Xuling Chang, Kevin Yiqiang Chua, Chih Chuan Shih, Jieqi Chen, Ai Shan Lee, Patrick Tan, Ling Wang, Jianjun Liu, Chew-Kiat Heng, Jian-Min Yuan, Chiea Chuen Khor, Rajkumar Dorajoo, Woon-Puay Koh
Background: Adult height has been associated with handgrip strength, which is a surrogate marker of physical frailty. However, it is uncertain if this association is causative or due to confounding bias.
Methods: We evaluated pairwise associations among handgrip strength, adult height and genetically determined height [using a polygenic score (PGS) for height in a mediation framework and a two-sample Mendelian randomisation approach] by means of multivariable regression model using a prospective cohort of Chinese living in Singapore. We additionally evaluated pathway enrichments of height-related genes in relation to increased handgrip strength to discover common biological mechanisms underlying associations of genetically determined height with handgrip strength.
Results: Height PGS exhibited a positive association with handgrip strength at late life after adjusting for midlife body weight and other baseline exposures (cigarette smoking, education and physical activity status, P=1.2×10-9). Approximately 66.4% of the total effect of height PGS on handgrip strength was mediated through adult height (βindirect-effect=0.034, Pindirect-effect=1.4×10-40). Two-sample Mendelian randomisation evaluations showed a consistent causal relationship between increased height and increased handgrip strength in late life (P between 6.6×10-4 and 3.9×10-18), with insignificant horizontal pleiotropic effects (PMR-Egger intercept=0.853). Pathway analyses of genes related to both increased adult height and handgrip strength revealed enrichment in ossification and adipogenesis pathways (Padj between 0.034 to 6.8×10-4).
Conclusions: The study highlights on a potentially causal effect between increased adult height and increased handgrip strength at late life, which may be explained by related biological processes underlying preservation of muscle mass and strength in ageing.
{"title":"The causal effect of adult height on late-life handgrip strength: The Singapore Chinese Health Study.","authors":"Xuling Chang, Kevin Yiqiang Chua, Chih Chuan Shih, Jieqi Chen, Ai Shan Lee, Patrick Tan, Ling Wang, Jianjun Liu, Chew-Kiat Heng, Jian-Min Yuan, Chiea Chuen Khor, Rajkumar Dorajoo, Woon-Puay Koh","doi":"10.1093/gerona/glae216","DOIUrl":"https://doi.org/10.1093/gerona/glae216","url":null,"abstract":"<p><strong>Background: </strong>Adult height has been associated with handgrip strength, which is a surrogate marker of physical frailty. However, it is uncertain if this association is causative or due to confounding bias.</p><p><strong>Methods: </strong>We evaluated pairwise associations among handgrip strength, adult height and genetically determined height [using a polygenic score (PGS) for height in a mediation framework and a two-sample Mendelian randomisation approach] by means of multivariable regression model using a prospective cohort of Chinese living in Singapore. We additionally evaluated pathway enrichments of height-related genes in relation to increased handgrip strength to discover common biological mechanisms underlying associations of genetically determined height with handgrip strength.</p><p><strong>Results: </strong>Height PGS exhibited a positive association with handgrip strength at late life after adjusting for midlife body weight and other baseline exposures (cigarette smoking, education and physical activity status, P=1.2×10-9). Approximately 66.4% of the total effect of height PGS on handgrip strength was mediated through adult height (βindirect-effect=0.034, Pindirect-effect=1.4×10-40). Two-sample Mendelian randomisation evaluations showed a consistent causal relationship between increased height and increased handgrip strength in late life (P between 6.6×10-4 and 3.9×10-18), with insignificant horizontal pleiotropic effects (PMR-Egger intercept=0.853). Pathway analyses of genes related to both increased adult height and handgrip strength revealed enrichment in ossification and adipogenesis pathways (Padj between 0.034 to 6.8×10-4).</p><p><strong>Conclusions: </strong>The study highlights on a potentially causal effect between increased adult height and increased handgrip strength at late life, which may be explained by related biological processes underlying preservation of muscle mass and strength in ageing.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142083000","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}
Archana Nagarajan, Jason Laird, Obiadada Ugochukwu, Sjur Reppe, Kaare Gautvik, Ryan D Ross, David A Bennett, Clifford Rosen, Douglas P Kiel, Lenora A Higginbotham, Nicholas T Seyfried, Christine W Lary
Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are two prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown. We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these two diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in five ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest. These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP.
