BACKGROUNDThe triglyceride-glucose (TyG) index, a practical and reliable indicator for insulin resistance, has been linked to an increased risk of dementia. However, the impact of its longitudinal changes on dementia risk remains unexplored.METHODSData were obtained from the Atherosclerosis Risk in Communities Study (ARIC). TyG index was calculated by combining triglyceride and fasting blood glucose levels. Longitudinal changes in TyG were evaluated using two indicators over two visits (median time interval: 2.9 years): the average TyG index and the difference in TyG index. Participants were stratified into tertiles based on these measures. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).RESULTSA total of 12,601 participants (54.9% female, mean age: 54.2 years) were included. During 264,735.5 person-years of follow-up, 2,460 (19.5%) participants developed incident dementia. Individuals in the highest tertile (T3) of the average TyG index had a 26% higher risk of dementia (HR: 1.26, 95% CI: 1.13-1.40, P-trend <0.001) compared to those in the lowest tertile (T1). Furthermore, independent of baseline levels, a greater increase in the TyG index between visit 1 and visit 2 was associated with an elevated dementia risk, with the HRT3 vs. T1 of 1.17 (95% CI: 1.05-1.29, P-trend = 0.003).CONCLUSIONSA higher level of average TyG index and difference in TyG index were both associated with a higher risk of dementia. These findings suggest that long-term monitoring of the TyG index may contribute to identifying individuals at elevated dementia risk.
{"title":"Longitudinal changes in triglyceride-glucose index and the risk of incident dementia: a prospective cohort study.","authors":"Tian Ge,Yihong Ding,Minqing Yan,Mengjia Zhao,Gulisiya Hailili,Minyu Wu,Jie Shen,Xiaoran Liu,Yuan Ma,Dan Zhou,Changzheng Yuan","doi":"10.1093/gerona/glaf237","DOIUrl":"https://doi.org/10.1093/gerona/glaf237","url":null,"abstract":"BACKGROUNDThe triglyceride-glucose (TyG) index, a practical and reliable indicator for insulin resistance, has been linked to an increased risk of dementia. However, the impact of its longitudinal changes on dementia risk remains unexplored.METHODSData were obtained from the Atherosclerosis Risk in Communities Study (ARIC). TyG index was calculated by combining triglyceride and fasting blood glucose levels. Longitudinal changes in TyG were evaluated using two indicators over two visits (median time interval: 2.9 years): the average TyG index and the difference in TyG index. Participants were stratified into tertiles based on these measures. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).RESULTSA total of 12,601 participants (54.9% female, mean age: 54.2 years) were included. During 264,735.5 person-years of follow-up, 2,460 (19.5%) participants developed incident dementia. Individuals in the highest tertile (T3) of the average TyG index had a 26% higher risk of dementia (HR: 1.26, 95% CI: 1.13-1.40, P-trend <0.001) compared to those in the lowest tertile (T1). Furthermore, independent of baseline levels, a greater increase in the TyG index between visit 1 and visit 2 was associated with an elevated dementia risk, with the HRT3 vs. T1 of 1.17 (95% CI: 1.05-1.29, P-trend = 0.003).CONCLUSIONSA higher level of average TyG index and difference in TyG index were both associated with a higher risk of dementia. These findings suggest that long-term monitoring of the TyG index may contribute to identifying individuals at elevated dementia risk.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"150 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145369474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jedd Pratt,Abadi Gebre,Carlos J Toro-Huamanchumo,Elsa Dent,Trent Bozanich,Wai E Lim,Elizabeth Byrnes,Julee McDonagh,Caleb Ferguson,Craig Sale,Kun Zhu,Carl Schultz,Richard L Prince,Joshua R Lewis,Marc Sim
Despite the nexus between cardiovascular health and frailty, the relevance of high-sensitivity cardiac troponin I (hs-cTnI), a biomarker of myocardial injury, to frailty is poorly understood. We examined whether hs-cTnI concentrations were associated with frailty in a well-characterised cohort of older women. A total of 1,151 community-dwelling women from the Perth Longitudinal Study of Aging Women (mean age±SD = 75.2 ± 2.7 years) were included. Frailty was operationalised using a validated Frailty Index (FI) of cumulative deficits, and a modified Fried phenotype. Plasma hs-cTnI were categorised into quartiles. Cross-sectional associations between hs-cTnI quartiles and frailty were assessed using multivariable-adjusted logistic regression models. A total of 235 (20.4%) women were classified as frail using the FI, while 74 (6.4%) were considered frail by Fried's phenotype. In a multivariable-adjusted model, compared to women in the lowest hs-cTnI quartile (Q1), those in Q3 and Q4 had 1.38 (95%CI 1.00-1.90) and 1.79 (1.20-2.67) greater odds for frailty when classified by the FI. When classified according to Fried's phenotype, women in Q2, Q3, and Q4 had 2.25 (1.10-4.09), 2.64 (1.19-5.21), and 2.44 (1.10-5.33) greater odds for frailty, compared to Q1. Associations remained largely unchanged when further adjusted for daily protein intake or systemic inflammation (lipocalin-2) and restricted to those with subclinical hs-cTnI levels (<15.6ng/L). Higher hs-cTnI levels are associated with greater odds for frailty, classified using a FI or Fried's phenotype, amongst older women. hs-cTnI may have applications beyond its typical use in cardiology, offering insight into the implications of underlying cardiovascular dysfunction relating to frailty.
