The cardio-ankle vascular index (CAVI) is a non-invasive parameter reflecting vascular stiffness. CAVI correlates with the burden of atherosclerosis and future cardiovascular events. Mitochondria of peripheral blood mononuclear cells (PBMCs) have been identified as a non-invasive source for assessing systemic mitochondrial bioenergetics. This study aimed to investigate the relationship between CAVI values and mitochondrial bioenergetics of PBMCs in the elderly population. This cross-sectional study enrolled participants from the Electricity Generating Authority of Thailand (EGAT) between 2017 and 2018. 1640 participants with an ankle-brachial index greater than 0.9 were included in this study. All participants were stratified into three groups based on their CAVI values as high (CAVI ≥9), moderate (9 >CAVI ≥8), and low (CAVI <8), in which each group comprised 702, 507 and 431 participants, respectively. The extracellular flux analyzer was used to measure mitochondrial respiration of isolated PBMCs. The mean age of the participants was 67.9 years, and 69.6% of them were male. After adjusted with potential confounders including age, sex, smoking status, body mass index, diabetes, dyslipidemia, hypertension, and creatinine clearance, participants with high CAVI values were independently associated with impaired mitochondrial bioenergetics, including decreased basal respiration, maximal respiration, and spare respiratory capacity, as well as increased mitochondrial reactive oxygen species. This study demonstrated that CAVI measurement reflects the underlying impairment of cellular mitochondrial bioenergetics in PBMCs. Further longitudinal studies are necessary to establish both a causal relationship between CAVI measurement and underlying cellular dysfunction.
{"title":"An Increase in Vascular Stiffness is Positively Associated with Mitochondrial Bioenergetics Impairment of Peripheral Blood Mononuclear Cells in the Elderly Population","authors":"Tanawat Attachaipanich, Sirawit Sriwichaiin, Nattayaporn Apaijai, Sasiwan Kerdphoo, Nisakron Thongmung, Prin Vathesatogkit, Piyamitr Sritara, Nipon Chattipakorn, Chagriya Kitiyakara, Siriporn C Chattipakorn","doi":"10.1093/gerona/glae095","DOIUrl":"https://doi.org/10.1093/gerona/glae095","url":null,"abstract":"The cardio-ankle vascular index (CAVI) is a non-invasive parameter reflecting vascular stiffness. CAVI correlates with the burden of atherosclerosis and future cardiovascular events. Mitochondria of peripheral blood mononuclear cells (PBMCs) have been identified as a non-invasive source for assessing systemic mitochondrial bioenergetics. This study aimed to investigate the relationship between CAVI values and mitochondrial bioenergetics of PBMCs in the elderly population. This cross-sectional study enrolled participants from the Electricity Generating Authority of Thailand (EGAT) between 2017 and 2018. 1640 participants with an ankle-brachial index greater than 0.9 were included in this study. All participants were stratified into three groups based on their CAVI values as high (CAVI ≥9), moderate (9 &gt;CAVI ≥8), and low (CAVI &lt;8), in which each group comprised 702, 507 and 431 participants, respectively. The extracellular flux analyzer was used to measure mitochondrial respiration of isolated PBMCs. The mean age of the participants was 67.9 years, and 69.6% of them were male. After adjusted with potential confounders including age, sex, smoking status, body mass index, diabetes, dyslipidemia, hypertension, and creatinine clearance, participants with high CAVI values were independently associated with impaired mitochondrial bioenergetics, including decreased basal respiration, maximal respiration, and spare respiratory capacity, as well as increased mitochondrial reactive oxygen species. This study demonstrated that CAVI measurement reflects the underlying impairment of cellular mitochondrial bioenergetics in PBMCs. Further longitudinal studies are necessary to establish both a causal relationship between CAVI measurement and underlying cellular dysfunction.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140349077","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}
David A Ganz, Denise Esserman, Nancy K Latham, Michael Kane, Lillian C Min, Thomas M Gill, David B Reuben, Peter Peduzzi, Erich J Greene
Background Diagnosis-code-based algorithms to identify fall injuries in Medicare data are useful for ascertaining outcomes in interventional and observational studies. However, these algorithms have not been validated against a fully external reference standard, in ICD-10-CM, or in Medicare Advantage (MA) data. Methods We linked self-reported fall injuries leading to medical attention (FIMA) from the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial (reference standard) to Medicare fee-for-service (FFS) and MA data from 2015-2019. We measured the area under the receiver operating characteristic curve (AUC) based on sensitivity and specificity of a diagnosis-code-based algorithm against the reference standard for presence or absence of ≥1 FIMA within a specified window of dates, varying the window size to obtain points on the curve. We stratified results by source (FFS versus MA), trial arm (intervention versus control), and STRIDE’s ten participating healthcare systems. Results Both reference standard data and Medicare data were available for 4941 (of 5451) participants. The reference standard and algorithm identified 2054 and 2067 FIMA, respectively. The algorithm had 45% sensitivity (95% confidence interval [CI], 43%-47%) and 99% specificity (95% CI, 99%-99%) to identify reference standard FIMA within the same calendar month. The AUC was 0.79 (95% CI, 0.78-0.81) and was similar by FFS or MA data source or trial arm, but showed variation among STRIDE healthcare systems (AUC range by healthcare system, 0.71 to 0.84). Conclusions An ICD-10-CM algorithm to identify fall injuries demonstrated acceptable performance against an external reference standard, in both MA and FFS data.
