acel.14113","url":null,"abstract":"<p>Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C₁₂FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C₁₂FDG⁺ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C₁₂FDG⁺ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C₁₂FDG⁺ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C₁₂FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140846725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal fluid proteomic profile of frailty: Results from the PROLIPHYC cohort","authors":"Sophie Guillotin,&nbsp;Amit Fulzele,&nbsp;Alexandra Vallet,&nbsp;Anne Gonzalez de Peredo,&nbsp;Emmanuelle Mouton-Barbosa,&nbsp;Philippe Cestac,&nbsp;Sandrine Andrieu,&nbsp;Odile Burlet-Schiltz,&nbsp;Nicolas Delcourt,&nbsp;Eric Schmidt","doi":"10.1111/acel.14168","DOIUrl":"10.1111/acel.14168","url":null,"abstract":"<p>Frailty is a clinical state reflecting a decrease in physiological reserve capacities, known to affect numerous biological pathways and is associated with health issues, including neurodegenerative diseases. However, how global protein expression is affected in the central nervous system in frail subject remains underexplored. In this post hoc cross-sectional biomarker analysis, we included 90 adults (52–85 years) suspected of normal pressure hydrocephalus (NPH) and presenting with markers of neurodegenerative diseases. We investigated the human proteomic profile of cerebrospinal fluid associated with frailty defined by an established cumulated frailty index (FI, average = 0.32), not enriched for neurology clinical features. Using a label-free quantitative proteomic approach, we identified and quantified 999 proteins of which 13 were positively associated with frailty. Pathway analysis with the top positively frailty-associated proteins revealed enrichment for proteins related to inflammation and immune response. Among the 60 proteins negatively associated with frailty, functional pathways enriched included neurogenesis, synaptogenesis and neuronal guidance. We constructed a frailty prediction model using ridge regression with 932 standardized proteins. Our results showed that the “proteomic model” could become an equivalent predictor of FI in order to study chronological age. This study represents the first comprehensive exploration of the proteomic profile of frailty within cerebrospinal fluid. It sheds light on the physiopathology of frailty, particularly highlighting processes of neuroinflammation and inhibition of neurogenesis. Our findings unveil a range of biological mechanisms that are dysregulated in frailty, in NPH subjects at risk of neurodegenerative impairment, offering new perspectives on frailty phenotyping and prediction.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}