Pub Date : 2023-09-15eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1260502
Brady M Owen, James Phie, Jennifer Huynh, Scott Needham, Cameron Fraser
Functional decline with age contributes significantly to the burden of disease in developed countries. There is growing interest in the development of therapeutic interventions which slow or even reverse aging. Time and cost constraints prohibit the testing of a large number of interventions for health and lifespan extension in model organisms. Cell-based models of aging could enable high throughput testing of potential interventions. Despite extensive reports in the literature of cell properties that correlate with donor age, few are robustly observed across different laboratories. This casts doubt on the extent that aging signatures are captured in cultured cells. We tested molecular changes previously reported to correlate with donor age in peripheral blood mononuclear cells (PBMCs) and evaluated their suitability for inclusion in a panel of functional aging measures. The tested measures spanned several pathways implicated in aging including epigenetic changes, apoptosis, proteostasis, and intracellular communication. Surprisingly, only two markers correlated with donor age. DNA methylation age accurately predicted donor age confirming this is a robust aging biomarker. Additionally, the apoptotic marker CD95 correlated with donor age but only within subsets of PBMCs. To demonstrate cellular rejuvenation in response to a treatment will require integration of multiple read-outs of cell function. However, building a panel of measures to detect aging in cells is challenging and further research is needed to identify robust predictors of age in humans.
{"title":"Evaluation of quantitative biomarkers of aging in human PBMCs.","authors":"Brady M Owen, James Phie, Jennifer Huynh, Scott Needham, Cameron Fraser","doi":"10.3389/fragi.2023.1260502","DOIUrl":"https://doi.org/10.3389/fragi.2023.1260502","url":null,"abstract":"<p><p>Functional decline with age contributes significantly to the burden of disease in developed countries. There is growing interest in the development of therapeutic interventions which slow or even reverse aging. Time and cost constraints prohibit the testing of a large number of interventions for health and lifespan extension in model organisms. Cell-based models of aging could enable high throughput testing of potential interventions. Despite extensive reports in the literature of cell properties that correlate with donor age, few are robustly observed across different laboratories. This casts doubt on the extent that aging signatures are captured in cultured cells. We tested molecular changes previously reported to correlate with donor age in peripheral blood mononuclear cells (PBMCs) and evaluated their suitability for inclusion in a panel of functional aging measures. The tested measures spanned several pathways implicated in aging including epigenetic changes, apoptosis, proteostasis, and intracellular communication. Surprisingly, only two markers correlated with donor age. DNA methylation age accurately predicted donor age confirming this is a robust aging biomarker. Additionally, the apoptotic marker CD95 correlated with donor age but only within subsets of PBMCs. To demonstrate cellular rejuvenation in response to a treatment will require integration of multiple read-outs of cell function. However, building a panel of measures to detect aging in cells is challenging and further research is needed to identify robust predictors of age in humans.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10540680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41124673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-14eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1260053
Miodrag Vrbic, Ana Milinkovic
Background: The immune-inflammatory response is the basis of the pathophysiology of SARS-Cov-2 infection. In severe cases of COVID-19 uncontrolled systemic inflammatory response causes multiorgan dysfunction (MODS), as the most common immediate cause of death. Unfavorable outcome of the COVID-19 most often occurs in elderly patients. The aim of the study was to establish parameters with prognostic significance in severe cases of COVID-19 according to life years, laboratory markers of sepsis and MODS, as well as the number of peripheral CD4+ and CD8+T lymphocytes in 20 consecutively selected critically ill patients. Results: Eleven subjects were male, 9 female, mean age 73.45 ± 11.59, among which the oldest patient was 94 and the youngest 43 years. All the patients met the sepsis and MODS criteria. Increased age and low CD4+ and CD8+T cell counts were identified as independent predictors of death. Only the two youngest patients (43 and 50 years old) survived 28 days, and they are the only ones with a CD4 lymphocyte count above 500 cells/mm3. Conclusion: Senescence of the immune system is mostly characterized by reduced regenerative capacity of adaptive immunity with diminished ability to respond to new antigens and a manifested proinflammatory phenotype. Additional reduction of protective capacity by further deterioration of T cell quantity and quality due to sepsis itself and mutual interaction of senescent T cells and vascular endothelial cells in the induction of cytokine storm represent two complementary vicious cycles in the development of sepsis-related multiorgan dysfunction.