{"title":"Validation of a Rule-Based ICD-10-CM Algorithm to Detect Fall Injuries in Medicare Data","authors":"David A Ganz, Denise Esserman, Nancy K Latham, Michael Kane, Lillian C Min, Thomas M Gill, David B Reuben, Peter Peduzzi, Erich J Greene","doi":"10.1093/gerona/glae096","DOIUrl":"https://doi.org/10.1093/gerona/glae096","url":null,"abstract":"Background Diagnosis-code-based algorithms to identify fall injuries in Medicare data are useful for ascertaining outcomes in interventional and observational studies. However, these algorithms have not been validated against a fully external reference standard, in ICD-10-CM, or in Medicare Advantage (MA) data. Methods We linked self-reported fall injuries leading to medical attention (FIMA) from the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial (reference standard) to Medicare fee-for-service (FFS) and MA data from 2015-2019. We measured the area under the receiver operating characteristic curve (AUC) based on sensitivity and specificity of a diagnosis-code-based algorithm against the reference standard for presence or absence of ≥1 FIMA within a specified window of dates, varying the window size to obtain points on the curve. We stratified results by source (FFS versus MA), trial arm (intervention versus control), and STRIDE’s ten participating healthcare systems. Results Both reference standard data and Medicare data were available for 4941 (of 5451) participants. The reference standard and algorithm identified 2054 and 2067 FIMA, respectively. The algorithm had 45% sensitivity (95% confidence interval [CI], 43%-47%) and 99% specificity (95% CI, 99%-99%) to identify reference standard FIMA within the same calendar month. The AUC was 0.79 (95% CI, 0.78-0.81) and was similar by FFS or MA data source or trial arm, but showed variation among STRIDE healthcare systems (AUC range by healthcare system, 0.71 to 0.84). Conclusions An ICD-10-CM algorithm to identify fall injuries demonstrated acceptable performance against an external reference standard, in both MA and FFS data.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140349232","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}
{"title":"Correction to: Epigenetic and Metabolomic Biomarkers for Biological Age: A Comparative Analysis of Mortality and Frailty Risk","authors":"","doi":"10.1093/gerona/glae090","DOIUrl":"https://doi.org/10.1093/gerona/glae090","url":null,"abstract":"","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"95 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140758889","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}
Priscila Chiavellini, Marianne Lehmann, Maria D Gallardo, Martina Canatelli Mallat, Diana C Pasquini, Joseph A Zoller, Juozas Gordevicius, Mauricio Girard, Ezequiel Lacunza, Claudia B Herenu, Steve Horvath, Rodolfo G Goya
There is converging evidence that young blood conveys cells, vesicles and molecules able to revitalize function and restore organ integrity in old individuals. We assessed the effects of young plasma on the lifespan, epigenetic age and healthspan of old female rats. Beginning at 25.6 months of age, a group of 9 rats (group T) was i.p. injected with plasma from young rats until their natural death. A group of 8 control rats of the same age received no treatment (group C). Blood samples were collected every other week. Survival curves showed that from age 26 to 30 months, none of the group T animals died, whereas the survival curve of group C rats began to decline at age 26 months. Blood DNAm age versus chronological age showed that DNAm age in young animals increased faster than chronological age, then slowed down, entering a plateau after 27 months. The DNAm age of the treated rats fell below the DNAm age of controls and, in numerical terms, remained consistently lower until natural death. When rats were grouped according to the similarities in their differential blood DNA methylation profile, samples from the treated and control rats clustered in separate groups. Analysis of promoter differential methylation in genes involved in systemic regulatory activities revealed specific GO term enrichment related to the insulin-like factors pathways as well as to cytokines and chemokines associated with immune and homeostatic functions. We conclude that young plasma therapy may constitute a natural noninvasive intervention for epigenetic rejuvenation and health enhancement.
