GeroScience最新文献

{"title":"Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment","authors":"Boglarka Csik, Kiana Vali Kordestan, Rafal Gulej, Roland Patai, Adam Nyul-Toth, Santny Shanmugarama, Peter Mukli, Anna Ungvari, Karl E. Balsara, Rene Y. McNall, Talayeh Razzaghi, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar","doi":"10.1007/s11357-025-01560-6","DOIUrl":"https://doi.org/10.1007/s11357-025-01560-6","url":null,"abstract":"<p>The increasing number of cancer survivors has brought heightened attention to the side effects of cancer therapies, including chemotherapy-related cognitive impairment (CRCI, commonly referred to as “chemobrain”). Cisplatin and methotrexate, commonly used first-line chemotherapeutics in gynecologic oncology for cancers such as breast, ovarian, and bladder cancer, are clinically associated with long-term cognitive deficits. Building on our previous preclinical studies demonstrating that paclitaxel chemotherapy induces cerebrovascular endothelial and microglial senescence—leading to blood–brain barrier (BBB) disruption, neuroinflammation, and cognitive impairments—we hypothesized that cisplatin and methotrexate might similarly promote senescence in these cells. Senescent endothelial cells and microglia are known to contribute to neuroinflammation, cerebral blood flow dysregulation, and white matter damage, exacerbating cognitive decline. Using the p16-3MR mouse model, which expresses red fluorescent protein (RFP) in p16 + senescent cells, we evaluated the impact of these drugs on brain endothelial and microglial senescence through flow cytometry. Our results show a significant increase in senescent endothelial and microglial cells two months post-treatment with cisplatin or methotrexate compared to controls. These findings offer new insights into the shared mechanisms underlying CRCI associated with cisplatin or methotrexate treatment, extending our understanding of chemotherapy-induced vascular cognitive impairments.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"14 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma homocysteine level and trajectories in association with longitudinal increase in plasma neurofilament light among urban adults","authors":"May A. Beydoun, Nicole Noren Hooten, Michael F. Georgescu, Hind A. Beydoun, Marie T. Fanelli-Kuczmarski, Jordan Weiss, Michele K. Evans, Alan B. Zonderman","doi":"10.1007/s11357-025-01567-z","DOIUrl":"https://doi.org/10.1007/s11357-025-01567-z","url":null,"abstract":"<p>We tested whether homocysteine (Hcy) was linked to longitudinal change in plasma neurofilament light chain (NfL) overall and differentially across sex and race in a sample of middle-aged urban adults. We used data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study [<i>n</i> = 690, Age at visit 1 (v₁:2004–2009): 30-66y, 42.1% male, 55.4% African American] to evaluate relationships between NfL levels and both visit 1 Hcy (Hcy_v1) and time-dependent Hcy concentrations (Hcy_td). Specifically, we examined the relationship between these measures and visit 1 NfL (NfL_v1) as well as annualized change in NfL (δNfL) over the study period of ~ 8y [2004–2009 (v₁), 2009–2013 (v₂) and/or 2013–2017 (v₃)] using mixed effects linear regression models. Hcy_v1 was positively associated with NfL_v1, but not with δNfL. However, when Hcy_td was considered along with time-dependent covariates on multiple-imputed data, both NfL_v1 and δNfL were associated with Hcy_td, with some significant sex difference in the longitudinal association, whereby this relationship was stronger among males. The Hcy exposure obtained from group-based trajectory models, indicated that individuals belonging to the \"High increasing\" group were consistently associated with both higher NfL_v1 and faster increase in NfL (overall, fully adjusted, High <i>vs</i>. Low: γ_0gbtm = + 0.226 ± 0.058, P &lt; 0.001; γ_1gbtm = + 0.022 ± 0.007, P &lt; 0.010). Dynamic Hcy exposures (Hcy_td and Hcy_gbtm) were associated with faster rate of increase in NfL over time, reflecting potentially faster rate of axonal degeneration. Further studies are needed in comparable populations to replicate our findings.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"19 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats","authors":"Anna Szilágyi, Barbara Takács, Réka Szekeres, Vera Tarjányi, Dávid Nagy, Dániel Priksz, Mariann Bombicz, Rita Kiss, Adrienn Mónika Szabó, Andrea Lehoczki, Rudolf Gesztelyi, Béla Juhász, Zoltán Szilvássy, Balázs Varga","doi":"10.1007/s11357-025-01558-0","DOIUrl":"https://doi.org/10.1007/s11357-025-01558-0","url":null,"abstract":"","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"361 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intact embodiment during perspective-taking in older adults is not affected by focal tDCS","authors":"Mandy Roheger, Anna Mäder, Steffen Riemann, Filip Niemann, Klaus Kessler, Andrew K. Martin, Marcus Meinzer","doi":"10.1007/s11357-025-01554-4","DOIUrl":"https://doi.org/10.1007/s11357-025-01554-4","url":null,"abstract":"<p>Embodied processing is crucial for