{"title":"High-Sensitivity Cardiac Troponin I and Frailty: Associations with the Frailty Index and Fried Phenotype in Older Women.","authors":"Jedd Pratt,Abadi Gebre,Carlos J Toro-Huamanchumo,Elsa Dent,Trent Bozanich,Wai E Lim,Elizabeth Byrnes,Julee McDonagh,Caleb Ferguson,Craig Sale,Kun Zhu,Carl Schultz,Richard L Prince,Joshua R Lewis,Marc Sim","doi":"10.1093/gerona/glaf235","DOIUrl":"https://doi.org/10.1093/gerona/glaf235","url":null,"abstract":"Despite the nexus between cardiovascular health and frailty, the relevance of high-sensitivity cardiac troponin I (hs-cTnI), a biomarker of myocardial injury, to frailty is poorly understood. We examined whether hs-cTnI concentrations were associated with frailty in a well-characterised cohort of older women. A total of 1,151 community-dwelling women from the Perth Longitudinal Study of Aging Women (mean age±SD = 75.2 ± 2.7 years) were included. Frailty was operationalised using a validated Frailty Index (FI) of cumulative deficits, and a modified Fried phenotype. Plasma hs-cTnI were categorised into quartiles. Cross-sectional associations between hs-cTnI quartiles and frailty were assessed using multivariable-adjusted logistic regression models. A total of 235 (20.4%) women were classified as frail using the FI, while 74 (6.4%) were considered frail by Fried's phenotype. In a multivariable-adjusted model, compared to women in the lowest hs-cTnI quartile (Q1), those in Q3 and Q4 had 1.38 (95%CI 1.00-1.90) and 1.79 (1.20-2.67) greater odds for frailty when classified by the FI. When classified according to Fried's phenotype, women in Q2, Q3, and Q4 had 2.25 (1.10-4.09), 2.64 (1.19-5.21), and 2.44 (1.10-5.33) greater odds for frailty, compared to Q1. Associations remained largely unchanged when further adjusted for daily protein intake or systemic inflammation (lipocalin-2) and restricted to those with subclinical hs-cTnI levels (<15.6ng/L). Higher hs-cTnI levels are associated with greater odds for frailty, classified using a FI or Fried's phenotype, amongst older women. hs-cTnI may have applications beyond its typical use in cardiology, offering insight into the implications of underlying cardiovascular dysfunction relating to frailty.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145369472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neuroinflammation is a critical aspect of aging and neurodegenerative disorders, increasingly recognized for its significant role in the progression of cognitive impairments. Mitochondrial homeostasis is closely linked to cognitive function in the aging brain. However, it remains unclear whether exercise can safeguard cognitive function by enhancing mitochondrial homeostasis in the aged hippocampus affected by neuroinflammation. In this study, we established mouse models exhibiting memory impairment and neuroinflammation in the aged hippocampus to investigate whether exercise can reverse LPS-induced cognitive dysfunction in aged mice, reduce neuroinflammation, and simultaneously improve mitochondrial homeostasis in the hippocampus. Eighteen-month-old male ICR mice underwent eight weeks of moderate-intensity aerobic exercise. The exercise regimen enhanced memory function in LPS-injected aged mice, which was accompanied by reductions in inflammation, oxidative stress, and apoptosis in the aged hippocampus. Importantly, exercise improved mitochondrial homeostasis in the hippocampus of LPS-injected aged mice. Collectively, our results provide the first evidence that exercise can protect cognitive function in the context of neuroinflammation in the aged hippocampus, suggesting that this effect may be associated with the improvement of mitochondrial homeostasis.