有越来越多的证据表明，年轻血液中输送的细胞、囊泡和分子能够振兴老年人的功能并恢复器官的完整性。我们评估了年轻血浆对老年雌性大鼠寿命、表观遗传年龄和健康寿命的影响。从 25.6 个月大的大鼠开始，给一组 9 只大鼠（T 组）注射年轻大鼠的血浆，直到它们自然死亡。8 只同龄对照组大鼠未接受任何治疗（C 组）。每隔一周采集一次血液样本。生存曲线显示，从 26 个月大到 30 个月大，T 组大鼠无一死亡，而 C 组大鼠的生存曲线在 26 个月大时开始下降。血液中DNAm年龄与实际年龄的对比显示，幼鼠DNAm年龄的增长速度快于实际年龄的增长速度，然后放缓，在27个月后进入平稳期。接受治疗的大鼠的DNAm年龄低于对照组的DNAm年龄，而且从数值上看，一直持续较低，直到自然死亡。当根据大鼠血液 DNA 甲基化差异图谱的相似性对大鼠进行分组时，治疗大鼠和对照组大鼠的样本被分成了不同的组。对参与系统调节活动的基因启动子差异甲基化的分析表明，特定的 GO 术语富集与胰岛素样因子通路以及与免疫和平衡功能相关的细胞因子和趋化因子有关。我们得出的结论是，年轻血浆疗法可能是一种天然的非侵入性干预措施，可用于表观遗传年轻化和增强健康。
{"title":"Young Plasma Rejuvenates Blood Dna Methylation Profile, Extends Mean Lifespan And Improves Physical Appearance In Old Rats","authors":"Priscila Chiavellini, Marianne Lehmann, Maria D Gallardo, Martina Canatelli Mallat, Diana C Pasquini, Joseph A Zoller, Juozas Gordevicius, Mauricio Girard, Ezequiel Lacunza, Claudia B Herenu, Steve Horvath, Rodolfo G Goya","doi":"10.1093/gerona/glae071","DOIUrl":"https://doi.org/10.1093/gerona/glae071","url":null,"abstract":"There is converging evidence that young blood conveys cells, vesicles and molecules able to revitalize function and restore organ integrity in old individuals. We assessed the effects of young plasma on the lifespan, epigenetic age and healthspan of old female rats. Beginning at 25.6 months of age, a group of 9 rats (group T) was i.p. injected with plasma from young rats until their natural death. A group of 8 control rats of the same age received no treatment (group C). Blood samples were collected every other week. Survival curves showed that from age 26 to 30 months, none of the group T animals died, whereas the survival curve of group C rats began to decline at age 26 months. Blood DNAm age versus chronological age showed that DNAm age in young animals increased faster than chronological age, then slowed down, entering a plateau after 27 months. The DNAm age of the treated rats fell below the DNAm age of controls and, in numerical terms, remained consistently lower until natural death. When rats were grouped according to the similarities in their differential blood DNA methylation profile, samples from the treated and control rats clustered in separate groups. Analysis of promoter differential methylation in genes involved in systemic regulatory activities revealed specific GO term enrichment related to the insulin-like factors pathways as well as to cytokines and chemokines associated with immune and homeostatic functions. We conclude that young plasma therapy may constitute a natural noninvasive intervention for epigenetic rejuvenation and health enhancement.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140016573","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}
Candace Y Parker-Autry, Scott Bauer, Cassie Ford, W Thomas Gregory, Gopal Badlani, Charles D Scales
Background Aging beyond 65 years is associated with increased prevalence of urinary incontinence (UI), frailty, and increased complication rate with UI treatments. To investigate this relationship, we examined frailty as a predictor of procedure-based UI treatment patterns and urologic complications in Medicare-eligible women. Methods We identified women undergoing procedures for UI between 2011-2018 in the 5% limited Medicare data set. A Claims-based Frailty Index (CFI) using data from the 12-months prior to the index procedure defined frailty (CFI≥0.25). Urologic complications were assessed during the 12-months following the index procedure. We used unadjusted logistic regression models to calculate odds of having a specific type of UI procedure based on frailty status. Odds of post-procedure urologic complications were examined with logistic regression adjusted for age and race. Results We identified 21,783 women who underwent a procedure-based intervention for UI, of whom 3,826 (17.5%) were frail. Frail women with stress UI were 2.6 times more likely to receive periurethral bulking (95%CI 2.26-2.95), compared to non-frail. Conversely, frailty was associated with lower odds of receiving a Sling or Burch colposuspension. Among women with urgency UI or overactive bladder (OAB), compared to non-frail, frailty was associated with higher odds of both sacral neuromodulation (OR=1.21, 95%CI 1.11-1.33) and intravesical Botox (OR=1.16, 95%CI 1.06-1.28), but lower odds of receiving posterior tibial nerve stimulation. Frailty was associated with higher odds of post-procedure urologic complications (OR=1.64, 95%CI 1.47-1.81). Conclusions Frailty status may influence treatment choice for treatment of stress or urgency UI symptoms and increase the odds of post-procedural complications in older women.