visual perspective taking (VPT), with evidence from non-invasive transcranial direct current stimulation (tDCS) suggesting a causal role of the right temporoparietal junction (rTPJ). However, it is not known whether such embodied factors are maintained in older adults or whether rTPJ-tDCS has comparable effects in advanced age. We employed a balanced and sham-tDCS controlled, double-blinded, cross-over design, including two randomized experimental groups of healthy older adults, receiving focal tDCS over either the rTPJ (<i>n</i> = 30), or a control region in the dorsomedial prefrontal cortex (dmPFC, <i>n</i> = 30). A healthy young control group (<i>n</i> = 30, not receiving tDCS) was included to investigate potential changes in embodied processing in older adults. All groups completed neuropsychological baseline testing and an experimental VPT paradigm, in which perspective-taking (requiring embodied rotation) and perspective-tracking (line-of-sight judgements) were assessed. Structural magnetic resonance imaging data were acquired to conduct individualized current flow simulations, aimed at identifying potential changes in neurophysiological effects of tDCS in older adults. Older adults responded slower across perspective tracking and perspective taking tasks but showed comparable embodied effects of body posture and angle of rotation during perspective taking. Contrary to previous results in younger adults that demonstrated regionally and task-specific effects of focal rTPJ-tDCS, no stimulation effects on embodied processing were found in older adults. Electrical field simulations suggested focal current delivery in both age-groups but also significantly reduced current strength in the target regions for tDCS in older adults. Older adults are as embodied as young adults during perspective taking. However, tDCS administered to the rTPJ or dmPFC had no effect, which may be explained by reduced current delivery to the target regions due to age-associated changes in skull and brain anatomy and/or functional brain reorganization. Our results are in line with previous studies suggesting that tDCS effects obtained in young participants may not translate directly to advanced age. Future studies could address this by using individualized modelling approaches aimed at adjusting current dose for (older) study participants and pre-stimulation functional imaging involving VPT tasks-of-interest, to identify optimized target regions for tDCS.</p><p>Registration: ClinicalTrials.gov Identifier: NCT04633499.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"80 6 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Center frequency as optimal frequency of visual stimulation for spreading entrained gamma rhythms to other target brain regions in cognitively normal older adults","authors":"Euisuk Yoon, Yeseung Park, Hong Jun Kim, Jaehyeok Park, Ji Won Han, Se Joon Woo, Seunghyup Yoo, Ki Woong Kim","doi":"10.1007/s11357-025-01552-6","DOIUrl":"https://doi.org/10.1007/s11357-025-01552-6","url":null,"abstract":"<p>Gamma entrainment using 40 Hz sensory stimulation has shown promise in AD mouse models, but inconsistent results in AD patients, possibly due to interspecies and interindividual differences in center frequency (CF). This study aimed to investigate whether gamma rhythms entrained by visual stimulation at an individual’s CF can spread better than those at other frequency conditions in older adults. We entrained gamma rhythms in 32 cognitively normal older participants using light flickering at 32 Hz, 34 Hz, 36 Hz, 38 Hz, and 40 Hz. We identified each individual’s CF among these five frequencies and compared the spread, strength, and stability of gamma connectivity induced by light stimulation flickering at an individual’s CF with those at other frequencies using generalized estimating equation and repeated measures ANOVA. In about two-thirds of the participants, 32 Hz (40.6%) and 34 Hz (28.1%) were identified as CF. The mean spread, strength, and stability of gamma connectivity involving the visual cortex (GC_V-NV) were higher than those do not involve the visual cortex (GC_NV-NV, <i>p</i> &lt; 0.05). Between the visual cortex and other brain regions, FLS induced with frequencies of high event related spectral perturbation values, including CF and non-center frequency (NCF) 1, generally induced broader, stronger, and more stable gamma connectivity compared to most other NCFs (<i>p</i> &lt; 0.001 when comparing NCFs with either CF and NCF1 for both strength and spread; <i>p</i> = 0.012 when comparing CF and NCF3 for stability). Gamma rhythms entrained by visual stimulation may better spread to other brain regions when its frequency matched to the individual’s CF.