{"title":"Exercise-induced alleviation of memory impairment in aged mice with neuroinflammation is linked with modulation of mitochondrial homeostasis in the hippocampus.","authors":"Peng-Da Li,Chong Han,Yuan-Yuan Qin,Zhi Jiang,Shan-Yao Pan,Bo Liao,Nan Wang,Xin-Han Cao,Gang Zhao,Jia-Qi Zhou,Zheng-Hong Qin,Yiqing Lu,Yaping Huai,Li Luo","doi":"10.1093/gerona/glaf233","DOIUrl":"https://doi.org/10.1093/gerona/glaf233","url":null,"abstract":"Neuroinflammation is a critical aspect of aging and neurodegenerative disorders, increasingly recognized for its significant role in the progression of cognitive impairments. Mitochondrial homeostasis is closely linked to cognitive function in the aging brain. However, it remains unclear whether exercise can safeguard cognitive function by enhancing mitochondrial homeostasis in the aged hippocampus affected by neuroinflammation. In this study, we established mouse models exhibiting memory impairment and neuroinflammation in the aged hippocampus to investigate whether exercise can reverse LPS-induced cognitive dysfunction in aged mice, reduce neuroinflammation, and simultaneously improve mitochondrial homeostasis in the hippocampus. Eighteen-month-old male ICR mice underwent eight weeks of moderate-intensity aerobic exercise. The exercise regimen enhanced memory function in LPS-injected aged mice, which was accompanied by reductions in inflammation, oxidative stress, and apoptosis in the aged hippocampus. Importantly, exercise improved mitochondrial homeostasis in the hippocampus of LPS-injected aged mice. Collectively, our results provide the first evidence that exercise can protect cognitive function in the context of neuroinflammation in the aged hippocampus, suggesting that this effect may be associated with the improvement of mitochondrial homeostasis.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brooke A Vaughan,Graciela Muniz-Terrera,Janet E Simon,Dustin R Grooms,Brian C Clark,Christos Davatzikos,Guray Erus,Qu Tian,Luigi Ferrucci,Susan M Resnick,Eleanor M Simonsick
Muscle weakness and poor brain health both contribute to mobility limitations in older adults, but their respective contributions and interaction are not well-understood. This study examines the relationship between MRI-estimated brain-predicted age difference (brain-predicted age-chronological age), leg strength, and their interaction on mobility decline using Baltimore Longitudinal Study of Aging data (N = 645, 78.1 ± 7.54 years, 56% women). Partial Spearman correlations evaluated the relationships between leg strength, brain-predicted age difference (BPAD), gait speed, and time to complete 5 chair stands (5CS). Mixed-effects linear regression models examined associations of baseline BPAD, leg strength, and lifestyle factors with mobility change over time (5.74 ± 2.87 years). Logistic regression modeled predictors of success in a narrow course walking task. Leg strength significantly correlated with gait speed (r = 0.26, p < 0.001) and 5CS (r=-0.27, p < 0.001). BPAD was associated with decreased gait speed (β=-0.022, p = 0.011) and slower 5CS (β = 0.331, p = 0.012). Greater leg strength was associated with preserved gait speed (β = 0.023, p = 0.022) and faster 5CS (β=-0.552, p < 0.001). BPAD (OR = 0.712, 95% CI: 0.687, 0.940) and leg strength (OR = 0.805, 95% CI: 0.696, 0.964) predicted lower likelihood of narrow walk success. Interactions between BPAD and leg strength were not significant for any measure. These findings suggest accelerated brain aging and leg weakness independently contribute to mobility decline, highlighting the need for interventions targeting brain health and muscle strength to preserve mobility in aging populations.
肌肉无力和大脑健康状况不佳都是老年人行动能力受限的原因，但它们各自的作用和相互作用尚不清楚。本研究利用巴尔的摩老龄化纵向研究数据（N = 645, 78.1±7.54岁，56%女性），研究mri估计的脑预测年龄差异（脑预测年龄-实足年龄）、腿部力量及其与活动能力下降的相互作用之间的关系。部分Spearman相关性评估了腿部力量、脑预测年龄差异（BPAD）、步态速度和完成5个椅子站立（5CS）的时间之间的关系。混合效应线性回归模型检验了基线BPAD、腿部力量和生活方式因素随时间（5.74±2.87年）与活动能力变化的关系。逻辑回归模型预测在狭窄路线步行任务的成功。腿部力量与步态速度（r= 0.26, p < 0.001）和5CS （r=-0.27, p < 0.001）显著相关。BPAD与步态速度降低（β=-0.022, p = 0.011）和5CS减慢（β= 0.331, p = 0.012）相关。更大的腿部力量与保持的步态速度（β= 0.023, p = 0.022）和更快的5CS （β=-0.552, p < 0.001）相关。BPAD （OR = 0.712, 95% CI: 0.687, 0.940）和腿部力量（OR = 0.805, 95% CI: 0.696, 0.964）预测狭窄行走成功的可能性较低。BPAD和腿部力量之间的相互作用在任何测量中都不显著。这些发现表明，加速的大脑老化和腿部无力分别导致了活动能力下降，强调了针对大脑健康和肌肉力量的干预措施的必要性，以保持老年人的活动能力。
{"title":"The Predictive Power of Brain-Predicted Age and Leg Strength on Mobility Decline in Aging: Findings from the Baltimore Longitudinal Study of Aging.","authors":"Brooke A Vaughan,Graciela Muniz-Terrera,Janet E Simon,Dustin R Grooms,Brian C Clark,Christos Davatzikos,Guray Erus,Qu Tian,Luigi Ferrucci,Susan M Resnick,Eleanor M Simonsick","doi":"10.1093/gerona/glaf222","DOIUrl":"https://doi.org/10.1093/gerona/glaf222","url":null,"abstract":"Muscle weakness and poor brain health both contribute to mobility limitations in older adults, but their respective contributions and interaction are not well-understood. This study examines the relationship between MRI-estimated brain-predicted age difference (brain-predicted age-chronological age), leg strength, and their interaction on mobility decline using Baltimore Longitudinal Study of Aging data (N = 645, 78.1 ± 7.54 years, 56% women). Partial Spearman correlations