{"title":"Examining the role of frailty on treatment patterns and complications among older women undergoing procedure-based treatment for urinary incontinence","authors":"Candace Y Parker-Autry, Scott Bauer, Cassie Ford, W Thomas Gregory, Gopal Badlani, Charles D Scales","doi":"10.1093/gerona/glae027","DOIUrl":"https://doi.org/10.1093/gerona/glae027","url":null,"abstract":"Background Aging beyond 65 years is associated with increased prevalence of urinary incontinence (UI), frailty, and increased complication rate with UI treatments. To investigate this relationship, we examined frailty as a predictor of procedure-based UI treatment patterns and urologic complications in Medicare-eligible women. Methods We identified women undergoing procedures for UI between 2011-2018 in the 5% limited Medicare data set. A Claims-based Frailty Index (CFI) using data from the 12-months prior to the index procedure defined frailty (CFI≥0.25). Urologic complications were assessed during the 12-months following the index procedure. We used unadjusted logistic regression models to calculate odds of having a specific type of UI procedure based on frailty status. Odds of post-procedure urologic complications were examined with logistic regression adjusted for age and race. Results We identified 21,783 women who underwent a procedure-based intervention for UI, of whom 3,826 (17.5%) were frail. Frail women with stress UI were 2.6 times more likely to receive periurethral bulking (95%CI 2.26-2.95), compared to non-frail. Conversely, frailty was associated with lower odds of receiving a Sling or Burch colposuspension. Among women with urgency UI or overactive bladder (OAB), compared to non-frail, frailty was associated with higher odds of both sacral neuromodulation (OR=1.21, 95%CI 1.11-1.33) and intravesical Botox (OR=1.16, 95%CI 1.06-1.28), but lower odds of receiving posterior tibial nerve stimulation. Frailty was associated with higher odds of post-procedure urologic complications (OR=1.64, 95%CI 1.47-1.81). Conclusions Frailty status may influence treatment choice for treatment of stress or urgency UI symptoms and increase the odds of post-procedural complications in older women.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"200 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568311","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}
We investigated the strength of the association between baseline epigenetic age, everyday discrimination, and trajectories of chronic health conditions (CHCs) across 3 study waves, among adults 50 years of age and older. We used 2016-2020 data from the Health and Retirement Study (HRS). Data for the PhenoAge and DNAm GrimAge second-generation epigenetic clocks were from the 2016 HRS Venous Blood Study. CHC trajectories were constructed using latent class growth curve models. Multinomial logistic regression models assessed the strength of the association between accelerated epigenetic age, everyday discrimination, and the newly constructed CHC trajectories for participants with complete data (n=2,893). In the fully adjusted model, accelerated PhenoAge (RRR=2.53, 95%CI= 1.81,3.55) and DNAm GrimAge (RRR=2.79, 95%CI= 1.95,4.00) were associated with classification into the high CHC trajectory class. Racial disparities were evident, with increased risk of classification into the high trajectory class for Black (PhenoAge: RRR=1.69, 95%CI=1.07, 2.68) and reduced risk for Hispanic (PhenoAge: RRR=0.32, 95%CI=0.16,0.64; DNAm GrimAge: RRR=0.34,95%CI=0.17,0.68), relative to White participants. Everyday discrimination was associated with classification into the medium-high (RRR=1.28, 95%CI=1.00,1.64) and high (RRR=1.52, 95%CI=1.07,2.16) trajectory classes in models assessing DNAm GrimAge. More research is needed to better understand the longitudinal health outcomes of accelerated aging and adverse social exposures. Such research may provide insights into vulnerable adults who may need varied welfare supports earlier than the mandated chronological age for access to federal and state resources.
