Aging biology最新文献

Pharmacology of Aging: Drosophila as a Tool to Validate Drug Targets for Healthy Lifespan. 衰老药理学：果蝇作为验证健康寿命药物靶点的工具。

Aging biology Pub Date : 2024-09-13 DOI: 10.59368/agingbio.20240034

Eliano Dos Santos, Helena M Cochemé

{"title":"Pharmacology of Aging: Drosophila as a Tool to Validate Drug Targets for Healthy Lifespan.","authors":"Eliano Dos Santos, Helena M Cochemé","doi":"10.59368/agingbio.20240034","DOIUrl":"https://doi.org/10.59368/agingbio.20240034","url":null,"abstract":"Finding effective therapies to manage age-related conditions is an emerging public health challenge. Although disease-targeted treatments are important, a preventive approach focused on aging can be more efficient. Pharmacological targeting of aging-related processes can extend lifespan and improve health in animal models. However, drug development and translation are particularly challenging in geroscience. Preclinical studies have survival as a major endpoint for drug screening, which requires years of research in mammalian models. Shorter-lived invertebrates can be exploited to accelerate this process. In particular, the fruit fly Drosophila melanogaster allows the validation of new drug targets using precise genetic tools and proof-of-concept experiments on drugs impacting conserved aging processes. Screening for clinically approved drugs that act on aging-related targets may further accelerate translation and create new tools for aging research. To date, 31 drugs used in clinical practice have been shown to extend the lifespan of flies. Here, we describe recent advances in the pharmacology of aging, focusing on Drosophila as a tool to repurpose these drugs and study age-related processes.","PeriodicalId":520022,"journal":{"name":"Aging biology","volume":"2 1","pages":"20240034"},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142336200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Damage-Induced Senescent Immune Cells Regulate Regeneration of the Zebrafish Retina. 损伤诱导的衰老免疫细胞调控斑马鱼视网膜的再生

Aging biology Pub Date : 2024-01-01 Epub Date: 2024-02-13 DOI: 10.59368/agingbio.20240021

Gregory J Konar, Zachary Flickinger, Shivani Sharma, Kyle T Vallone, Charles E Lyon, Claire Doshier, Audrey Lingan, William Lyon, James G Patton

{"title":"Damage-Induced Senescent Immune Cells Regulate Regeneration of the Zebrafish Retina.","authors":"Gregory J Konar, Zachary Flickinger, Shivani Sharma, Kyle T Vallone, Charles E Lyon, Claire Doshier, Audrey Lingan, William Lyon, James G Patton","doi":"10.59368/agingbio.20240021","DOIUrl":"10.59368/agingbio.20240021","url":null,"abstract":"Zebrafish spontaneously regenerate their retinas in response to damage through the action of Müller glia (MG). Even though MG are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration, with temporal roles for macrophages and microglia. Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging but are still metabolically active, releasing a variety of signaling molecules as part of the senescence-associated secretory phenotype. Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after N-methyl-D-aspartate damage. Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.","PeriodicalId":520022,"journal":{"name":"Aging biology","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ezetimibe Lowers Risk of Alzheimer's and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction. 依泽替米贝通过抑制 14-3-3G::Hexokinase 相互作用，减少模型系统中的聚集，从而将阿尔茨海默氏症和相关痴呆症的风险降低了七倍多。

Aging biology Pub Date : 2024-01-01 Epub Date: 2024-06-26 DOI: 10.59368/agingbio.20240028

Akshatha Ganne, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Ramani Atluri, Sonu Pahal, Joseph Asante, Corey Nagel, Srikanth Vallurupalli, Robert J Shmookler Reis, Srinivas Ayyadevara

