Aging Cell最新文献

{"title":"Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)","authors":"Cole J. Lukasiewicz,&nbsp;Gregory J. Tranah,&nbsp;Daniel S. Evans,&nbsp;Paul M. Coen,&nbsp;Haley N. Barnes,&nbsp;Zhiguang Huo,&nbsp;Karyn A. Esser,&nbsp;Xiping Zhang,&nbsp;Christopher Wolff,&nbsp;Kevin Wu,&nbsp;Nancy E. Lane,&nbsp;Steven B. Kritchevsky,&nbsp;Anne B. Newman,&nbsp;Steven R. Cummings,&nbsp;Peggy M. Cawthon,&nbsp;Russell T. Hepple","doi":"10.1111/acel.14115","DOIUrl":"10.1111/acel.14115","url":null,"abstract":"<p>With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO_2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO_2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236542","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":"A novel senolytic drug for pulmonary fibrosis: BTSA1 targets apoptosis of senescent myofibroblasts by activating BAX","authors":"Mengxia Shen,&nbsp;Jiafeng Fu,&nbsp;Yunna Zhang,&nbsp;Yanfen Chang,&nbsp;Xiaohong Li,&nbsp;Haipeng Cheng,&nbsp;Yujia Qiu,&nbsp;Min Shao,&nbsp;Yang Han,&nbsp;Yan Zhou,&nbsp;Ziqiang Luo","doi":"10.1111/acel.14229","DOIUrl":"10.1111/acel.14229","url":null,"abstract":"<p>Idiopathic pulmonary fibrosis is a progressive and age-related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL-2 and BCL-XL, leading to BAX inactivation. We further showed that high levels of inactive BAX-mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (QVD-OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1-activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236539","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":"Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice","authors":"Zhun Wang,&nbsp;Jinpeng Dong,&nbsp;Mengxue Zhang,&nbsp;Sixuan Wang,&nbsp;Jiangnan Wu,&nbsp;Shengran Wang,&nbsp;Yuan Luo,&nbsp;Yongan Wang,&nbsp;Yiqing Yin","doi":"10.1111/acel.14209","DOIUrl":"10.1111/acel.14209","url":null,"abstract":"<p>Perioperative neurocognitive disorder (PND) is a serious neurologic complication in aged patients and might be associated with sevoflurane exposure. However, the specific pathogenesis is still unclear. The distribution of α5-GABA_AR, a γ-aminobutyric acid type A receptor (GABA_AR) subtype, at extrasynaptic sites is influenced by the anchor protein radixin, whose phosphorylation is regulated via the RhoA/ROCK2 signaling pathway and plays a crucial role in cognition. However, whether sevoflurane affects the ability of radixin phosphorylation to alter extrasynaptic receptor expression is unknown. Aged mice were exposed to sevoflurane to induce cognitive impairment. Both total proteins and membrane proteins were extracted for analysis. Cognitive function was evaluated using the Morris water maze and fear conditioning test. Western blotting was used to determine the expression of ROCK2 and the phosphorylation of radixin. Furthermore, the colocalization of p-radixin and α5-GABA_AR was observed. To inhibit ROCK2 activity, either an adeno-associated virus (AAV) or fasudil hydrochloride was administered. Aged mice treated with sevoflurane exhibited significant cognitive impairment accompanied by increased membrane expression of α5-GABA_AR. Moreover, the colocalization of α5-GABA_AR and p-radixin increased after treatment with sevoflurane, and this change was accompanied by an increase in ROCK2 expression and radixin phosphorylation. Notably, inhibiting the RhoA/ROCK2 pathway significantly decreased the distribution of extrasynaptic α5-GABA_AR and improved cognitive function. Sevoflurane activates the RhoA/ROCK2 pathway and increases the phosphorylation of radixin. Excess α5-GABA_AR is anchored to extrasynaptic sites and impairs cognitive ability in aged mice. Fasudil hydrochloride administration improves cognitive function.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198680","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":"Age-related changes to macrophage subpopulations and TREM2 dysregulation characterize attenuated fracture healing in old mice","authors":"Daniel Clark,&nbsp;Sloane Brazina,&nbsp;Ted Miclau,&nbsp;Sangmin Park,&nbsp;Christine L. Hsieh,&nbsp;Mary Nakamura,&nbsp;Ralph Marcucio","doi":"10.1111/acel.14212","DOIUrl":"10.1111/acel.14212","url":null,"abstract":"<p>Fracture healing complications increase with age, with higher rates of delayed unions and nonunions and an associated increase in morbidity and mortality in older adults. Macrophages have a dynamic role in fracture healing, and we have previously demonstrated that age-related changes in macrophages are associated with attenuated fracture repair in old mice. Here, we provide a single cell characterization of the immune cells involved in the early phase of fracture healing. We show that there were multiple transcriptionally distinct macrophage subpopulations present simultaneously within the healing tissue. Fracture healing was attenuated in old mice compared to young, and macrophages from the fracture callus of old mice demonstrated a pro-inflammatory phenotype compared to young. Interestingly, Trem2 expression was decreased in old macrophages compared to young. Young mice lacking Trem2 demonstrated attenuated fracture healing and inflammatory dysregulation similar to old mice. Trem2 dysregulation has previously been implicated in other age-related diseases, but its role in fracture healing is unknown. This work provides a robust characterization of the macrophage subpopulations involved in fracture healing, and further reveals the important role of Trem2 in fracture healing and may be a potential driver of age-related inflammatory dysregulation. Future work may further examine macrophages and Trem2 as potential therapeutic targets for management of fracture repair in older adults.