{"title":"Association of epigenetic age and everyday discrimination with longitudinal trajectories of chronic health conditions in older adults","authors":"Miriam Mutambudzi, Maria T Brown, Nai-Wei Chen","doi":"10.1093/gerona/glae005","DOIUrl":"https://doi.org/10.1093/gerona/glae005","url":null,"abstract":"We investigated the strength of the association between baseline epigenetic age, everyday discrimination, and trajectories of chronic health conditions (CHCs) across 3 study waves, among adults 50 years of age and older. We used 2016-2020 data from the Health and Retirement Study (HRS). Data for the PhenoAge and DNAm GrimAge second-generation epigenetic clocks were from the 2016 HRS Venous Blood Study. CHC trajectories were constructed using latent class growth curve models. Multinomial logistic regression models assessed the strength of the association between accelerated epigenetic age, everyday discrimination, and the newly constructed CHC trajectories for participants with complete data (n=2,893). In the fully adjusted model, accelerated PhenoAge (RRR=2.53, 95%CI= 1.81,3.55) and DNAm GrimAge (RRR=2.79, 95%CI= 1.95,4.00) were associated with classification into the high CHC trajectory class. Racial disparities were evident, with increased risk of classification into the high trajectory class for Black (PhenoAge: RRR=1.69, 95%CI=1.07, 2.68) and reduced risk for Hispanic (PhenoAge: RRR=0.32, 95%CI=0.16,0.64; DNAm GrimAge: RRR=0.34,95%CI=0.17,0.68), relative to White participants. Everyday discrimination was associated with classification into the medium-high (RRR=1.28, 95%CI=1.00,1.64) and high (RRR=1.52, 95%CI=1.07,2.16) trajectory classes in models assessing DNAm GrimAge. More research is needed to better understand the longitudinal health outcomes of accelerated aging and adverse social exposures. Such research may provide insights into vulnerable adults who may need varied welfare supports earlier than the mandated chronological age for access to federal and state resources.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"208 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139400410","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}
Qiuyu Li, Xiaolong Lin, Xiaowen Bo, Siyuan Chen, Donghui Zhao, Qin Ma, Yuhao Zhao, Hong Yang, Jinghua Liu, Qian Fan
The mechanisms through which aging increases heart injury remain partially understood. Protein phosphorylation plays a critical regulatory role in cell survival and death. Using an unbiased phosphoproteomics approach, we aimed to identify the protein(s) whose phosphorylation could be causatively related to aging-related cardiomyocyte apoptosis and elucidate the underlying mechanisms. Comparative phosphoproteomics were conducted on cardiac tissues obtained from young (8 weeks) and aged (24 months) mice. Our findings revealed that Mammalian Target of Rapamycin phosphorylation at T1262 (mTORT1262) was reduced in the aging heart. Immunohistochemical and Western blot analyses confirmed these findings in aging myocardia and D-galactose-induced senescent AC16 cardiomyocytes. In hypoxia/reoxygenation cardiomyocytes, mTORT1262 phosphorylation deficiency (mTORT1262A, lentivirus-mediated transfection) inhibited AKT1, suppressed NF-κB, activated FOXO1/3a signaling, and ultimately exacerbated apoptosis. Conversely, mTORT1262 pseudophosphorylation (mTORT1262E) exhibited opposite effects. Through bioinformatics and CO-IP, purinergic receptor P2X4 (P2X4R) was found to be the possible receptor responsible for mTORT1262 phosphorylation. Knockdown of P2X4R increased apoptosis, whereas its overexpression decreased it. In senescent cardiomyocytes, P2X4R expression and mTORT1262 and AKT1S473 phosphorylation were reduced, NF-κB signaling was suppressed, and FOXO1/3a signaling was activated. We demonstrated that P2X4R downregulation and the subsequent reduction of mTORT1262 phosphorylation is a novel mechanism contributing to cardiomyocyte apoptosis in aging hearts. The P2X4R-mTOR-AKT1 signaling pathway represents a potential therapeutic target against accelerated cardiac injury in aging.