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"6 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Test of Rapamycin in Aging Dogs (TRIAD): study design and rationale for a prospective, parallel-group, double-masked, randomized, placebo-controlled, multicenter trial of rapamycin in healthy middle-aged dogs from the Dog Aging Project.","authors":"Amanda E Coleman, Kate E Creevy, Rozalyn Anderson, May J Reed, Virginia R Fajt, Kathleen M Aicher, Genna Atiee, Brian G Barnett, Ryan D Baumwart, Beth Boudreau, Suzanne M Cunningham, Matthew D Dunbar, Bobbie Ditzler, Anna M Ferguson, Kiersten K Forsyth, Anya N Gambino, Sonya G Gordon, Hillary K Hammond, Sydney N Holland, Mary K Iannaccone, Kate Illing, Saki Kadotani, Shelby A Knowles, Evan L MacLean, Brian A Maran, Lauren E Markovic, Stephanie McGrath, Rachel L Melvin, Mikaela S Mueller, O Lynne Nelson, Natasha J Olby, Theresa E Pancotto, Elizabeth Parsley, Brianna M Potter, Jena O Prescott, Ashley B Saunders, Holly M Sawyer, Brian A Scansen, Sarah M Schmid, Courtney C Smith, Sonja S Tjostheim, M Katherine Tolbert, Melissa A Tropf, Lance C Visser, Jessica L Ward, Sonya R Wesselowski, Rebecca C Windsor, Vicky K Yang, Audrey Ruple, Daniel E L Promislow, Matt Kaeberlein","doi":"10.1007/s11357-024-01484-7","DOIUrl":"10.1007/s11357-024-01484-7","url":null,"abstract":"<p><p>Companion dogs are a powerful model for aging research given their morphologic and genetic variability, risk for age-related disease, and habitation of the human environment. In addition, the shorter life expectancy of dogs compared to human beings provides a unique opportunity for an accelerated timeline to test interventions that might extend healthy lifespan. The Test of Rapamycin In Aging Dogs (TRIAD) randomized clinical trial is a parallel-group, double-masked, randomized, placebo-controlled, multicenter trial that will test the ability of rapamycin to prolong lifespan and improve several healthspan metrics in healthy, middle-aged dogs recruited from Dog Aging Project participants. Here, we describe the rationale, design, and goals of the TRIAD randomized clinical trial, the first rigorous test of a pharmacologic intervention against biological aging with lifespan and healthspan metrics as endpoints to be performed outside of the laboratory in any species.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose chemokine ligand CX3CL1 contributes to maintaining the hippocampal BDNF level, and the effect is attenuated in advanced age","authors":"Yoshinori Takei, Yoko Amagase, Ai Goto, Ryuichi Kambayashi, Hiroko Izumi-Nakaseko, Akira Hirasawa, Atsushi Sugiyama","doi":"10.1007/s11357-025-01546-4","DOIUrl":"https://doi.org/10.1007/s11357-025-01546-4","url":null,"abstract":"<p>Aging alters signaling that involves brain-derived neurotrophic factor (BDNF) in the hippocampus. An adequate level of BDNF is essential for maintaining cognitive function in older adults. Previously, we showed that repeated intraperitoneal administration of the chemokine ligand CX3CL1 modulates peritoneal immune cells and the vagal nerve to increase hippocampal BDNF, consequently improving cognitive decline in aged mice. Here, we examined the contribution of endogenous CX3CL1 in the peritoneal cavity to the age-associated regulation of hippocampal BDNF levels. Hippocampal BDNF protein levels were comparable between 5-month-old and 10-month-old mice but were reduced in 18-month-old. CX3CL1 expression in the visceral adipose tissue, which is prominent in the peritoneal cavity, was also lower in 18-month-old mice than in 10-month-old mice. Visceral adipose tissue-specific knockdown of CX3CL1 reduced hippocampal BDNF levels in 10-month-old mice. Reciprocally, a single intraperitoneal injection of CX3CL1 recovered hippocampal BDNF levels in 18-month-old mice. Moreover, the naturally occurring glucocorticoids, corticosterone and hydrocortisone, increased CX3CL1 expression in a concentration-dependent manner. In the visceral adipose tissue, both protein level and enzymatic activity of the glucocorticoid activating enzyme 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1) were lower in 18-month-old mice than in 10-month-old. Tissue-specific knockdown of 11β-HSD1 in visceral adipose tissue decreased both adipose CX3CL1 expression and hippocampal BDNF levels in 10-month-old mice. Our results demonstrate that adipose CX3CL1 is involved in maintaining hippocampal BDNF levels. This inter-tissue crosstalk is impaired in aged mice due to low 11β-HSD1 expression in visceral adipose tissue, which contributes to the age-associated decline in hippocampal BDNF.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"62 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measuring thymic output across the human lifespan: a critical challenge in laboratory medicine","authors":"Vera Middelkamp, Eliisa Kekäläinen","doi":"10.1007/s11357-025-01555-3","DOIUrl":"https://doi.org/10.1007/s11357-025-01555-3","url":null,"abstract":"<p>Age-associated thymic involution leads to a significant decline in thymic T cell output, a major contributor to immunosenescence in the elderly. Accurately measuring thymic output is therefore critical for understanding the mechanisms behind immune aging. Furthermore, robust quantification of thymic output is essential in various other clinical and research settings, including the diagnosis of immunodeficiencies and the monitoring of T cell reconstitution following therapeutic interventions like