阿尔茨海默病及相关痴呆症(ADRD)和骨质疏松症(OP)是两种常见的老龄化疾病,两者之间存在明显的流行病学关联,但导致这种关联的潜在分子机制尚不清楚。我们利用骨骼和大脑转录组的网络分析发现了这两种疾病的共同分子机制。我们的研究包括来自 ROSMAP(宗教教派研究和拉什记忆与衰老项目)629 名参与者尸检大脑背外侧前额叶皮层组织的 RNA 序列数据,其中 298 人的亚组符合纳入五种 ADRD 类别的标准;以及来自奥斯陆绝经后妇女研究 84 名参与者经髂骨活检的 RNA 阵列数据。在每个组织中建立每个网络后,我们分析了模块(共表达基因组)与多种骨骼和神经特征之间的关联,检查了网络间模块的重叠,并进行了通路富集分析以发现保守机制。我们在 ROSMAP 中发现了与 ADRD 和骨骼相关特征有显著关联的三个模块,在 Oslo 中发现了与多种骨骼结果有显著关联的四个模块。我们发现这两个网络中与信号传导、组织稳态和发育相关的模块有明显的模块重叠,并且在 OP 和 ADRD 感兴趣的模块中发现了高度富集的无翼鸟相关整合位点(Wnt)信号传导。这些结果为开发 ADRD 和 OP 的治疗方法和生物标记物提供了转化机会。
{"title":"Network analysis of brain and bone tissue transcripts reveals shared molecular mechanisms underlying Alzheimer's Disease and related dementias (ADRD) and Osteoporosis.","authors":"Archana Nagarajan, Jason Laird, Obiadada Ugochukwu, Sjur Reppe, Kaare Gautvik, Ryan D Ross, David A Bennett, Clifford Rosen, Douglas P Kiel, Lenora A Higginbotham, Nicholas T Seyfried, Christine W Lary","doi":"10.1093/gerona/glae211","DOIUrl":"https://doi.org/10.1093/gerona/glae211","url":null,"abstract":"<p><p>Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are two prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown. We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these two diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in five ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest. These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082999","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}
Mandi Luo, Dan Yan, Yi Huang, Tianyi Ji, Pengcheng Luo, Zhen Yang, Shangbang Gao, Le Zhang, Yiwu Zhou, Qing Shi, Yongping Bai, Tao Li, Lei Ruan, Cuntai Zhang
Vascular aging, a common pathogenesis of senile chronic diseases, significantly increases morbidity and mortality in older adults; its intricate cellular and molecular mechanisms necessitate further investigation. Lumican (LUM) and integrin α2β1(ITGα2β1) are profibrotic extracellular matrix proteins and vital cell regulatory receptors, respectively. However, their roles in vascular aging remain unclear. This study sought to elucidate the connection between LUM and vascular aging as well as the biological mechanism of LUM/ITGα2β1 in this process. Using an enzyme-linked immunosorbent assay, we discovered that plasma LUM was elevated in vascular aging individuals and was positively correlated with brachial-ankle pulse wave velocity. Additionally, immunohistochemical and western blot analyses confirmed LUM upregulation in arteries of older adults and aged mice, as well as in senescent vascular smooth cells (VSMCs). Wild-type and LUM semiknockout (Lum-/+) mice, along with primary VSMCs extracted from these mice, were exposed to angiotensin II (Ang II) to induce stress-induced senescence model. LUM semiknockout mitigated Ang Ⅱ-induced arteriosclerosis, hypertension, vascular aging and remodeling in mice. Both in vitro and in vivo studies revealed that LUM deficiency suppressed p53, p21, collagen 1 and collagen 3 upregulation and synthetic phenotype formation in VSMCs stimulated by Ang Ⅱ. Treating VSMCs with a ITGα2β1 antagonist reversed the aforementioned changes triggered by LUM proteins. Briefly, LUM functions as a potential marker and risk factor for vascular aging and promotes pathological changes by affecting ITGα2β1 in VSMCs. This study introduces a novel molecular target for the early diagnosis and treatment of vascular aging and age-related vascular diseases.