{"title":"Identification of Reduced mTOR T1262 Phosphorylation as a Novel Mechanism and Therapeutic Target of Apoptosis in Senescent Cardiomyocytes","authors":"Qiuyu Li, Xiaolong Lin, Xiaowen Bo, Siyuan Chen, Donghui Zhao, Qin Ma, Yuhao Zhao, Hong Yang, Jinghua Liu, Qian Fan","doi":"10.1093/gerona/glae003","DOIUrl":"https://doi.org/10.1093/gerona/glae003","url":null,"abstract":"The mechanisms through which aging increases heart injury remain partially understood. Protein phosphorylation plays a critical regulatory role in cell survival and death. Using an unbiased phosphoproteomics approach, we aimed to identify the protein(s) whose phosphorylation could be causatively related to aging-related cardiomyocyte apoptosis and elucidate the underlying mechanisms. Comparative phosphoproteomics were conducted on cardiac tissues obtained from young (8 weeks) and aged (24 months) mice. Our findings revealed that Mammalian Target of Rapamycin phosphorylation at T1262 (mTORT1262) was reduced in the aging heart. Immunohistochemical and Western blot analyses confirmed these findings in aging myocardia and D-galactose-induced senescent AC16 cardiomyocytes. In hypoxia/reoxygenation cardiomyocytes, mTORT1262 phosphorylation deficiency (mTORT1262A, lentivirus-mediated transfection) inhibited AKT1, suppressed NF-κB, activated FOXO1/3a signaling, and ultimately exacerbated apoptosis. Conversely, mTORT1262 pseudophosphorylation (mTORT1262E) exhibited opposite effects. Through bioinformatics and CO-IP, purinergic receptor P2X4 (P2X4R) was found to be the possible receptor responsible for mTORT1262 phosphorylation. Knockdown of P2X4R increased apoptosis, whereas its overexpression decreased it. In senescent cardiomyocytes, P2X4R expression and mTORT1262 and AKT1S473 phosphorylation were reduced, NF-κB signaling was suppressed, and FOXO1/3a signaling was activated. We demonstrated that P2X4R downregulation and the subsequent reduction of mTORT1262 phosphorylation is a novel mechanism contributing to cardiomyocyte apoptosis in aging hearts. The P2X4R-mTOR-AKT1 signaling pathway represents a potential therapeutic target against accelerated cardiac injury in aging.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139400514","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}
Jeong-Hyun Kang, Jeong-Hwa Baek, Jin Kwang Lee, Seok Woo Hong
Skeletal muscle and bone interact with each other via mechanical and biochemical ways. This study aimed to investigate the molecular mechanisms of interaction between muscle and bone and by analyzing the transcriptional profiles of total RNA from muscle tissue of females with distal radius fractures. A total 30 female participants (mean age 71.1 ± 8.9 years) with distal radius fractures were recruited. Participants were categorized into two groups; the NORM group consisted of participants with T score of the areal bone mineral density (aBMD) of the femoral neck higher than -1.0, handgrip strength greater than 18 kg, and gait speed faster than 1.0 m/sec (n = 10). Otherwise, participants with T score of the aBMD of the femoral neck equal or less than -1.0, handgrip strength lower than 18 kg, and gait speed slower than 1.0 m/sec (n = 20) were categorized into EXP group. Pronator quadratus muscle samples were obtained from all participants. Total RNA was extracted from frozen muscle samples and sequenced. The gene ontology analysis demonstrated that the potential interactions between attached muscle function and density of the associated bone would be linked with collagen biosynthetic activity, and maintenance of extracellular matrix structures. The analysis of the pathway, network, and protein class exhibited that integrin signaling, inflammatory reactions, matrix metalloproteinase (MMP) activity, and extracellular matrix protein structure had possible associations with the molecular background of muscle-bone interaction. Through integrin signaling, MMP activity, inflammatory reactions, and collagen biosynthesis, muscle and bone may mutually interact with one another.
{"title":"Transcriptional Profiling of Muscle in Females with Distal Radius Fracture and Functional Sarcopenia","authors":"Jeong-Hyun Kang, Jeong-Hwa Baek, Jin Kwang Lee, Seok Woo Hong","doi":"10.1093/gerona/glae002","DOIUrl":"https://doi.org/10.1093/gerona/glae002","url":null,"abstract":"Skeletal muscle and bone interact with each other via mechanical and biochemical ways. This study aimed to investigate the molecular mechanisms of interaction between muscle and bone and by analyzing the transcriptional profiles of total RNA from muscle tissue of females with distal radius fractures. A total 30 female participants (mean age 71.1 ± 8.9 years) with distal radius fractures were recruited. Participants were categorized into two groups; the NORM group consisted of participants with T score of the areal bone mineral density (aBMD) of the femoral neck higher than -1.0, handgrip strength greater than 18 kg, and gait speed faster than 1.0 m/sec (n = 10). Otherwise, participants with T score of the aBMD of the femoral neck equal or less than -1.0, handgrip strength lower than 18 kg, and gait speed slower than 1.0 m/sec (n = 20) were categorized into EXP group. Pronator quadratus muscle samples were obtained from all participants. Total RNA was extracted from frozen muscle samples and sequenced. The gene ontology analysis demonstrated that the potential interactions between attached muscle function and density of the associated bone would be linked with collagen biosynthetic activity, and maintenance of extracellular matrix structures. The analysis of the pathway, network, and protein class exhibited that integrin signaling, inflammatory reactions, matrix metalloproteinase (MMP) activity, and extracellular matrix protein structure had possible associations with the molecular background of muscle-bone interaction. Through integrin signaling, MMP activity, inflammatory reactions, and collagen biosynthesis, muscle and bone may mutually interact with one another.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139400505","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}