{"title":"Two vicious circles associated with the aging of the immune system in the development of severe forms of COVID-19.","authors":"Miodrag Vrbic, Ana Milinkovic","doi":"10.3389/fragi.2023.1260053","DOIUrl":"https://doi.org/10.3389/fragi.2023.1260053","url":null,"abstract":"<p><p><b>Background:</b> The immune-inflammatory response is the basis of the pathophysiology of SARS-Cov-2 infection. In severe cases of COVID-19 uncontrolled systemic inflammatory response causes multiorgan dysfunction (MODS), as the most common immediate cause of death. Unfavorable outcome of the COVID-19 most often occurs in elderly patients. The aim of the study was to establish parameters with prognostic significance in severe cases of COVID-19 according to life years, laboratory markers of sepsis and MODS, as well as the number of peripheral CD4<sup>+</sup> and CD8<sup>+</sup>T lymphocytes in 20 consecutively selected critically ill patients. <b>Results:</b> Eleven subjects were male, 9 female, mean age 73.45 ± 11.59, among which the oldest patient was 94 and the youngest 43 years. All the patients met the sepsis and MODS criteria. Increased age and low CD4<sup>+</sup> and CD8<sup>+</sup>T cell counts were identified as independent predictors of death. Only the two youngest patients (43 and 50 years old) survived 28 days, and they are the only ones with a CD4 lymphocyte count above 500 cells/mm<sup>3</sup>. <b>Conclusion:</b> Senescence of the immune system is mostly characterized by reduced regenerative capacity of adaptive immunity with diminished ability to respond to new antigens and a manifested proinflammatory phenotype. Additional reduction of protective capacity by further deterioration of T cell quantity and quality due to sepsis itself and mutual interaction of senescent T cells and vascular endothelial cells in the induction of cytokine storm represent two complementary vicious cycles in the development of sepsis-related multiorgan dysfunction.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10537960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41164742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-06eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1231706
Samar F Darwish, Abdullah M M Elbadry, Amir S Elbokhomy, Ghidaa A Salama, Rania M Salama
The pathophysiology of different neurodegenerative illnesses is significantly influenced by the polarization regulation of microglia and macrophages. Traditional classifications of macrophage phenotypes include the pro-inflammatory M1 and the anti-inflammatory M2 phenotypes. Numerous studies demonstrated dynamic non-coding RNA modifications, which are catalyzed by microglia-induced neuroinflammation. Different nutraceuticals focus on the polarization of M1/M2 phenotypes of microglia and macrophages, offering a potent defense against neurodegeneration. Caeminaxin A, curcumin, aromatic-turmerone, myricetin, aurantiamide, 3,6'-disinapoylsucrose, and resveratrol reduced M1 microglial inflammatory markers while increased M2 indicators in Alzheimer's disease. Amyloid beta-induced microglial M1 activation was suppressed by andrographolide, sulforaphane, triptolide, xanthoceraside, piperlongumine, and novel plant extracts which also prevented microglia-mediated necroptosis and apoptosis. Asarone, galangin, baicalein, and a-mangostin reduced oxidative stress and pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in M1-activated microglia in Parkinson's disease. Additionally, myrcene, icariin, and tenuigenin prevented the nod-like receptor family pyrin domain-containing 3 inflammasome and microglial neurotoxicity, while a-cyperone, citronellol, nobiletin, and taurine prevented NADPH oxidase 2 and nuclear factor kappa B activation. Furthermore, other nutraceuticals like plantamajoside, swertiamarin, urolithin A, kurarinone, Daphne genkwa flower, and Boswellia serrata extracts showed promising neuroprotection in treating Parkinson's disease. In Huntington's disease, elderberry, curcumin, iresine celosia, Schisandra chinensis, gintonin, and pomiferin showed promising results against microglial activation and improved patient symptoms. Meanwhile, linolenic acid, resveratrol, Huperzia serrata, icariin, and baicalein protected against activated macrophages and microglia in experimental autoimmune encephalomyelitis and multiple sclerosis. Additionally, emodin, esters of gallic and rosmarinic acids, Agathisflavone, and sinomenine offered promising multiple sclerosis treatments. This review highlights the therapeutic potential of using nutraceuticals to treat neurodegenerative diseases involving microglial-related pathways.