evaluated the relationships between leg strength, brain-predicted age difference (BPAD), gait speed, and time to complete 5 chair stands (5CS). Mixed-effects linear regression models examined associations of baseline BPAD, leg strength, and lifestyle factors with mobility change over time (5.74 ± 2.87 years). Logistic regression modeled predictors of success in a narrow course walking task. Leg strength significantly correlated with gait speed (r = 0.26, p < 0.001) and 5CS (r=-0.27, p < 0.001). BPAD was associated with decreased gait speed (β=-0.022, p = 0.011) and slower 5CS (β = 0.331, p = 0.012). Greater leg strength was associated with preserved gait speed (β = 0.023, p = 0.022) and faster 5CS (β=-0.552, p < 0.001). BPAD (OR = 0.712, 95% CI: 0.687, 0.940) and leg strength (OR = 0.805, 95% CI: 0.696, 0.964) predicted lower likelihood of narrow walk success. Interactions between BPAD and leg strength were not significant for any measure. These findings suggest accelerated brain aging and leg weakness independently contribute to mobility decline, highlighting the need for interventions targeting brain health and muscle strength to preserve mobility in aging populations.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yaru Chen,Xin Liu,Yuyang Song,Lei Wang,Shang Wu,Jiawei Zhou,Xianwen Peng,Shuqi Mei,Fenge Li
Inflammation is a hallmark of aging and negatively affects ovarian function and female fertility. ISGylation is a post-translational modification regulating many life activities, including inflammation, immunomodulation and embryo implantation. However, the exact role of ISGylation in ovarian aging remains unclear. In this study, age-dependent increase in Isg15 expression was observed in murine ovaries during reproductive aging. Wild-type female mice displayed progressively reduced ovarian reserve, disrupted endocrine function, and ultimately impaired fertility with age, but Isg15 knockdown partly mitigated this phenomenon. Transcriptome sequencing of ovaries from Isg15-/- and WT mice at 12 months of age revealed that Isg15 deletion ameliorated the genes and pathways associated with inflammation process and ovarian function. Meanwhile, Isg15 knockout in mice inhibited ovarian oxidative stress and then protected ovarian mitochondrial structure and function. Mechanistically, ISG15 resulted in degradation of proteasome 26S subunit non-ATPase 14 (PSMD14), a negative regulator of inflammasome activation. Furthermore, the degradation of ISGylated PSMD14 suppressed the K63-linked ubiquitination of Pro-IL-1β, and eventually facilitated inflammatory cytokine IL-1β maturation and inflammation activation. These results suggest that Isg15 accelerates the senescence of ovarian granulosa cells by promoting inflammation and thereby reduces reproductive lifespan during aging. The present study demonstrates that a novel regulatory axis of ISG15-PSMD14-IL-1β activates inflammation, and therefore Isg15 deficiency mitigates the age-related decline in female fertility via reducing ovarian inflammation. Overall, our findings provide a new mechanistic insight into the decline of female fertility during ovarian aging, and offer a potential therapeutic strategy for ameliorating age-related female infertility.
炎症是衰老的标志，对卵巢功能和女性生育能力有负面影响。isg酰化是一种翻译后修饰，可调节许多生命活动，包括炎症、免疫调节和胚胎着床。然而，isg酰化在卵巢衰老中的确切作用尚不清楚。在本研究中，Isg15的表达在小鼠卵巢中随着年龄的增长而增加。野生型雌性小鼠表现出卵巢储备逐渐减少，内分泌功能紊乱，最终随着年龄的增长而降低生育能力，但Isg15基因敲除在一定程度上缓解了这一现象。12月龄Isg15-/-和WT小鼠卵巢转录组测序显示，Isg15缺失改善了与炎症过程和卵巢功能相关的基因和途径。同时，敲除Isg15抑制小鼠卵巢氧化应激，进而保护卵巢线粒体结构和功能。在机制上，ISG15导致蛋白酶体26S亚基非atp酶14 （PSMD14）的降解，PSMD14是炎症小体激活的负调节因子。此外，isglated PSMD14的降解抑制了k63连接的Pro-IL-1β泛素化，最终促进了炎症细胞因子IL-1β的成熟和炎症激活。这些结果表明，Isg15通过促进炎症加速卵巢颗粒细胞的衰老，从而在衰老过程中缩短生殖寿命。目前的研究表明，Isg15 - psmd14 - il -1β的一个新的调控轴激活炎症，因此Isg15缺乏通过减少卵巢炎症来减轻与年龄相关的女性生育能力下降。总之，我们的研究结果为卵巢衰老过程中女性生育能力下降提供了新的机制见解，并为改善与年龄相关的女性不孕症提供了潜在的治疗策略。
{"title":"Inhibition of the ISG15 Prevents Inflammation-Dependent Ovarian Aging.","authors":"Yaru Chen,Xin Liu,Yuyang Song,Lei Wang,Shang Wu,Jiawei Zhou,Xianwen Peng,Shuqi Mei,Fenge Li","doi":"10.1093/gerona/glaf230","DOIUrl":"https://doi.org/10.1093/gerona/glaf230","url":null,"abstract":"Inflammation is a hallmark of aging and negatively affects ovarian function and female fertility. ISGylation is a post-translational modification regulating many life activities, including inflammation, immunomodulation and embryo implantation. However, the exact role of ISGylation in ovarian aging remains unclear. In this study, age-dependent increase in Isg15 expression was observed in murine ovaries during reproductive aging. Wild-type female mice displayed progressively reduced ovarian reserve, disrupted endocrine function, and ultimately impaired fertility with age, but Isg15 knockdown partly mitigated this phenomenon. Transcriptome sequencing of ovaries from Isg15-/- and WT mice at 12 months of age revealed that Isg15 deletion ameliorated the genes and pathways associated with inflammation process and ovarian function. Meanwhile, Isg15 knockout in mice inhibited ovarian oxidative stress and then protected ovarian mitochondrial structure and function. Mechanistically, ISG15 resulted in degradation of proteasome 26S subunit non-ATPase 14 (PSMD14), a negative regulator of inflammasome activation. Furthermore, the degradation of ISGylated PSMD14 suppressed the K63-linked ubiquitination of Pro-IL-1β, and eventually facilitated inflammatory cytokine IL-1β maturation and inflammation activation. These results suggest that Isg15 accelerates the senescence of ovarian granulosa cells by promoting inflammation and thereby reduces reproductive lifespan during aging. The present study demonstrates that a novel regulatory axis of ISG15-PSMD14-IL-1β activates inflammation, and therefore Isg15 deficiency mitigates the age-related decline in female fertility via reducing ovarian inflammation. Overall, our findings provide a new mechanistic insight into the decline of female fertility during ovarian aging, and offer a potential therapeutic strategy for ameliorating age-related female infertility.