Veronica Vega-Cabello, Ellen A Struijk, Francisco Felix Caballero, Humberto Yévenes-Briones, Rosario Ortolá, Amaia Calderón-Larrañaga, Alberto Lana, Fernando Rodríguez-Artalejo, Esther Lopez-Garcia
Background The role of diet quality in the accumulation of multiple chronic conditions is mostly unknown. This study examined diet quality in association with the number of chronic conditions and the rate of multimorbidity development among community-dwelling older adults. Methods We used data from 2784 adults aged ≥65 years from the Seniors-ENRICA 2 cohort. Diet quality was assessed at baseline (2015–2017) with the Alternate Healthy Eating Index-2010 (AHEI-2010) and the Mediterranean Diet Adherence Screener (MEDAS). Information on medical diagnoses was obtained from electronic clinical records up to 2021. Results Higher adherence to the AHEI-2010 was associated with a lower number of total chronic conditions [β (95% CI) quartile 4 vs. 1: -0.57 (-0.86, 0.27), P trend <0.001] and cardiometabolic conditions [-0.30 (-0.44, -0.17), P trend <0.001] at baseline, while higher adherence to the MEDAS was associated with lower number of total chronic conditions [-0.30 (-0.58, -0.02), P trend =0.01] and neuropsychiatric and neurodegenerative conditions [-0.09 (-0.17, -0.01), P trend =0.01]. After a median follow-up of 5.2 years (range: 0.1–6.1 years) higher adherence to the AHEI-2010 was associated with a lower increase in chronic conditions [β (95% confidence interval) quartile 4 vs. 1: -0.16 (-0.30, -0.01), P trend =0.04] and with lower rate of chronic disease accumulation. Conclusion Higher diet quality, as measured by the AHEI-2010, was associated with a lower number of chronic health conditions and a lower rate of multimorbidity development over time.
{"title":"Diet quality and multimorbidity in older adults: a prospective cohort study","authors":"Veronica Vega-Cabello, Ellen A Struijk, Francisco Felix Caballero, Humberto Yévenes-Briones, Rosario Ortolá, Amaia Calderón-Larrañaga, Alberto Lana, Fernando Rodríguez-Artalejo, Esther Lopez-Garcia","doi":"10.1093/gerona/glad285","DOIUrl":"https://doi.org/10.1093/gerona/glad285","url":null,"abstract":"Background The role of diet quality in the accumulation of multiple chronic conditions is mostly unknown. This study examined diet quality in association with the number of chronic conditions and the rate of multimorbidity development among community-dwelling older adults. Methods We used data from 2784 adults aged ≥65 years from the Seniors-ENRICA 2 cohort. Diet quality was assessed at baseline (2015–2017) with the Alternate Healthy Eating Index-2010 (AHEI-2010) and the Mediterranean Diet Adherence Screener (MEDAS). Information on medical diagnoses was obtained from electronic clinical records up to 2021. Results Higher adherence to the AHEI-2010 was associated with a lower number of total chronic conditions [β (95% CI) quartile 4 vs. 1: -0.57 (-0.86, 0.27), P trend &lt;0.001] and cardiometabolic conditions [-0.30 (-0.44, -0.17), P trend &lt;0.001] at baseline, while higher adherence to the MEDAS was associated with lower number of total chronic conditions [-0.30 (-0.58, -0.02), P trend =0.01] and neuropsychiatric and neurodegenerative conditions [-0.09 (-0.17, -0.01), P trend =0.01]. After a median follow-up of 5.2 years (range: 0.1–6.1 years) higher adherence to the AHEI-2010 was associated with a lower increase in chronic conditions [β (95% confidence interval) quartile 4 vs. 1: -0.16 (-0.30, -0.01), P trend =0.04] and with lower rate of chronic disease accumulation. Conclusion Higher diet quality, as measured by the AHEI-2010, was associated with a lower number of chronic health conditions and a lower rate of multimorbidity development over time.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139060849","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}
Yuanyuan Wang, Rakibul M Islam, Sultana Monira Hussain, John J McNeil, Susan R Davis
Background Blood concentrations of testosterone and oestrone tend to increase in women aged >70 years, while concentrations of their precursor hormone dehydroepiandrosterone decline. It is unknown whether these changes influence physical function. We investigated whether concentrations of these hormones were associated with grip strength and self-reported physical function in community-dwelling older women. Methods 9179 Australian women, aged >70 years, were recruited to the ASPREE trial. Sex hormones were measured in SHOW, an ASPREE sub-study, by liquid chromatography-tandem mass spectrometry in 6358 women. The associations between hormone concentrations and physical function [handgrip strength and self-reported physical function assessed by SF-12v2 physical component summary (PCS)] were examined using multiple linear regression. Results The median age of the 5447 participants was 74.0 (IQR 71.7-77.6) years. Testosterone concentrations above the lowest quartile were associated with less decline in grip strength [mean -1.39 (95% CI -1.54 to -1.24) versus -1.75 (-2.00 to -1.50) kg, p=0.02], and dehydroepiandrosterone concentrations above the lowest quartile were associated with less decline in grip strength [-1.39 (-1.54 to -1.25) versus -1.82 (-2.11 to -1.55) kg, p=0.007] and PCS scores [-1.49 (-1.80 to -1.17) versus -2.33 (-2.93 to -1.72), p=0.02] over four years, compared with those in the respective lowest quartile. Conclusions Low endogenous concentrations of testosterone and dehydroepiandrosterone were associated the greatest likelihood of physical function decline in community-based women aged >70 years. Further studies are warranted to determine whether testosterone and dehydroepiandrosterone therapy prevents functional decline in this at-risk group using sensitive measures of muscle strength and performance.
