Experimental gerontology最新文献

{"title":"A retrospective study of Parkinson's disease in Southwest China 2021–2024: An age-based approach","authors":"","doi":"10.1016/j.exger.2024.112532","DOIUrl":"10.1016/j.exger.2024.112532","url":null,"abstract":"<div><h3>Background</h3><p>Globally, Parkinson's disease (PD) is one of the common neurodegenerative diseases in the elderly with increasing morbidity and disability, and its clinical pathogenesis is not clear.</p></div><div><h3>Objective</h3><p>To compare the differences in disease severity and blood biomarkers levels and their correlation between patients with early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD).</p></div><div><h3>Methods</h3><p>A total of 342 patients diagnosed with PD were retrospectively collected. PD patients were categorized into EOPD (24 patients) and LOPD (318 patients) according to the age of onset of the disease. The Hoehn-Yahr (HY) staging was used to assess the severity of the disease in PD patients. Subjective rating scales such as the Mini-mental State Examination (MMSE) were used to assess the motor and non-motor functions of the patients. The differences of objective blood biomarkers such as triglyceride (TG) between the two groups were investigated. The correlation between them and PD was explored by logistic analysis.</p></div><div><h3>Results</h3><p>Percentage of EOPD group with HY staged as intermediate to late and Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Movement Disorder Society-Unified Parkinson's disease Rating Scale-III (MDS-UPDRS-III), Montreal Cognitive Assessment (MoCA) score and TG, non-high-density lipoprotein-cholesterol (N-HDL-C), homocysteine (HCY), apolipoprotein B (Apo-B), free triiodothyronine (FT3), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP) levels were lower than those in the LOPD group (<em>P</em> &lt; 0.05); and the proportion of HY staged as early stage, Hamilton Anxiety Scale (HAMA) and Fatigue severity scale (FSS) scores and the levels of vitamin B12 were higher than those in the LOPD group (<em>P</em> &lt; 0.05). The results of Multifactorial Logistic regression analysis showed that N-HDL-C [OR = 1.409, 95 % CI (1.063, 1.868)], Apo-B [OR = 0.797, 95 % CI (0.638, 0.997)], Vitamin B12 [OR = 0.992, 95 % CI (0.987, 0.998)] and hs-CRP [OR = 1.124, 95 % CI (1.070, 1.182)] were independent factors affecting the severity of PD, with significant differences between groups (<em>P</em> &lt; 0.05).</p></div><div><h3>Conclusion</h3><p>N-HDL-C, Apo-B, Vitamin B12, and hs-CRP levels play an important role in the progression of PD.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001748/pdfft?md5=0edcc672c5822b55cc78711bd1566bb6&pid=1-s2.0-S0531556524001748-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790600","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}

{"title":"Contribution of impaired autophagy, mitochondrial dysfunction and abnormal lipolysis to epididymal aging in mice","authors":"","doi":"10.1016/j.exger.2024.112528","DOIUrl":"10.1016/j.exger.2024.112528","url":null,"abstract":"<div><p>With the increase of the aged population in modern society, research on aging and aging-related diseases has attracted increasing attention. Unlike women, men experience changes gradually in the reproductive system during aging. The epididymis is an important organ for sperm maturation and storage, but less study has been conducted to investigate cellular senescence in aging epididymis and the corresponding influences on sperm. This study aims to explore cellular and molecular mechanisms underlying aging changes in epididymal tissues. Cellular senescence in the epididymis of 18-month-old C57BL/6 J mice was evaluated with SA (senescence-associated)-β-galactosidase staining and molecular markers such as P21 and Lamin B, compared to the 2-month-old young group. Western blot analysis and immunofluorescence staining were performed to examine the proteins expressions involved in AMPKα/SIRT1 pathway, autophagy/mitophagy, mitochondrial dynamics and lipolysis. The results showed that in old mice AMPKα/ SIRT1 pathway was downregulated with increased acetylation in the epididymal tissues. Reduced expressions of autophagy related genes and PINK1/PARK2 were detected as well as increased P62 protein level and decreased colocalization of LC3 and LAMP2, which indicated deficient autophagy and mitophagy occurred in aging epididymal tissues. Significant decreased expressions of MFN1, MFN2, p-DRP1(Ser637) and FIS1 showed an imbalance in mitochondrial dynamics in aging epididymal tissues. Additionally, intracellular lipid droplets accumulation occurred in epididymal epithelial cells in old mice, with reduced expressions of the lipolysis enzymes ATGL, HSL and Ascl4. Lipophagy impairment was further detected by minimal colocalization of lipid droplets with either LC3 or LAMP2 in the epididymal ductal epithelial cells of old mice. Our study provides new insights into the molecular mechanisms of impaired autophagy, imbalanced mitochondrial dynamics and disrupted lipolysis, which together contribute to senescent changes and may be detrimental to the epididymal function during aging.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001700/pdfft?md5=7eddcdc60a571878e3741000d38eb61f&pid=1-s2.0-S0531556524001700-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790601","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}