{"title":"The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases.","authors":"Samar F Darwish, Abdullah M M Elbadry, Amir S Elbokhomy, Ghidaa A Salama, Rania M Salama","doi":"10.3389/fragi.2023.1231706","DOIUrl":"10.3389/fragi.2023.1231706","url":null,"abstract":"<p><p>The pathophysiology of different neurodegenerative illnesses is significantly influenced by the polarization regulation of microglia and macrophages. Traditional classifications of macrophage phenotypes include the pro-inflammatory M1 and the anti-inflammatory M2 phenotypes. Numerous studies demonstrated dynamic non-coding RNA modifications, which are catalyzed by microglia-induced neuroinflammation. Different nutraceuticals focus on the polarization of M1/M2 phenotypes of microglia and macrophages, offering a potent defense against neurodegeneration. Caeminaxin A, curcumin, aromatic-turmerone, myricetin, aurantiamide, 3,6'-disinapoylsucrose, and resveratrol reduced M1 microglial inflammatory markers while increased M2 indicators in Alzheimer's disease. Amyloid beta-induced microglial M1 activation was suppressed by andrographolide, sulforaphane, triptolide, xanthoceraside, piperlongumine, and novel plant extracts which also prevented microglia-mediated necroptosis and apoptosis. Asarone, galangin, baicalein, and <i>a</i>-mangostin reduced oxidative stress and pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in M1-activated microglia in Parkinson's disease. Additionally, myrcene, icariin, and tenuigenin prevented the nod-like receptor family pyrin domain-containing 3 inflammasome and microglial neurotoxicity, while <i>a</i>-cyperone, citronellol, nobiletin, and taurine prevented NADPH oxidase 2 and nuclear factor kappa B activation. Furthermore, other nutraceuticals like plantamajoside, swertiamarin, urolithin A, kurarinone, Daphne genkwa flower, and <i>Boswellia serrata</i> extracts showed promising neuroprotection in treating Parkinson's disease. In Huntington's disease, elderberry, curcumin, iresine celosia, <i>Schisandra chinensis</i>, gintonin, and pomiferin showed promising results against microglial activation and improved patient symptoms. Meanwhile, linolenic acid, resveratrol, <i>Huperzia serrata</i>, icariin, and baicalein protected against activated macrophages and microglia in experimental autoimmune encephalomyelitis and multiple sclerosis. Additionally, emodin, esters of gallic and rosmarinic acids, Agathisflavone, and sinomenine offered promising multiple sclerosis treatments. This review highlights the therapeutic potential of using nutraceuticals to treat neurodegenerative diseases involving microglial-related pathways.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-05eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1031161
Xingyu Zhang, Sider Penkov, Teymuras V Kurzchalia, Vasily Zaburdaev
The dauer larva is a specialized stage of worm development optimized for survival under harsh conditions that have been used as a model for stress resistance, metabolic adaptations, and longevity. Recent findings suggest that the dauer larva of Caenorhabditis elegans may utilize external ethanol as an energy source to extend their lifespan. It was shown that while ethanol may serve as an effectively infinite source of energy, some toxic compounds accumulating as byproducts of its metabolism may lead to the damage of mitochondria and thus limit the lifespan of larvae. A minimal mathematical model was proposed to explain the connection between the lifespan of a dauer larva and its ethanol metabolism. To explore theoretically if it is possible to extend even further the lifespan of dauer larvae, we incorporated two natural mechanisms describing the recovery of damaged mitochondria and elimination of toxic compounds, which were previously omitted in the model. Numerical simulations of the revised model suggested that while the ethanol concentration is constant, the lifespan still stays limited. However, if ethanol is supplied periodically, with a suitable frequency and amplitude, the dauer could survive as long as we observe the system. Analytical methods further help to explain how feeding frequency and amplitude affect lifespan extension. Based on the comparison of the model with experimental data for fixed ethanol concentration, we proposed the range of feeding protocols that could lead to even longer dauer survival and it can be tested experimentally.