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"127 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jure Mur,Lucy E Stirland,Graciela Muniz-Terrera,Anja K Leist
BACKGROUNDpolypharmacy and use of anticholinergics are associated with adverse health outcomes. Because these two exposures covary, it is not known to what extent the detrimental health effects attributed to anticholinergic burden measured by anticholinergic burden scales (ABS) may be due to polypharmacy.METHODSour aims were to evaluate the added effect beyond polypharmacy of (1) anticholinergic use, and (2) scores according to existing ABS. We used linked data from the UK Biobank prospective cohort study to investigate drugs prescribed in primary care in the year 2015 (n=∼200,000; median age = 65 years). We randomly sampled among drugs to create 2,000 pseudoscales-drug burden scales designed to reflect the strength of the background effect of polypharmacy. We differentiated pseudoscales constructed to capture either general polypharmacy or putative anticholinergic polypharmacy. For each scale, we fitted logistic regression adjusted for confounders to assess associations between pseudoscales from each set and risk of death, dementia, or delirium. We also assessed 23 existing ABS by comparing them to the effects of pseudoscales that included the same numbers of drugs as each ABS.RESULTSodds ratios for death, dementia, and delirium using anticholinergic-polypharmacy pseudoscales (median = 1.09-1.10) were greater than those of general-polypharmacy pseudoscales (1.05-1.06). The added effect of anticholinergic use beyond polypharmacy was greater in adjusted models and when prescribed to participants when they were older. 35%-90% of ABS exhibited stronger effects than most pseudoscales.CONCLUSIONSthe models show an anticholinergic effect of drugs beyond polypharmacy or drug count, but it is small, ABS-dependent, and varies between outcomes.
{"title":"A simulation study comparing anticholinergic drug use with polypharmacy for risk of death, dementia, and delirium in UK Biobank.","authors":"Jure Mur,Lucy E Stirland,Graciela Muniz-Terrera,Anja K Leist","doi":"10.1093/gerona/glaf232","DOIUrl":"https://doi.org/10.1093/gerona/glaf232","url":null,"abstract":"BACKGROUNDpolypharmacy and use of anticholinergics are associated with adverse health outcomes. Because these two exposures covary, it is not known to what extent the detrimental health effects attributed to anticholinergic burden measured by anticholinergic burden scales (ABS) may be due to polypharmacy.METHODSour aims were to evaluate the added effect beyond polypharmacy of (1) anticholinergic use, and (2) scores according to existing ABS. We used linked data from the UK Biobank prospective cohort study to investigate drugs prescribed in primary care in the year 2015 (n=∼200,000; median age = 65 years). We randomly sampled among drugs to create 2,000 pseudoscales-drug burden scales designed to reflect the strength of the background effect of polypharmacy. We differentiated pseudoscales constructed to capture either general polypharmacy or putative anticholinergic polypharmacy. For each scale, we fitted logistic regression adjusted for confounders to assess associations between pseudoscales from each set and risk of death, dementia, or delirium. We also assessed 23 existing ABS by comparing them to the effects of pseudoscales that included the same numbers of drugs as each ABS.RESULTSodds ratios for death, dementia, and delirium using anticholinergic-polypharmacy pseudoscales (median = 1.09-1.10) were greater than those of general-polypharmacy pseudoscales (1.05-1.06). The added effect of anticholinergic use beyond polypharmacy was greater in adjusted models and when prescribed to participants when they were older. 35%-90% of ABS exhibited stronger effects than most pseudoscales.CONCLUSIONSthe models show an anticholinergic effect of drugs beyond polypharmacy or drug count, but it is small, ABS-dependent, and varies between outcomes.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abudunaibi Wupuer,Xing Peng,Jie Wang,Yihan Li,Kaidiriyan Kuribanjiang,Shikang Yan,Lei Yang