{"title":"Lumican is Both a Novel Risk Factor and Potential Plasma Biomarker for Vascular Aging, Capable of Promoting VSMCs Senescence through Interacting with Integrin α2β1.","authors":"Mandi Luo, Dan Yan, Yi Huang, Tianyi Ji, Pengcheng Luo, Zhen Yang, Shangbang Gao, Le Zhang, Yiwu Zhou, Qing Shi, Yongping Bai, Tao Li, Lei Ruan, Cuntai Zhang","doi":"10.1093/gerona/glae214","DOIUrl":"https://doi.org/10.1093/gerona/glae214","url":null,"abstract":"<p><p>Vascular aging, a common pathogenesis of senile chronic diseases, significantly increases morbidity and mortality in older adults; its intricate cellular and molecular mechanisms necessitate further investigation. Lumican (LUM) and integrin α2β1(ITGα2β1) are profibrotic extracellular matrix proteins and vital cell regulatory receptors, respectively. However, their roles in vascular aging remain unclear. This study sought to elucidate the connection between LUM and vascular aging as well as the biological mechanism of LUM/ITGα2β1 in this process. Using an enzyme-linked immunosorbent assay, we discovered that plasma LUM was elevated in vascular aging individuals and was positively correlated with brachial-ankle pulse wave velocity. Additionally, immunohistochemical and western blot analyses confirmed LUM upregulation in arteries of older adults and aged mice, as well as in senescent vascular smooth cells (VSMCs). Wild-type and LUM semiknockout (Lum-/+) mice, along with primary VSMCs extracted from these mice, were exposed to angiotensin II (Ang II) to induce stress-induced senescence model. LUM semiknockout mitigated Ang Ⅱ-induced arteriosclerosis, hypertension, vascular aging and remodeling in mice. Both in vitro and in vivo studies revealed that LUM deficiency suppressed p53, p21, collagen 1 and collagen 3 upregulation and synthetic phenotype formation in VSMCs stimulated by Ang Ⅱ. Treating VSMCs with a ITGα2β1 antagonist reversed the aforementioned changes triggered by LUM proteins. Briefly, LUM functions as a potential marker and risk factor for vascular aging and promotes pathological changes by affecting ITGα2β1 in VSMCs. This study introduces a novel molecular target for the early diagnosis and treatment of vascular aging and age-related vascular diseases.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074914","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}
Jennifer N Harmon, Preeja Chandran, Abarajithan Chandrasekaran, Jeffrey E Hyde, Gustavo J Hernandez, May J Reed, Matthew F Bruce, Zin Z Khaing
Normal aging is associated with significant deleterious cerebrovascular changes; these have been implicated in disease pathogenesis and increased susceptibility to ischemic injury. While these changes are well documented in the brain, few studies have been conducted in the spinal cord. Here, we utilize specialized contrast-enhanced ultrasound (CEUS) imaging to investigate age-related changes in cervical spinal vascular anatomy and hemodynamics in male Fisher 344 rats, a common strain in aging research. Aged rats (24-26 mo., N=6) exhibited significant tortuosity in the anterior spinal artery and elevated vascular resistance compared to adults (4-6 mo., N=6; tortuosity index 2.20±0.15 vs 4.74±0.45, p<0.05). Baseline blood volume was lower in both larger vessels and the microcirculation in the aged cohort, specifically in white matter (4.44e14±1.37e13 vs 3.66e14±2.64e13 CEUS bolus AUC, p<0.05). To elucidate functional differences, animals were exposed to a hypoxia challenge; whereas adult rats exhibited significant functional hyperemia in both gray and white matter (GM: 1.13±0.10-fold change from normoxia, p<0.05; WM: 1.16±0.13, p<0.05), aged rats showed no response. Immunohistochemistry revealed reduced pericyte coverage and activated microglia behavior in aged rats, which may partially explain the lack of vascular response. This study provides the first in vivo description of age-related hemodynamic differences in the cervical spinal cord.