背景 70 岁女性血液中睾酮和雌酮的浓度呈上升趋势，而其前体激素脱氢表雄酮的浓度却在下降。目前还不清楚这些变化是否会影响身体机能。我们研究了这些激素的浓度是否与社区老年妇女的握力和自我报告的身体功能有关。方法 ASPREE 试验招募了 9179 名年龄为 70 岁的澳大利亚女性。在 ASPREE 子研究 SHOW 中，通过液相色谱-串联质谱法对 6358 名妇女的性激素进行了测定。采用多元线性回归法研究了激素浓度与身体功能（手握力和通过 SF-12v2 身体成分总表 (PCS) 评估的自我报告身体功能）之间的关系。结果 5447 名参与者的中位年龄为 74.0（IQR 71.7-77.6）岁。睾酮浓度高于最低四分位数与握力下降幅度较小有关[平均-1.39（95% CI -1.54 至-1.24）公斤对-1.75（-2.00 至-1.50）公斤，P=0.02]，脱氢表雄酮浓度高于最低四分位数与握力下降幅度较小有关[-1.39 (-1.54 to -1.25) versus -1.82 (-2.11 to -1.55) kg, p=0.007]和 PCS 评分[-1.49 (-1.80 to -1.17) versus -2.33 (-2.93 to -1.72), p=0.02]在四年内的下降幅度较小。结论 在年龄为 70 岁的社区妇女中，内源性睾酮和脱氢表雄酮浓度低与身体机能下降的可能性最大有关。有必要开展进一步的研究，利用对肌肉力量和表现的敏感测量来确定睾酮和脱氢表雄酮疗法是否能预防这一高风险人群的功能衰退。
{"title":"Associations between blood concentrations of sex hormones and physical function in community-dwelling older women: a prospective cohort study","authors":"Yuanyuan Wang, Rakibul M Islam, Sultana Monira Hussain, John J McNeil, Susan R Davis","doi":"10.1093/gerona/glad287","DOIUrl":"https://doi.org/10.1093/gerona/glad287","url":null,"abstract":"Background Blood concentrations of testosterone and oestrone tend to increase in women aged &gt;70 years, while concentrations of their precursor hormone dehydroepiandrosterone decline. It is unknown whether these changes influence physical function. We investigated whether concentrations of these hormones were associated with grip strength and self-reported physical function in community-dwelling older women. Methods 9179 Australian women, aged &gt;70 years, were recruited to the ASPREE trial. Sex hormones were measured in SHOW, an ASPREE sub-study, by liquid chromatography-tandem mass spectrometry in 6358 women. The associations between hormone concentrations and physical function [handgrip strength and self-reported physical function assessed by SF-12v2 physical component summary (PCS)] were examined using multiple linear regression. Results The median age of the 5447 participants was 74.0 (IQR 71.7-77.6) years. Testosterone concentrations above the lowest quartile were associated with less decline in grip strength [mean -1.39 (95% CI -1.54 to -1.24) versus -1.75 (-2.00 to -1.50) kg, p=0.02], and dehydroepiandrosterone concentrations above the lowest quartile were associated with less decline in grip strength [-1.39 (-1.54 to -1.25) versus -1.82 (-2.11 to -1.55) kg, p=0.007] and PCS scores [-1.49 (-1.80 to -1.17) versus -2.33 (-2.93 to -1.72), p=0.02] over four years, compared with those in the respective lowest quartile. Conclusions Low endogenous concentrations of testosterone and dehydroepiandrosterone were associated the greatest likelihood of physical function decline in community-based women aged &gt;70 years. Further studies are warranted to determine whether testosterone and dehydroepiandrosterone therapy prevents functional decline in this at-risk group using sensitive measures of muscle strength and performance.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139060860","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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