BACKGROUNDFrailty and sarcopenia are age-related conditions linked to mitochondrial dysfunction, but their causal mechanisms remain poorly defined. This study aimed to identify mitochondrial-related genes causally associated with frailty and sarcopenia using comprehensive multi-omics approaches.METHODSWe performed summary-data-based Mendelian randomization (SMR) using genome-wide association study (GWAS) summary statistics for the frailty index (FI) and sarcopenia-related traits. Quantitative trait loci (QTL) data for DNA methylation, gene expression, and plasma protein abundance were analyzed across 1,136 mitochondrial-related genes. Colocalization analysis was applied to confirm shared causal variants.RESULTSFor frailty, GRPEL1 showed tissue-specific associations at methylation and expression levels (protective in blood: β = -0.15, FDR = 1.5e-02; adverse in brain/muscle), while LRPPRC demonstrated consistent protective effects across tissues (β = -0.05 to -0.13, PPH4 > 0.93). For sarcopenia-related traits, GATM was associated with appendicular lean mass (ALM) across all omics levels with opposing tissue effects (negative in blood: β = -0.03, FDR = 1.9e-09; positive in muscle), and ETFDH showed positive associations with ALM (β = 0.03, FDR = 1.4e-06). Additional genes included CPS1 and MMAB for frailty, NTHL1 and MTCH2 for grip strength, and TOMM70, BNIP3, TUFM for walking pace. Complete regulatory pathways were identified for GRPEL1 and GATM linking methylation to expression to phenotype.CONCLUSIONThis multi-omics study identified distinct mitochondrial genetic signatures for frailty and sarcopenia, with key genes including GRPEL1, LRPPRC, GATM, ETFDH, and others showing tissue-specific causal associations. These findings advance understanding of mitochondrial mechanisms in age-related functional decline and identify multiple therapeutic targets.
{"title":"From Mitochondrial Dysfunction to Frailty and Sarcopenia: Genetic Evidence from Multi-Omics Data via Mendelian Randomization and Colocalization.","authors":"Abudunaibi Wupuer,Xing Peng,Jie Wang,Yihan Li,Kaidiriyan Kuribanjiang,Shikang Yan,Lei Yang","doi":"10.1093/gerona/glaf234","DOIUrl":"https://doi.org/10.1093/gerona/glaf234","url":null,"abstract":"BACKGROUNDFrailty and sarcopenia are age-related conditions linked to mitochondrial dysfunction, but their causal mechanisms remain poorly defined. This study aimed to identify mitochondrial-related genes causally associated with frailty and sarcopenia using comprehensive multi-omics approaches.METHODSWe performed summary-data-based Mendelian randomization (SMR) using genome-wide association study (GWAS) summary statistics for the frailty index (FI) and sarcopenia-related traits. Quantitative trait loci (QTL) data for DNA methylation, gene expression, and plasma protein abundance were analyzed across 1,136 mitochondrial-related genes. Colocalization analysis was applied to confirm shared causal variants.RESULTSFor frailty, GRPEL1 showed tissue-specific associations at methylation and expression levels (protective in blood: β = -0.15, FDR = 1.5e-02; adverse in brain/muscle), while LRPPRC demonstrated consistent protective effects across tissues (β = -0.05 to -0.13, PPH4 > 0.93). For sarcopenia-related traits, GATM was associated with appendicular lean mass (ALM) across all omics levels with opposing tissue effects (negative in blood: β = -0.03, FDR = 1.9e-09; positive in muscle), and ETFDH showed positive associations with ALM (β = 0.03, FDR = 1.4e-06). Additional genes included CPS1 and MMAB for frailty, NTHL1 and MTCH2 for grip strength, and TOMM70, BNIP3, TUFM for walking pace. Complete regulatory pathways were identified for GRPEL1 and GATM linking methylation to expression to phenotype.CONCLUSIONThis multi-omics study identified distinct mitochondrial genetic signatures for frailty and sarcopenia, with key genes including GRPEL1, LRPPRC, GATM, ETFDH, and others showing tissue-specific causal associations. These findings advance understanding of mitochondrial mechanisms in age-related functional decline and identify multiple therapeutic targets.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDIntrinsic capacity (IC), reflecting an individual's physical and mental capacities, is a core concept proposed by WHO to promote healthy aging. This study aimed to examine the association between IC and chronic kidney disease (CKD) incidence and outcomes.METHODSWe analyzed 389,805 UK Biobank participants without baseline CKD. Functional decline was quantified using an IC deficit proxy score derived from eight biomarkers across five IC domains. A polygenic score (PGS) for estimated glomerular filtration rate (eGFR) was also calculated. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CKD, and two-sample Mendelian randomization (MR) was conducted to explore potential causal relationships.RESULTSA one-point increment in the IC deficit proxy score was associated with a 67% higher risk of developing CKD (HR = 1.67, 95% CI: 1.57-1.77; P-trend < 0.0001), independent of genetic susceptibility to eGFR. The highest risk of CKD was observed among individuals with a high IC deficit and low genetically predicted eGFR (HR = 1.88, 95% CI: 1.72-2.06). MR analysis supported a causal relationship between faster walking pace and lower CKD risk. Among individuals with CKD, a higher IC deficit proxy score was linked to reduced life expectancy at age 45 (1.09 years lost in life expectancy; 95% CI: 0.68, 1.51).CONCLUSIONSIC decline was independently associated with increased CKD risk and with further reductions in life expectancy among CKD patients. Enhancing IC may be a viable strategy for CKD prevention and healthy aging.