正常衰老与严重的脑血管有害变化有关;这些变化与疾病的发病机制和缺血性损伤的易感性增加有关。虽然这些变化在大脑中得到了很好的记录,但对脊髓的研究却很少。在这里,我们利用专门的对比增强超声(CEUS)成像技术来研究雄性费舍尔 344 大鼠(衰老研究中常见的品系)颈椎血管解剖结构和血液动力学中与年龄相关的变化。与成年大鼠(4-6 个月,N=6;迂曲指数为 2.20±0.15 vs 4.74±0.45, p)相比,老年大鼠(24-26 个月,N=6)的脊髓前动脉表现出明显的迂曲和血管阻力升高。
{"title":"Contrast-enhanced ultrasound imaging detects anatomical and functional changes in rat cervical spine microvasculature with normal aging.","authors":"Jennifer N Harmon, Preeja Chandran, Abarajithan Chandrasekaran, Jeffrey E Hyde, Gustavo J Hernandez, May J Reed, Matthew F Bruce, Zin Z Khaing","doi":"10.1093/gerona/glae215","DOIUrl":"10.1093/gerona/glae215","url":null,"abstract":"<p><p>Normal aging is associated with significant deleterious cerebrovascular changes; these have been implicated in disease pathogenesis and increased susceptibility to ischemic injury. While these changes are well documented in the brain, few studies have been conducted in the spinal cord. Here, we utilize specialized contrast-enhanced ultrasound (CEUS) imaging to investigate age-related changes in cervical spinal vascular anatomy and hemodynamics in male Fisher 344 rats, a common strain in aging research. Aged rats (24-26 mo., N=6) exhibited significant tortuosity in the anterior spinal artery and elevated vascular resistance compared to adults (4-6 mo., N=6; tortuosity index 2.20±0.15 vs 4.74±0.45, p<0.05). Baseline blood volume was lower in both larger vessels and the microcirculation in the aged cohort, specifically in white matter (4.44e14±1.37e13 vs 3.66e14±2.64e13 CEUS bolus AUC, p<0.05). To elucidate functional differences, animals were exposed to a hypoxia challenge; whereas adult rats exhibited significant functional hyperemia in both gray and white matter (GM: 1.13±0.10-fold change from normoxia, p<0.05; WM: 1.16±0.13, p<0.05), aged rats showed no response. Immunohistochemistry revealed reduced pericyte coverage and activated microglia behavior in aged rats, which may partially explain the lack of vascular response. This study provides the first in vivo description of age-related hemodynamic differences in the cervical spinal cord.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074913","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}
Jia-Wei Gao, Hang Shi, Fu-Ping Gao, Zhi-Min Zhou, Xin Peng, Rui Sun, V L F Cabral, Jian Li, Yun-Tao Wang, Xiao-Hu Wang, Xiao-Tao Wu
Targeting cellular senescence and Senescence Associated Secretory Phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified Oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management.
{"title":"Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis.","authors":"Jia-Wei Gao, Hang Shi, Fu-Ping Gao, Zhi-Min Zhou, Xin Peng, Rui Sun, V L F Cabral, Jian Li, Yun-Tao Wang, Xiao-Hu Wang, Xiao-Tao Wu","doi":"10.1093/gerona/glae204","DOIUrl":"https://doi.org/10.1093/gerona/glae204","url":null,"abstract":"<p><p>Targeting cellular senescence and Senescence Associated Secretory Phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified Oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142038108","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}
Axenic dietary restriction (ADR) is highly effective in extending lifespan of C. elegans but its effects on healthspan improvement is less well characterized. Using transmission electron microscopy, morphometric analyses, and functional assays, we found ADR can preserve tissue ultrastructure, including the cuticle, epidermis, and intestinal lumen, and reduce age-associated pathologies like gonad degeneration, uterine tumor clusters, pharyngeal deterioration, and intestinal atrophy. However, there was no notable improvement in behavioral and functional metrics. Our results underscore that lifespan extension through ADR does not inherently translate to broad healthspan improvements.