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198671","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":"Mapping the unicellular transcriptome of the ascending thoracic aorta to changes in mechanosensing and mechanoadaptation during aging","authors":"Cristobal F. Rivera,&nbsp;Yasmeen M. Farra,&nbsp;Michele Silvestro,&nbsp;Steven Medvedovsky,&nbsp;Jacqueline Matz,&nbsp;Muhammad Yogi Pratama,&nbsp;John Vlahos,&nbsp;Bhama Ramkhelawon,&nbsp;Chiara Bellini","doi":"10.1111/acel.14197","DOIUrl":"10.1111/acel.14197","url":null,"abstract":"<p>Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo-1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198676","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":"Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium","authors":"Edwina Yeung,&nbsp;Richard J. Biedrzycki,&nbsp;Laura C. Gómez Herrera,&nbsp;Prachand Issarapu,&nbsp;John Dou,&nbsp;Irene Fontes Marques,&nbsp;Sohail Rafik Mansuri,&nbsp;Christian Magnus Page,&nbsp;Justin Harbs,&nbsp;Dennis Khodasevich,&nbsp;Eric Poisel,&nbsp;Zhongzheng Niu,&nbsp;Catherine Allard,&nbsp;Emma Casey,&nbsp;Fernanda Morales Berstein,&nbsp;Giulia Mancano,&nbsp;Hannah R. Elliott,&nbsp;Rebecca Richmond,&nbsp;Yiyan He,&nbsp;Justiina Ronkainen,&nbsp;Sylvain Sebert,&nbsp;Erin M. Bell,&nbsp;Gemma Sharp,&nbsp;Sunni L. Mumford,&nbsp;Enrique F. Schisterman,&nbsp;Giriraj R. Chandak,&nbsp;Caroline H. D. Fall,&nbsp;Sirazul A. Sahariah,&nbsp;Matt J. Silver,&nbsp;Andrew M. Prentice,&nbsp;Luigi Bouchard,&nbsp;Magnus Domellof,&nbsp;Christina West,&nbsp;Nina Holland,&nbsp;Andres Cardenas,&nbsp;Brenda Eskenazi,&nbsp;Lea Zillich,&nbsp;Stephanie H. Witt,&nbsp;Tabea Send,&nbsp;Carrie Breton,&nbsp;Kelly M. Bakulski,&nbsp;M. Daniele Fallin,&nbsp;Rebecca J. Schmidt,&nbsp;Dan J. Stein,&nbsp;Heather J. Zar,&nbsp;Vincent W. V. Jaddoe,&nbsp;John Wright,&nbsp;Regina Grazuleviciene,&nbsp;Kristine Bjerve Gutzkow,&nbsp;Jordi Sunyer,&nbsp;Anke Huels,&nbsp;Martine Vrijheid,&nbsp;Sophia Harlid,&nbsp;Stephanie London,&nbsp;Marie-France Hivert,&nbsp;Janine Felix,&nbsp;Mariona Bustamante,&nbsp;Weihua Guan","doi":"10.1111/acel.14194","DOIUrl":"10.1111/acel.14194","url":null,"abstract":"<p>Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (P_FDR &lt; 0.05). Eight of these CpGs were located near/in the <i>MTNR1B</i> gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near <i>MTNR1B</i>, at which higher DNAm was associated with greater maternal age (P_FDR = 6.92 × 10⁻⁸) in newborns. In childhood blood samples, these differences in blood DNAm of <i>MTNR1B</i> CpGs were nominally significant (<i>p</i> &lt; 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in <i>RTEL1-TNFRSF6B</i> at birth (P_FDR &lt; 0.05) and nominally in childhood (<i>p</i> &lt; 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in <i>YPEL3/BOLA2B</i> in external data was associated with expression of <i>ITGAL</i>, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160044","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":"Unveiling ceramide dynamics: Shedding light on healthy aging in growth hormone-releasing hormone knockout mice","authors":"Alexander Tate Lasher,&nbsp;Liping Wang,&nbsp;Jooyoung Hyun,&nbsp;Scott A. Summers,&nbsp;Liou Y. Sun","doi":"10.1111/acel.14226","DOIUrl":"10.1111/acel.14226","url":null,"abstract":"<p>Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth hormone-releasing hormone knockout (GHRH-KO) female mice and their littermate controls. Employing a targeted lipidomic approach, we specifically investigated ceramide levels in GHRH-KO mice, a well-established model of enhanced longevity. While younger GHRH-KO mice did not exhibit notable differences in serum lipids, older counterparts demonstrated significant reductions in over one-third of the evaluated lipids. In employing the same analysis in liver tissue, GHRH-KO mice showed pronounced downregulation of numerous ceramides and hexosylceramides, which have been shown to elicit many of the tissue defects that accompany aging (e.g., insulin resistance, oxidative stress, and cell death). Additionally, gene expression analysis in the liver tissue of adult GHRH-KO mice identified substantial decreases in several ceramide synthesis genes, indicating that these alterations are, at least in part, attributed to GHRH-KO-induced transcriptional changes. These findings provide the first evidence of disrupted ceramide metabolism in a long-lived mammal. This study sheds light on the intricate connections between GH deficiency, ceramide levels, and the molecular mechanisms influencing lifespan extension.