{"title":"Associations of intrinsic capacity deficit proxy score and genetic susceptibility with incident CKD and life expectancy.","authors":"Gang Zheng,Fengrong Ou,Shuxian Chen,Chao Ji,Qing Chang,Difei Wang,Honghao Yang,Zheng Ma,Yang Xia,Yuhong Zhao","doi":"10.1093/gerona/glaf187","DOIUrl":"https://doi.org/10.1093/gerona/glaf187","url":null,"abstract":"BACKGROUNDIntrinsic capacity (IC), reflecting an individual's physical and mental capacities, is a core concept proposed by WHO to promote healthy aging. This study aimed to examine the association between IC and chronic kidney disease (CKD) incidence and outcomes.METHODSWe analyzed 389,805 UK Biobank participants without baseline CKD. Functional decline was quantified using an IC deficit proxy score derived from eight biomarkers across five IC domains. A polygenic score (PGS) for estimated glomerular filtration rate (eGFR) was also calculated. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CKD, and two-sample Mendelian randomization (MR) was conducted to explore potential causal relationships.RESULTSA one-point increment in the IC deficit proxy score was associated with a 67% higher risk of developing CKD (HR = 1.67, 95% CI: 1.57-1.77; P-trend < 0.0001), independent of genetic susceptibility to eGFR. The highest risk of CKD was observed among individuals with a high IC deficit and low genetically predicted eGFR (HR = 1.88, 95% CI: 1.72-2.06). MR analysis supported a causal relationship between faster walking pace and lower CKD risk. Among individuals with CKD, a higher IC deficit proxy score was linked to reduced life expectancy at age 45 (1.09 years lost in life expectancy; 95% CI: 0.68, 1.51).CONCLUSIONSIC decline was independently associated with increased CKD risk and with further reductions in life expectancy among CKD patients. Enhancing IC may be a viable strategy for CKD prevention and healthy aging.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"130 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Haiyan Wang,Søren Madsen,Elise J Needham,Sean J Humphrey,Amy Zheng,Edward B Arias,Jacqueline Stöckli,Harry B Cutler,David E James,Gregory D Cartee
Calorie restriction (CR; calorie intake reduced by ∼20-40% below ad libitum, AL, intake) potentiates skeletal muscle insulin sensitivity during old age by incompletely understood mechanisms. We aimed to identify CR-induced changes in muscle insulin signaling that may explain this enhanced sensitivity. We examined how CR (65% of AL intake for 8-weeks) alters muscle insulin action and signaling in aged rats (24-months-old) of both sexes. We assessed insulin-stimulated glucose uptake (ISGU) in muscle together with deep phosphoproteomic profiling. CR enhanced ISGU in both sexes, with higher ISGU in females regardless of diet. We identified 590 diet-responsive phosphosites, indicating extensive CR-induced remodelling of muscle phosphorylation, particularly within structural and contractile pathways. Strikingly, 70% of these sites were sex-specific. Numerous insulin-responsive sites were identified (193 in females; 107 in males) with 60 overlapping sites. The magnitude of the insulin-effects among all significantly regulated sites correlated between sexes. S1443 phosphorylation on EH domain-binding protein 1-like protein-1 (Ehbp1l1; a potential regulator of Rab proteins that control GLUT4 glucose transporter trafficking) was insulin-responsive in both sexes but only associated to ISGU in females. Personalized phosphoproteomic analysis also identified insulin-responsive sites on Leiomodin-1 (Lmod1) that correlated with ISGU across individuals. Both Lmod1 and Ehbp1l1 have strong genetic association with glycemic traits in humans, reinforcing their translational relevance. This study revealed sex-dependent and sex-independent phosphosignaling mechanisms that associate with muscle insulin responsiveness as well as hundreds of sex-specific, CR-responsive phosphosites. These findings provide a rich resource for future research on CR and insulin sensitivity.