{"title":"The effect of axenic dietary restriction on the age-related changes in C. elegans.","authors":"Ping Wu, Lieselot Vandemeulebroucke, Myriam Claeys, Wim Bert, Bart P Braeckman","doi":"10.1093/gerona/glae205","DOIUrl":"https://doi.org/10.1093/gerona/glae205","url":null,"abstract":"<p><p>Axenic dietary restriction (ADR) is highly effective in extending lifespan of C. elegans but its effects on healthspan improvement is less well characterized. Using transmission electron microscopy, morphometric analyses, and functional assays, we found ADR can preserve tissue ultrastructure, including the cuticle, epidermis, and intestinal lumen, and reduce age-associated pathologies like gonad degeneration, uterine tumor clusters, pharyngeal deterioration, and intestinal atrophy. However, there was no notable improvement in behavioral and functional metrics. Our results underscore that lifespan extension through ADR does not inherently translate to broad healthspan improvements.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142020052","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}
Tyler R Bell, Carol E Franz, Kelsey R Thomas, Mc Kenna E Williams, Lisa T Eyler, Imanuel Lerman, Christine Fennema-Notestine, Olivia K Puckett, Stephen M Dorros, Matthew S Panizzon, Rahul C Pearce, Donald J Hagler, Michael J Lyons, Jeremy A Elman, William S Kremen
Background: Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with AD-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation.
Methods: Participants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n=871), Aβ40 (n=887), total tau (t-tau, n=841), and neurofilament light chain (NfL, n=915), and serum high-sensitivity C-reactive protein (hs-CRP, n=968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n=385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use.
Results: Chronic pain related to higher Aβ40 (β=.25, p=.009), but hs-CRP was unrelated to AD-related biomarkers (ps>05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β=.36, p=.001) and Aβ40 (β=.29, p=.003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP*Aβ42: β=-.19, p=.002; hs-CRP*Aβ40: β=-.21, p=.001), regardless of chronic pain status.
Conclusions: Chronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate risk of neurodegeneration in AD-vulnerable regions.
{"title":"Elevated C-Reactive Protein in Older Men with Chronic Pain: Association with Plasma Amyloid Levels and Hippocampal Volume.","authors":"Tyler R Bell, Carol E Franz, Kelsey R Thomas, Mc Kenna E Williams, Lisa T Eyler, Imanuel Lerman, Christine Fennema-Notestine, Olivia K Puckett, Stephen M Dorros, Matthew S Panizzon, Rahul C Pearce, Donald J Hagler, Michael J Lyons, Jeremy A Elman, William S Kremen","doi":"10.1093/gerona/glae206","DOIUrl":"https://doi.org/10.1093/gerona/glae206","url":null,"abstract":"<p><strong>Background: </strong>Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with AD-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation.</p><p><strong>Methods: </strong>Participants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n=871), Aβ40 (n=887), total tau (t-tau, n=841), and neurofilament light chain (NfL, n=915), and serum high-sensitivity C-reactive protein (hs-CRP, n=968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n=385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use.</p><p><strong>Results: </strong>Chronic pain related to higher Aβ40 (β=.25, p=.009), but hs-CRP was unrelated to AD-related biomarkers (ps>05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β=.36, p=.001) and Aβ40 (β=.29, p=.003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP*Aβ42: β=-.19, p=.002; hs-CRP*Aβ40: β=-.21, p=.001), regardless of chronic pain status.</p><p><strong>Conclusions: </strong>Chronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate risk of neurodegeneration in AD-vulnerable regions.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142020051","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}
Heather E Mast, Pierre U Blier, Mirko Ɖorđević, Uroš Savković, Claudia D Holody, Stephane L Bourque, Hélène Lemieux
Mitochondria play a key role in aging. Here, we measured integrated mitochondrial functions in experimentally evolved lines of the seed beetle Acanthoscelides obtectus that were selected for early (E) or late (L) reproduction for nearly four decades. The two lines have markedly different lifespans (8 days and 13 days in the E and L lines, respectively). The contribution of the NADH pathway to maximal flux was lower in the L compared to the E beetles at young stages, associated to increased control by complex I. In contrast, the contribution of the Succinate pathway was higher in the L than in the E line, while the Proline pathway showed no differences between the lines. Our data suggest that selection of age at reproduction leads to a modulation of complex I activity in mitochondria and that mitochondria are a functional link between evolutionary and mechanistic theories of aging.