{"title":"FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells","authors":"","doi":"10.1016/j.exger.2024.112522","DOIUrl":"10.1016/j.exger.2024.112522","url":null,"abstract":"<div><p>Male ageing is always accompanied by decreased fertility. The forkhead O (FOXO) transcription factor FOXO4 is reported to be highly expressed in senescent cells. Upon activation, it binds p53 in the nucleus, preventing senescent cell apoptosis and maintaining senescent cells in situ. Leydig cells play key roles in assisting spermatogenesis. Leydig cell senescence leads to deterioration of the microenvironment of the testes and impairs spermatogenesis. In this study, we observed that FOXO4-DRI, a specific FOXO4- p53 binding blocker, induced apoptosis in senescent Leydig cells, reduced the secretion of certain Senescence-Associated Secretory Phenotype and improved the proliferation of cocultured GC-1 SPG cells. In naturally aged mice, FOXO4-DRI-treated aged mice exhibited increased sperm quality and improved spermatogenesis.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001645/pdfft?md5=4f058d7d9355076618699d17f6152241&pid=1-s2.0-S0531556524001645-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141725393","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}

{"title":"Aerobic exercise alleviates skeletal muscle aging in male rats by inhibiting apoptosis via regulation of the Trx system","authors":"","doi":"10.1016/j.exger.2024.112523","DOIUrl":"10.1016/j.exger.2024.112523","url":null,"abstract":"<div><p>Skeletal muscle aging in rats is a reduction in skeletal muscle mass caused by a decrease in the number or volume of skeletal muscle myofibers. Apoptosis has been recognized to play a key role in accelerating the process of skeletal muscle aging in rats. The thioredoxin (Trx) system is a widely expressed oxidoreductase system that controls the cellular reduction/oxidation state and has both potent anti-free radical damage and important pro-growth and apoptosis inhibitory functions. Previous studies have shown that exercise delays skeletal muscle aging. However, it is unclear whether exercise attenuates skeletal muscle aging via the Trx system. Therefore, the present study used the Trx system as an entry point to explore the effect of aerobic exercise to improve skeletal muscle aging in rats and its possible mechanisms, and to provide a theoretical basis for exercise to delay skeletal muscle aging in rats. It was shown that aerobic exercise in senescent rats resulted in increased gastrocnemius index, decreased body weight, increased endurance, decreased skeletal muscle cell apoptosis, increased activity and protein expression of the Trx system, and decreased expression of p38 and ASK1. Based on these findings, we conclude that 10 weeks of aerobic exercise may enhance the anti-apoptotic effect of Trx by up-regulating Trx and Trx reductase (TR) protein expression, which in turn increases Trx activity in rat skeletal muscle, and ultimately alleviates apoptosis in senescent skeletal muscle cells.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001657/pdfft?md5=860e87f356219cef3371443b124c7ee4&pid=1-s2.0-S0531556524001657-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638719","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}