hematopoietic stem cell transplantation. Current methodologies for measuring thymic output include T cell receptor excision circle (TREC) quantification via quantitative polymerase chain reaction and the enumeration of recent thymic emigrants (RTEs) using flow cytometry. However, TREC-based assays are inherently insensitive to subtle changes in thymic output, limiting their applicability beyond neonatal immunodeficiency screening. Similarly, RTE enumeration presents challenges; while surface markers exist for CD4⁺ RTEs, validated markers for CD8⁺ cytotoxic T lymphocytes are lacking. This represents a significant knowledge gap, particularly as aging has been shown to disproportionally affect the CD8 T cell pool. Moreover, while flow cytometry effectively measures mature naïve T cells, these cells do not accurately represent real-time thymic output, as they can persist in peripheral circulation for extended periods. These limitations highlight the pressing need for more accurate and sensitive methods to assess thymic output. Improved measurement techniques would not only enhance our understanding of thymic involution in the context of aging but also enable large-scale investigations into thymic function and the mechanisms driving its decline in both health and disease. In this review, we examine current methodologies for measuring thymic output in humans, critically evaluate their limitations, and discuss emerging approaches to address these gaps in the field.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"3 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-omic single-cell landscape of the aging mouse ovary","authors":"Jian Zhang, Shunze Jia, Zehua Zheng, Lanrui Cao, Jingyi Zhou, Xudong Fu","doi":"10.1007/s11357-025-01556-2","DOIUrl":"https://doi.org/10.1007/s11357-025-01556-2","url":null,"abstract":"<p>The ovary is one of the first organs in humans to exhibit age-related functional impairments. As an organ composed of diverse heterogeneous cell types, the ovary exhibits cell-type-specific changes during the aging process, ultimately leading to a decline in female fertility. Investigating the molecular mechanisms of ovarian aging is crucial for understanding age-related fertility dysfunction in females. In this study, we combine scRNA-seq and scATAC-seq from mouse young/aged ovaries to characterize molecular features during ovarian aging. Using the single-cell multi-omic data, we revealed the cell-type-specific transcriptional changes during the aging process in seven major ovarian cell types and identified the cis/trans-regulatory elements governing these transcriptional changes. Specifically, we uncovered the transcriptional alterations of TGF-beta signaling in mesenchymal cells and endoplasmic reticulum stress in granulosa cells of aged mouse ovaries and further identified the potential corresponding cis/trans-regulatory elements. These molecular alterations may contribute to aging-induced functional impairments in mouse ovaries. In summary, this work provides transcriptome and chromatin accessibility landscape of ovarian aging in mice, which serve as a resource for identifying the cell-type-specific molecular mechanisms underlying ovarian aging, aiding in the identification of potential diagnostic biomarkers and treatment strategies.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"132 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan","authors":"Sabira Mohammed, Phoebe Ohene-Marfo, Chao Jiang, Zongkai Peng, Nidheesh Thadathil, Albert Tran, Evan Nicklas, Shylesh Bhaskaran, Dawei Wang, Ramasamy Selvarani, Amit Singh, Zhibo Yang, Nagib Ahsan, Sathyaseelan S. Deepa","doi":"10.1007/s11357-025-01553-5","DOIUrl":"https://doi.org/10.1007/s11357-025-01553-5","url":null,"abstract":"<p>Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3. The absence of Mlkl or Ripk3 significantly reduced liver inflammation, steatosis, and fibrosis in aged male mice, supporting the role of necroptosis in age-associated MASLD. Additionally, Mlkl or Ripk3 deletion impacted other non-necroptotic cellular processes that drive inflammation and MASLD, such as cellular senescence, apoptosis, and autophagy in aged liver. Levels of plasma TNFα and IL6, key proinflammatory cytokines associated with inflammaging, are reduced in <i>Mlkl</i>^{<i>−/−</i>} or <i>Ripk3</i>^{<i>−/−</i>} aged mice, supporting a systemic effect of necroptosis inhibition on inflammation. Proteomic analysis of liver tissues emphasizes the critical role of lipid and immune regulatory processes in maintaining liver homeostasis when Mlkl or Ripk3 is absent in aging liver. While Mlkl deletion did not affect the lifespan of mice, Ripk3 deletion shortened it. Additionally, Mlkl deficiency improved insulin sensitivity, whereas Ripk3 deficiency exacerbated glucose intolerance in aged mice. Thus, selective inhibition of Mlkl, not Ripk3, represents a potential therapeutic avenue for mitigating age-related liver disease and enhancing metabolic outcomes in the elderly.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"12 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}