线粒体在衰老过程中起着关键作用。在这里,我们测量了经过近 40 年早期繁殖(E)或晚期繁殖(L)选择的种子甲虫 Acanthoscelides obtectus 实验进化品系的线粒体综合功能。这两个品系的寿命明显不同(E 和 L 品系分别为 8 天和 13 天)。与 E 型甲虫相比,L 型甲虫在幼虫期的 NADH 途径对最大通量的贡献较低,这与复合体 I 的控制增加有关。我们的数据表明,繁殖年龄的选择导致线粒体中复合体 I 活性的调节,线粒体是衰老的进化理论和机理理论之间的功能性联系。
{"title":"Selection for late reproduction leads to loss of complex I mitochondrial capacity and associated increased longevity in seed beetles.","authors":"Heather E Mast, Pierre U Blier, Mirko Ɖorđević, Uroš Savković, Claudia D Holody, Stephane L Bourque, Hélène Lemieux","doi":"10.1093/gerona/glae208","DOIUrl":"https://doi.org/10.1093/gerona/glae208","url":null,"abstract":"<p><p>Mitochondria play a key role in aging. Here, we measured integrated mitochondrial functions in experimentally evolved lines of the seed beetle Acanthoscelides obtectus that were selected for early (E) or late (L) reproduction for nearly four decades. The two lines have markedly different lifespans (8 days and 13 days in the E and L lines, respectively). The contribution of the NADH pathway to maximal flux was lower in the L compared to the E beetles at young stages, associated to increased control by complex I. In contrast, the contribution of the Succinate pathway was higher in the L than in the E line, while the Proline pathway showed no differences between the lines. Our data suggest that selection of age at reproduction leads to a modulation of complex I activity in mitochondria and that mitochondria are a functional link between evolutionary and mechanistic theories of aging.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001668","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}
Daniel Clayton-Chubb, Ammar Majeed, Stuart K Roberts, Hans G Schneider, Isabella Commins, Jessica Fitzpatrick, Robyn L Woods, Joanne Ryan, Sultana Monira Hussain, Natassia Tan, John S Lubel, Cammie Tran, Alexander D Hodge, John J McNeil, William W Kemp
Background: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly ordered tests in general medical practice. However, their distribution and significance in older adults is understudied. As such, we aimed to evaluate sex-stratified distribution of both ALT and AST in older adults (≥ 70 years) and assess for associations with mortality.
Methods: Post-hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) randomised, placebo-controlled trial of daily low-dose aspirin for initially relatively healthy older persons. Univariate analysis and multiple logistic regression were used to explore baseline characteristics. Cox regression and restricted cubic splines were used to examine links between transaminase levels and mortality.
Results: Of the 11853 participants with ALT and AST levels, 1054 (8.9%) deaths were recorded over median 6.4 (IQR 5.4-7.6) years. For ALT, the lowest quintiles for males and females were 6-15 U/L and 5-13 U/L respectively; for AST, the lowest quintiles were 8-18 U/L and 7-17 U/L. On both univariate and models adjusted for covariates including age, BMI, frailty, diabetes, and kidney disease, males and females in the lowest quintile of ALT had an increased hazard of mortality (aHR 1.51 [95% CI 1.14-1.99] and aHR 1.39 [95% CI 1.03-1.88] respectively). For the lowest quintile of AST, only males were at increased risk (aHR 1.33 [95% CI 1.04-1.70]). Associations remained significant when removing outliers.