{"title":"Exploring the effects of combining health qigong and dance on working memory in middle-aged and elderly women: A preliminary investigation","authors":"","doi":"10.1016/j.exger.2024.112515","DOIUrl":"10.1016/j.exger.2024.112515","url":null,"abstract":"<div><h3>Objective</h3><p>Cognitive decline represents a critical clinical and public health issue that adversely affects the quality of life for older patients and their families. This concern was exacerbated by the reduced engagement in outdoor activities among seniors during the COVID-19 pandemic, presenting substantial challenges to aging societies. The objective of this study was to investigate the impact of health qigong combined with Tibetan dance on working memory in middle-aged and elderly women, and to determine its potential as a preventive strategy against cognitive disorders.</p></div><div><h3>Methods</h3><p>A pilot study was conducted to compare the effects of a Health Qigong exercise intervention with those of everyday life and sports routines. The primary outcome measure was working memory assessed using a 2-Back working memory task research paradigm. Between July and September 2021, a total of 33 women were divided into four groups: two middle-aged groups (<em>N</em> = 18, with 8 women in the experimental group and 10 in the control group) and two elderly groups (<em>N</em> = 15, with 7 in the experimental group and 8 in the control group). Participants in the experimental groups underwent a 10-week intervention, consisting of three 60-min sessions per week. Each session included a warm-up, Health Qigong combined with Tibetan dance, and a cool-down. Throughout the study, all participants continued their daily routines. Response times and error rates were analyzed using a mixed-design repeated-measures analysis of variance.</p></div><div><h3>Results</h3><p>A simple effects analysis revealed that Health Qigong combined with Tibetan dance significantly enhanced 2-Back response time and error rate in the middle-aged group. In contrast, the 2-Back error rate significantly increased in the elderly control group that did not receive the intervention (<em>p</em> &lt; 0.05).</p></div><div><h3>Conclusion</h3><p>Health Qigong demonstrates beneficial effects on middle-aged and elderly women. Combining Health Qigong with dance may serve as a preventive measure against cognitive disorders. This pioneering study conducted during the COVID-19 pandemic, assesses the new possibility of Health Qigong and dance, with the objective to offer more diverse indoor exercise options for middle-aged and elderly women.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001578/pdfft?md5=0126b3ab2113097952639e9aa905cd05&pid=1-s2.0-S0531556524001578-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141556237","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}

{"title":"Comparative effects of lifelong moderate-intensity continuous training and high-intensity interval training on blood lipid levels and mental well-being in naturally ageing mice","authors":"","doi":"10.1016/j.exger.2024.112519","DOIUrl":"10.1016/j.exger.2024.112519","url":null,"abstract":"<div><h3>Objective</h3><p>This study aimed to investigate the impact of lifelong exercise, including both moderate-intensity continuous training and high-intensity interval training, on blood lipid levels and mental behaviour in naturally ageing mice to identify effective exercise strategies for ageing-related health issues.</p></div><div><h3>Methods</h3><p>Six-week-old male BALB/c mice were randomly assigned to one of four groups: young control (YC), natural ageing control (OC), lifelong moderate-intensity continuous exercise (EM), and lifelong high-intensity interval exercise (EH) groups. The EM group was trained at a speed corresponding to 70 % of the maximum running speed, while the EH group was trained at a running speed alternating between 50 % of the maximum running speed, 70 % of the maximum running speed, and 90 % of the maximum running speed. All exercise sessions were conducted three times per week, with each session lasting 50 min. Behavioural tests and blood sample collection were conducted at 72 weeks of age.</p></div><div><h3>Results</h3><p>Ageing in mice led to changes in muscle and fat mass. Both the EM and EH groups showed greater muscle mass and lower fat mass than did the OC group. Ageing was associated with elevated anxiety (fewer open arm entries, time spent in the central region) and depression (lower sucrose preference) indicators. However, these changes were reversed in both exercise groups, with no differences between the two exercise groups. Blood lipid levels, including total cholesterol (TC), total triglycerides (TGs), low-density lipoprotein (LDL), and free fatty acid (FFA) levels, were greater in the OC group than in the YC group. Additionally, the OC group exhibited lower high-density lipoprotein (HDL) levels. However, both the EM and EH groups exhibited improved lipid profiles compared to those of the YC group.</p></div><div><h3>Conclusion</h3><p>Lifelong exercise, whether moderate-intensity continuous or high-intensity interval training, can preserve body health during ageing, prevent anxiety and depression, and maintain stable blood lipid levels. Both exercise types are equally effective, suggesting that exercise intensity may not be the critical factor underlying these beneficial adaptations.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S053155652400161X/pdfft?md5=e7693ff392dd229450331f74cf3e8481&pid=1-s2.0-S053155652400161X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592409","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}