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160083","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":"Long-term demyelination and aging-associated changes in mice corpus callosum; evidence for the role of accelerated aging in remyelination failure in a mouse model of multiple sclerosis","authors":"Elham Parandavar,&nbsp;Mahshid Shafizadeh,&nbsp;Shahin Ahmadian,&nbsp;Mohammad Javan","doi":"10.1111/acel.14211","DOIUrl":"10.1111/acel.14211","url":null,"abstract":"<p>Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder affecting the central nervous system. Evidence suggests that age-related neurodegeneration contributes to disability progression during the chronic stages of MS. Aging is characterized by decreased regeneration potential and impaired myelin repair in the brain. It is hypothesized that accelerated cellular aging contributes to the functional decline associated with neurodegenerative diseases. We assessed the impact of aging on myelin content in the corpus callosum (CC) and compared aging with the long-term demyelination (LTD) consequents induced by 12 weeks of feeding with a cuprizone (CPZ) diet. Initially, evaluating myelin content in 2-, 6-, and 18-month-old mice revealed a reduction in myelin content, particularly at 18 months. Myelin thickness was decreased and the g-ratio increased in aged mice. Although a lower myelin content and higher g-ratio were observed in LTD model mice, compared to the normally aged mice, both aging and LTD exhibited relatively similar myelin ultrastructure. Our findings provide evidence that LTD exhibits the hallmarks of aging such as elevated expression of senescence-associated genes, mitochondrial dysfunction, and high level of oxidative stress as observed following normal aging. We also investigated the senescence-associated β-galactosidase activity in O4⁺ late oligodendrocyte progenitor cells (OPCs). The senescent O4⁺/β-galactosidase⁺ cells were elevated in the CPZ diet. Our data showed that the myelin degeneration in CC occurs throughout the lifespan, and LTD induced by CPZ accelerates the aging process which may explain the impairment of myelin repair in patients with progressive MS.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157071","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":"Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations","authors":"Sarah A. Ashiqueali,&nbsp;Augusto Schneider,&nbsp;Xiang Zhu,&nbsp;Ewelina Juszczyk,&nbsp;Mishfak A. M. Mansoor,&nbsp;Yun Zhu,&nbsp;Yimin Fang,&nbsp;Bianka M. Zanini,&nbsp;Driele N. Garcia,&nbsp;Natalie Hayslip,&nbsp;David Medina,&nbsp;Samuel McFadden,&nbsp;Robert Stockwell,&nbsp;Rong Yuan,&nbsp;Andrzej Bartke,&nbsp;Michael Zasloff,&nbsp;Shadab Siddiqi,&nbsp;Michal M. Masternak","doi":"10.1111/acel.14227","DOIUrl":"10.1111/acel.14227","url":null,"abstract":"<p>Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (<i>Ptp1b</i>), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (<i>Pi3k</i>), protein kinase B (<i>Akt</i>), and mammalian target of rapamycin (<i>Mtor</i>) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154219","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":"Translatability of life-extending pharmacological treatments between different species","authors":"Daiana Burdusel,&nbsp;Cristin Coman,&nbsp;Diana–Larisa Ancuta,&nbsp;Dirk M. Hermann,&nbsp;Thorsten R. Doeppner,&nbsp;Andrei Gresita,&nbsp;Aurel Popa-Wagner","doi":"10.1111/acel.14208","DOIUrl":"10.1111/acel.14208","url":null,"abstract":"<p>Anti-aging research has made significant strides in identifying treatments capable of extending lifespan across a range of organisms, from simple invertebrates to mammals. This review showcases the current state of anti-aging interventions, highlighting the lifespan extensions observed in animal models through various treatments and the challenges encountered in translating these findings to humans. Despite promising results in lower organisms, the translation of anti-aging treatments to human applications presents a considerable challenge. This discrepancy can be attributed to the increasing complexity of biological systems, species-specific metabolic and genetic differences, and the redundancy of metabolic pathways linked to longevity. Our review focuses on analyzing these challenges, offering insights into the efficacy of anti-aging mechanisms across species and identifying key barriers to their translation into human treatments. By synthesizing current knowledge and identifying gaps in translatability, this review aims to underscore the importance of advancing these therapies for human benefit. Bridging this gap is essential to assess the potential of such treatments in extending the human healthspan.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154244","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}