Conclusion: Low ALT levels independently confer an increased hazard of mortality for older males and females; low AST only impacted older male survival. Further evaluation of mechanisms would be worthwhile, and re-evaluating the lower limit of normal for ALT in older adults should be considered.
背景:丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)是普通医疗实践中常见的检测项目。然而,它们在老年人中的分布和意义却未得到充分研究。因此,我们旨在评估 ALT 和 AST 在老年人(≥ 70 岁)中的性别分层分布情况,并评估其与死亡率的关系:方法:对 "阿司匹林减少老年人疾病事件"(ASPREE)随机安慰剂对照试验进行事后分析,该试验针对最初相对健康的老年人,每天服用低剂量阿司匹林。采用单变量分析和多元逻辑回归探讨基线特征。采用 Cox 回归和限制性立方样条来研究转氨酶水平与死亡率之间的联系:在 11853 名检测到谷丙转氨酶和谷草转氨酶水平的参与者中,有 1054 人(8.9%)在中位 6.4(IQR 5.4-7.6)年期间死亡。就谷丙转氨酶而言,男性和女性的最低五分位数分别为 6-15 U/L和5-13 U/L;就谷草转氨酶而言,最低五分位数分别为8-18 U/L和7-17 U/L。在单变量模型和根据年龄、体重指数、虚弱程度、糖尿病和肾脏疾病等协变量调整的模型中,ALT 最低五分位数的男性和女性的死亡风险均有所增加(aHR 分别为 1.51 [95% CI 1.14-1.99] 和 1.39 [95% CI 1.03-1.88])。就谷草转氨酶的最低五分位数而言,只有男性的风险增加(aHR 1.33 [95% CI 1.04-1.70])。剔除异常值后,两者之间的关联仍有意义:低谷丙转氨酶水平会增加老年男性和女性的死亡风险,而低谷草转氨酶水平只影响老年男性的存活率。值得进一步评估其机制,并考虑重新评估老年人 ALT 的正常值下限。
{"title":"Serum Transaminases And Older Adults: Distribution And Associations With All-Cause Mortality.","authors":"Daniel Clayton-Chubb, Ammar Majeed, Stuart K Roberts, Hans G Schneider, Isabella Commins, Jessica Fitzpatrick, Robyn L Woods, Joanne Ryan, Sultana Monira Hussain, Natassia Tan, John S Lubel, Cammie Tran, Alexander D Hodge, John J McNeil, William W Kemp","doi":"10.1093/gerona/glae203","DOIUrl":"https://doi.org/10.1093/gerona/glae203","url":null,"abstract":"<p><strong>Background: </strong>Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are commonly ordered tests in general medical practice. However, their distribution and significance in older adults is understudied. As such, we aimed to evaluate sex-stratified distribution of both ALT and AST in older adults (≥ 70 years) and assess for associations with mortality.</p><p><strong>Methods: </strong>Post-hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) randomised, placebo-controlled trial of daily low-dose aspirin for initially relatively healthy older persons. Univariate analysis and multiple logistic regression were used to explore baseline characteristics. Cox regression and restricted cubic splines were used to examine links between transaminase levels and mortality.</p><p><strong>Results: </strong>Of the 11853 participants with ALT and AST levels, 1054 (8.9%) deaths were recorded over median 6.4 (IQR 5.4-7.6) years. For ALT, the lowest quintiles for males and females were 6-15 U/L and 5-13 U/L respectively; for AST, the lowest quintiles were 8-18 U/L and 7-17 U/L. On both univariate and models adjusted for covariates including age, BMI, frailty, diabetes, and kidney disease, males and females in the lowest quintile of ALT had an increased hazard of mortality (aHR 1.51 [95% CI 1.14-1.99] and aHR 1.39 [95% CI 1.03-1.88] respectively). For the lowest quintile of AST, only males were at increased risk (aHR 1.33 [95% CI 1.04-1.70]). Associations remained significant when removing outliers.</p><p><strong>Conclusion: </strong>Low ALT levels independently confer an increased hazard of mortality for older males and females; low AST only impacted older male survival. Further evaluation of mechanisms would be worthwhile, and re-evaluating the lower limit of normal for ALT in older adults should be considered.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001669","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}
Purpose: This observational study aimed to investigate associations between dietary live microbe intake and mortality, as well as biological aging.