{"title":"Is sharpest scalpel more important than a good surgeon?","authors":"","doi":"10.1016/j.exger.2024.112521","DOIUrl":"10.1016/j.exger.2024.112521","url":null,"abstract":"","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001633/pdfft?md5=97deef4df16597915b331bdf8427654c&pid=1-s2.0-S0531556524001633-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621967","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}

{"title":"Electroacupuncture remodels gut microbiota and metabolites in mice with perioperative neurocognitive impairment","authors":"Lu Tang ,&nbsp;Xiaojia Zhang ,&nbsp;Binsen Zhang ,&nbsp;Tianren Chen ,&nbsp;Zhongying Du ,&nbsp;Wenjing Song ,&nbsp;Wenqiang Chen ,&nbsp;Chunai Wang","doi":"10.1016/j.exger.2024.112507","DOIUrl":"10.1016/j.exger.2024.112507","url":null,"abstract":"<div><p>Gut microbiota and metabolites are considered key factors in the pathogenesis of perioperative neurocognitive disorders (PND), and the brain-gut axis may be a promising target for PND treatment. Electroacupuncture has been shown to improve a wide range of neurological disorders and to restore function to the gastrointestinal tract. Thus, we hypothesized whether electroacupuncture could remodel gut microbiota and neuroinflammation induced by anesthesia/surgery. First, we observed electroacupuncture at acupoints GV20, LI4 and PC6 significantly improved memory in behavioral tests. Next, we found electroacupuncture decreased the levels of inflammatory factors (NSE, S-100β, IL-6, etc.) in the hippocampus, indicating that nerve inflammation was blocked by electroacupuncture. Furthermore, via 16S rRNA sequence analysis and LC-MS analysis, the gut microbiota and its metabolites were appropriately restored after electroacupuncture treatment. Additionally, we further confirmed the restorative effect of electroacupuncture on PND by fecal transplantation. In conclusion, the role of electroacupuncture in improving cognitive function and protecting neurons may be related to the modulation of gut microbiota and their metabolite dysregulation, thereby inhibiting neuroinflammation in PND mice.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001499/pdfft?md5=be0ef80036f444ebc1b2b6e647482fc6&pid=1-s2.0-S0531556524001499-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545651","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}