{"title":"Sex-specific Phosphoproteome Responses to Calorie Restriction and Insulin in Skeletal Muscle from Older Rats.","authors":"Haiyan Wang,Søren Madsen,Elise J Needham,Sean J Humphrey,Amy Zheng,Edward B Arias,Jacqueline Stöckli,Harry B Cutler,David E James,Gregory D Cartee","doi":"10.1093/gerona/glaf231","DOIUrl":"https://doi.org/10.1093/gerona/glaf231","url":null,"abstract":"Calorie restriction (CR; calorie intake reduced by ∼20-40% below ad libitum, AL, intake) potentiates skeletal muscle insulin sensitivity during old age by incompletely understood mechanisms. We aimed to identify CR-induced changes in muscle insulin signaling that may explain this enhanced sensitivity. We examined how CR (65% of AL intake for 8-weeks) alters muscle insulin action and signaling in aged rats (24-months-old) of both sexes. We assessed insulin-stimulated glucose uptake (ISGU) in muscle together with deep phosphoproteomic profiling. CR enhanced ISGU in both sexes, with higher ISGU in females regardless of diet. We identified 590 diet-responsive phosphosites, indicating extensive CR-induced remodelling of muscle phosphorylation, particularly within structural and contractile pathways. Strikingly, 70% of these sites were sex-specific. Numerous insulin-responsive sites were identified (193 in females; 107 in males) with 60 overlapping sites. The magnitude of the insulin-effects among all significantly regulated sites correlated between sexes. S1443 phosphorylation on EH domain-binding protein 1-like protein-1 (Ehbp1l1; a potential regulator of Rab proteins that control GLUT4 glucose transporter trafficking) was insulin-responsive in both sexes but only associated to ISGU in females. Personalized phosphoproteomic analysis also identified insulin-responsive sites on Leiomodin-1 (Lmod1) that correlated with ISGU across individuals. Both Lmod1 and Ehbp1l1 have strong genetic association with glycemic traits in humans, reinforcing their translational relevance. This study revealed sex-dependent and sex-independent phosphosignaling mechanisms that associate with muscle insulin responsiveness as well as hundreds of sex-specific, CR-responsive phosphosites. These findings provide a rich resource for future research on CR and insulin sensitivity.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiyong Yang, Miaoling Gong, Yi Zhou, Jifeng Zhao, Weijian Chen, Wengang Liu
Background Osteosarcopenia, defined by the coexistence of osteoporosis and sarcopenia, presents a significant health challenge for aging populations. The purpose of current study was to identify potential therapeutic targets for osteosarcopenia using integrative analysis methods, including multi-omics Mendelian Randomization (MR) and single-cell RNA sequencing (scRNA-seq). Methods An integrative analysis using transcriptome, proteome wide MR, Summary-based MR (SMR), and colocalization analysis was performed. Data from large-scale genome-wide association studies (GWAS) of plasma transcriptome, proteome were analyzed. The expression data for these candidate targets across different tissues and cell types to further explore how they might contribute to the development of osteosarcopenia. Results The MR analysis identified 331 genes, 20 and 24 proteins in the eQTLgen, deCODE and Fenland datasets that were causally associated with osteosarcopenia traits. Twelve causal targets were validated in at least two datasets, and the causal direction was generally consistent. Among these, MGP, CTSS and SNUPN were recognized as protective factors, while MMP16, ART4, and PSMD9 were associated with an increased risk of osteosarcopenia. Validation was further supported by SMR and colocalization analyses. The tissue and single-cell expression of these candidate targets suggested that MGP and CTSS may directly influence the musculoskeletal system, while the others might not. Conclusions : Our findings suggest that ART4, MMP16, and PSMD9 may be risk factors for osteosarcopenia, whereas MGP, SNUPN and CTSS show protective potential. Further investigations are needed to validate these targets and investigate their roles in specific tissues and cellular contexts, advancing osteosarcopenia management strategies.
{"title":"Multi-omics Mendelian Randomization and Single-Cell Analysis Identify Novel Therapeutic Targets for Osteosarcopenia","authors":"Jiyong Yang, Miaoling Gong, Yi Zhou, Jifeng Zhao, Weijian Chen, Wengang Liu","doi":"10.1093/gerona/glaf228","DOIUrl":"https://doi.org/10.1093/gerona/glaf228","url":null,"abstract":"Background Osteosarcopenia, defined by the coexistence of osteoporosis and sarcopenia, presents a significant health challenge for aging populations. The purpose of current study was to identify potential therapeutic targets for osteosarcopenia using integrative analysis methods, including multi-omics Mendelian Randomization (MR) and single-cell RNA sequencing (scRNA-seq). Methods An integrative analysis using transcriptome, proteome wide MR, Summary-based MR (SMR), and colocalization analysis was performed. Data from large-scale genome-wide association studies (GWAS) of plasma transcriptome, proteome were analyzed. The expression data for these candidate targets across different tissues and cell types to further explore how they might contribute to the development of osteosarcopenia. Results The MR analysis identified 331 genes, 20 and 24 proteins in the eQTLgen, deCODE and Fenland datasets that were causally associated with osteosarcopenia traits. Twelve causal targets were validated in at least two datasets, and the causal direction was generally consistent. Among these, MGP, CTSS and SNUPN were recognized as protective factors, while MMP16, ART4, and PSMD9 were associated with an increased risk of osteosarcopenia. Validation was further supported by SMR and colocalization analyses. The tissue and single-cell expression of these candidate targets suggested that MGP and CTSS may directly influence the musculoskeletal system, while the others might not. Conclusions : Our findings suggest that ART4, MMP16, and PSMD9 may be risk factors for osteosarcopenia, whereas MGP, SNUPN and CTSS show protective potential. Further investigations are needed to validate these targets and investigate their roles in specific tissues and cellular contexts, advancing osteosarcopenia management strategies.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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