Methods: Adults from the 1999-2018 National Health and Nutrition Examination Survey were categorized into low, medium, and high dietary live microbe groups. Foods with medium and high live microbe content were aggregated into a medium-high consumption category. The outcomes included all-cause, cardiovascular, and cancer mortality, along with biological age (BA) acceleration assessed by the Klemera-Doubal method (KDM) and PhenoAge. Multiple regression analyses and mediation analyses were conducted to assess associations, adjusting for potential confounders.
Results: A total of 34,133 adults were included in our analyses. Over an average follow-up period of 9.92 years, 5,462 deaths occurred. In multivariate adjusted models, every 100 grams of medium-high group foods consumed was associated with reduced all-cause mortality (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.91 to 0.97, P < 0.001) and cardiovascular mortality (HR 0.91, 95% CI 0.86 to 0.96, P < 0.001), but not with cancer mortality (HR 1.01, 95% CI 0.95 to 1.07, P = 0.768). Every 100 grams medium-high group foods consumption was associated with decreased KDM BA acceleration (fully adjusted regression coefficient -0.09, 95% CI -0.15 to -0.04, P = 0.001) and PhenoAge acceleration (fully adjusted regression coefficient -0.07, 95% CI -0.11 to -0.03, P < 0.001). Mediation analysis showed that BA acceleration partially mediated live microbes-mortality associations.
Conclusion: Our results suggest that higher dietary live microbe intake is associated with lower mortality risk and slower biological aging. However, further research is needed to verify these findings.
{"title":"Dietary Live Microbes Intake Associated with Biological Aging and Mortality.","authors":"Xu Zhu, Wenhang Chen, Jing Xue, Wenjie Dai, Rehanguli Maimaitituerxun, Yamin Liu, Hui Xu, Qiaoling Zhou, Quan Zhou, Chunyuan Chen, Zhenxing Wang, Hui Xie","doi":"10.1093/gerona/glae202","DOIUrl":"https://doi.org/10.1093/gerona/glae202","url":null,"abstract":"<p><strong>Purpose: </strong>This observational study aimed to investigate associations between dietary live microbe intake and mortality, as well as biological aging.</p><p><strong>Methods: </strong>Adults from the 1999-2018 National Health and Nutrition Examination Survey were categorized into low, medium, and high dietary live microbe groups. Foods with medium and high live microbe content were aggregated into a medium-high consumption category. The outcomes included all-cause, cardiovascular, and cancer mortality, along with biological age (BA) acceleration assessed by the Klemera-Doubal method (KDM) and PhenoAge. Multiple regression analyses and mediation analyses were conducted to assess associations, adjusting for potential confounders.</p><p><strong>Results: </strong>A total of 34,133 adults were included in our analyses. Over an average follow-up period of 9.92 years, 5,462 deaths occurred. In multivariate adjusted models, every 100 grams of medium-high group foods consumed was associated with reduced all-cause mortality (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.91 to 0.97, P < 0.001) and cardiovascular mortality (HR 0.91, 95% CI 0.86 to 0.96, P < 0.001), but not with cancer mortality (HR 1.01, 95% CI 0.95 to 1.07, P = 0.768). Every 100 grams medium-high group foods consumption was associated with decreased KDM BA acceleration (fully adjusted regression coefficient -0.09, 95% CI -0.15 to -0.04, P = 0.001) and PhenoAge acceleration (fully adjusted regression coefficient -0.07, 95% CI -0.11 to -0.03, P < 0.001). Mediation analysis showed that BA acceleration partially mediated live microbes-mortality associations.</p><p><strong>Conclusion: </strong>Our results suggest that higher dietary live microbe intake is associated with lower mortality risk and slower biological aging. However, further research is needed to verify these findings.</p>","PeriodicalId":94243,"journal":{"name":"The journals of gerontology. Series A, Biological sciences and medical sciences","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001666","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}