{"title":"Ezetimibe Lowers Risk of Alzheimer's and Related Dementias over Sevenfold, Reducing Aggregation in Model Systems by Inhibiting 14-3-3G::Hexokinase Interaction.","authors":"Akshatha Ganne, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Ramani Atluri, Sonu Pahal, Joseph Asante, Corey Nagel, Srikanth Vallurupalli, Robert J Shmookler Reis, Srinivas Ayyadevara","doi":"10.59368/agingbio.20240028","DOIUrl":"https://doi.org/10.59368/agingbio.20240028","url":null,"abstract":"Numerous factors predispose to progression of cognitive impairment to Alzheimer's disease and related dementias (ADRD), most notably age, APOE(ε4) alleles, traumatic brain injury, heart disease, hypertension, obesity/diabetes, and Down's syndrome. Protein aggregation is diagnostic for neurodegenerative diseases, and may be causal through promotion of chronic neuroinflammation. We isolated aggregates from postmortem hippocampi of ADRD patients, heart-disease patients, and age-matched controls. Aggregates, characterized by high-resolution proteomics (with or without crosslinking), were significantly elevated in heart-disease and ADRD hippocampi. Hexokinase-1 (HK1) and 14-3-3G/γ proteins, previously implicated in neuronal signaling and neurodegeneration, are especially enriched in ADRD and heart-disease aggregates vs. controls (each P<0.008), and their interaction was implied by extensive crosslinking in both disease groups. Screening the hexokinase-1::14-3-3G interface with FDA-approved drug structures predicted strong affinity for ezetimibe, a benign cholesterol-lowering medication. Diverse cultured human-cell and whole-nematode models of ADRD aggregation showed that this drug potently disrupts HK1::14-3-3G adhesion, reduces disease-associated aggregation, and activates autophagy. Mining clinical databases supports drug reduction of ADRD risk, decreasing it to 0.14 overall (P<0.0001; 95% C.I. 0.06-0.34), and <0.12 in high-risk heart-disease subjects (P<0.006). These results suggest that drug disruption of the 14-3-3G::HK1 interface blocks an early \"lynchpin\" adhesion, prospectively reducing aggregate accrual and progression of ADRD.","PeriodicalId":520022,"journal":{"name":"Aging biology","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11389752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ketogenic Diet Reduces Age-Induced Chronic Neuroinflammation in Mice. 生酮饮食减少小鼠年龄诱导的慢性神经炎症。

Aging biology Pub Date : 2024-01-01 Epub Date: 2024-12-16 DOI: 10.59368/agingbio.20240038

Mitsunori Nomura, Natalia Faraj Murad, Sidharth S Madhavan, Wei-Chieh Mu, Brenda Eap, Thelma Y Garcia, Carlos Galicia Aguirre, Eric Verdin, Lisa Ellerby, David Furman, John C Newman

{"title":"Ketogenic Diet Reduces Age-Induced Chronic Neuroinflammation in Mice.","authors":"Mitsunori Nomura, Natalia Faraj Murad, Sidharth S Madhavan, Wei-Chieh Mu, Brenda Eap, Thelma Y Garcia, Carlos Galicia Aguirre, Eric Verdin, Lisa Ellerby, David Furman, John C Newman","doi":"10.59368/agingbio.20240038","DOIUrl":"10.59368/agingbio.20240038","url":null,"abstract":"The ketone body beta-hydroxybutyrate (BHB) is an acidic energy metabolite that is synthesized during periods of fasting or exercise. Our previous study demonstrated that an every other week cyclic ketogenic diet (Cyclic KD), which induces blood BHB levels similar to those observed during fasting, reduces midlife mortality and improves memory in aging mice. In addition to its canonical role as an energy metabolite, BHB regulates gene expression and inflammatory activation through non-energetic signaling pathways. The precise mechanisms by which BHB or KD affects brain function during aging remain incompletely understood. Using bulk RNA-sequencing (RNA-Seq), we examined whole brain gene expression of 12-month-old C57BL/6JN male mice fed KD for either one week or 14 months. While one-week KD increases some inflammatory gene expression, the 14-month Cyclic KD largely reduces age-induced neuroinflammatory gene expression. Next, a gene expression analysis of human primary brain cells (microglia, astrocytes, and neurons) using RNA-Seq revealed that BHB alone induces a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced inflammatory gene expression induced by lipopolysaccharide (LPS) in microglia. BHB exhibits a comparable inhibitory effect on LPS-induced inflammation in mouse primary microglia, which we used as an in vitro model to test and exclude known mechanisms by which BHB regulates inflammation and gene expression as responsible for this modulation of LPS-induced inflammatory gene expression. An acidic milieu resulting from BHB may be required for or contribute to the effect. Overall, we observe that BHB has the potential to attenuate the microglial response to inflammatory stimuli, such as LPS. This may contribute to an observed reduction in chronic inflammation in the brain following long-term Cyclic KD treatment in aging mice.","PeriodicalId":520022,"journal":{"name":"Aging biology","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0