{"title":"Anthropometric indicators and cardiovascular diseases risk in pre-diabetic and diabetic adults: NHANES 1999–2018 cross-sectional analysis","authors":"Yi He ,&nbsp;Lingfeng Shi","doi":"10.1016/j.exger.2024.112516","DOIUrl":"10.1016/j.exger.2024.112516","url":null,"abstract":"<div><h3>Background</h3><p>Since cardiovascular disease (CVD) stands as the primary cause of death in those with diabetes, and given the substantial influence of obesity as a common risk factor for both diabetes and atherosclerotic conditions, this investigation sought to find the relationship between anthropometric indicators and CVD risk within these populations.</p></div><div><h3>Methods</h3><p>Our study examined 36,329 adults, including those with diagnosed diabetes, pre-diabetes, and without diabetes from National Health and Nutrition Examination Survey (NHANES) data spanning 1999 to 2018. Various anthropometric indicators such as body mass index (BMI), waist circumference, weight-adjusted waist index (WWI), waist-to-height ratio (WHtR), weight, and height were assessed. Baseline characteristics were compared among the three groups after weighting. Participants were then grouped based on anthropometric indicators, and logistic regression models were used to analyze the association between these indicators and CVD risk in the total diabetes group (including diabetic and pre-diabetic individuals). Threshold effect analysis was conducted to explore nonlinear relationships, and mediation analyses assessed whether serum parameters influenced these relationships.</p></div><div><h3>Results</h3><p>This cross-sectional study involved 36,329 participants, weighted to a count of approximately 160.9 million, including over 45.9 million pre-diabetic individuals and around 16.6 million diabetic individuals. Baseline analysis showed significant associations between all six anthropometric indicators and CVD risk across patients with different diabetes statuses. Weighted restricted cubic spline (RCS) curve analysis highlighted increased CVD risk among the total diabetes group for each anthropometric indicator compared to the non-diabetic group. Anthropometric indicators were then divided into quartiles, and after adjusting for confounders, Model 3 revealed that the highest BMI group had a heightened risk of CVD compared to the lowest BMI group. Similar trends were observed in the WWI and WHtR subgroups. Threshold effect analysis of anthropometric indicators unveiled nonlinear associations between waist circumference, height, WWI and CVD risk. Mediation analysis suggested that lipid parameters, especially HDL, significantly mediated these relationships.</p></div><div><h3>Conclusion</h3><p>In individuals with diabetes and pre-diabetes, BMI, weight, and WHtR displayed a consistent, linear increase correlation with CVD risk. Conversely, the link between waist circumference, height, and WWI and CVD risk showcased a more complex, nonlinear pattern. Moreover, HDL level emerged as notable mediator in the association between anthropometric indicators and the risk of CVD.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S053155652400158X/pdfft?md5=147d8d7f6b11e8c4e78e9a24710d179b&pid=1-s2.0-S053155652400158X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560569","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}

{"title":"Identification of novel drug targets for multiple sclerosis by integrating plasma genetics and proteomes","authors":"Yi Liu ,&nbsp;Qian Wang ,&nbsp;Yuhui Zhao ,&nbsp;Liu Liu ,&nbsp;Jingxi Hu ,&nbsp;Yao Qiao ,&nbsp;Jinyi Chen ,&nbsp;Chao Qin","doi":"10.1016/j.exger.2024.112505","DOIUrl":"10.1016/j.exger.2024.112505","url":null,"abstract":"<div><h3>Background</h3><p>Genome-wide association studies (GWAS) have revealed numerous loci associated with multiple sclerosis (MS). However, the challenge lies in deciphering the mechanisms by which these loci influence the target traits. Here, we employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for MS.</p></div><div><h3>Methods</h3><p>We systematically integrated MS GWAS data (N = 115,803) with human plasma proteome data (N = 7213) and conducted proteome-wide association studies (PWAS) to identify MS-associated pathogenic proteins. Following this, we employed Mendelian randomization and Bayesian colocalization analyses to verify the causal relationship between these significant plasma proteins and MS. Lastly, we utilized the Drug-Gene Interaction Database (DGIdb) to identify potential drug targets for MS.</p></div><div><h3>Results</h3><p>The PWAS identified 25 statistically significant cis-regulated plasma proteins associated with MS at a false discovery rate of <em>P</em> &lt; 0.05. Further analysis revealed that the abundance of 7 of these proteins (PLEK, TNXB, CASP3, CD59, CR1, TAPBPL, ATXN3) was causally related to the incidence of MS. Our findings indicated that genetically predicted higher levels of TNXB and CD59 were associated with a lower risk of MS, whereas higher levels of PLEK, CASP3, CR1, TAPBPL, and ATXN3 were associated with an increased risk of MS. Three plasma proteins (PLEK, CR1, CD59) were validated by colocalization analysis. Among these, CR1 was prioritized as a target for Eculizumab due to its significant association with MS risk. Additionally, PLEK, CR1, and CD59 were identified as druggable target genes.</p></div><div><h3>Conclusions</h3><p>Our proteomic analysis has identified PLEK, CR1, and CD59 as potential drug targets for MS treatment. Developing pharmacological inducers or inhibitors for these proteins could pave the way for new therapeutic approaches, potentially improving outcomes for MS patients.</p></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0531556524001475/pdfft?md5=a786f464c549e3fcdbc219ea6f8647fe&pid=1-s2.0-S0531556524001475-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536253","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}