{"title":"Periodic ethanol supply as a path toward unlimited lifespan of <i>Caenorhabditis elegans</i> dauer larvae.","authors":"Xingyu Zhang, Sider Penkov, Teymuras V Kurzchalia, Vasily Zaburdaev","doi":"10.3389/fragi.2023.1031161","DOIUrl":"https://doi.org/10.3389/fragi.2023.1031161","url":null,"abstract":"<p><p>The dauer larva is a specialized stage of worm development optimized for survival under harsh conditions that have been used as a model for stress resistance, metabolic adaptations, and longevity. Recent findings suggest that the dauer larva of <i>Caenorhabditis elegans</i> may utilize external ethanol as an energy source to extend their lifespan. It was shown that while ethanol may serve as an effectively infinite source of energy, some toxic compounds accumulating as byproducts of its metabolism may lead to the damage of mitochondria and thus limit the lifespan of larvae. A minimal mathematical model was proposed to explain the connection between the lifespan of a dauer larva and its ethanol metabolism. To explore theoretically if it is possible to extend even further the lifespan of dauer larvae, we incorporated two natural mechanisms describing the recovery of damaged mitochondria and elimination of toxic compounds, which were previously omitted in the model. Numerical simulations of the revised model suggested that while the ethanol concentration is constant, the lifespan still stays limited. However, if ethanol is supplied periodically, with a suitable frequency and amplitude, the dauer could survive as long as we observe the system. Analytical methods further help to explain how feeding frequency and amplitude affect lifespan extension. Based on the comparison of the model with experimental data for fixed ethanol concentration, we proposed the range of feeding protocols that could lead to even longer dauer survival and it can be tested experimentally.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10507685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41163308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-02eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1234958
Oliver Daniel Schreiner, Thomas Gabriel Schreiner
Neurodegenerative disorders, particularly Alzheimer's disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from in vitro and in vivo studies, new research directions are suggested to enhance the development of effective antidementia therapies.
神经退行性疾病,尤其是阿尔茨海默病(AD),在寻找有效治疗方法方面仍面临巨大挑战,其中一个主要原因是对其病因的认识不全面。在众多争论不休的假说中,一种基于铁失衡对中枢神经系统神经变性的影响的新方法越来越受欢迎。铁平衡的改变导致特定脑区的铁积累增加,从而解释了注意力缺失症患者的临床表现。此外,越来越多的证据表明,铁代谢与受 AD 影响的大脑中出现的其他病理过程(如淀粉样蛋白生成途径、慢性炎症或氧化应激)之间的关系具有重要影响。在此背景下,本篇微型综述旨在以说教的方式总结不断扩展的相关文献中的新数据。因此,在第一部分中,作者简要强调了与铁在大脑水平的吸收、转运、调节和消除有关的最相关方面,重点是血脑屏障的作用和较新的铁跃迁概念。随后,讨论了目前可用的铁螯合疗法,包括对该主题最相关临床试验的概述。最后,根据体外和体内研究的最新结果,提出了新的研究方向,以促进有效抗痴呆疗法的开发。
{"title":"Iron chelators as a therapeutic option for Alzheimer's disease-A mini-review.","authors":"Oliver Daniel Schreiner, Thomas Gabriel Schreiner","doi":"10.3389/fragi.2023.1234958","DOIUrl":"10.3389/fragi.2023.1234958","url":null,"abstract":"<p><p>Neurodegenerative disorders, particularly Alzheimer's disease (AD), remain a great challenge regarding the finding of effective treatment, one main reason being the incomplete understanding of their etiology. With many intensely debated hypotheses, a newer approach based on the impact of iron imbalance in sustaining neurodegeneration in the central nervous system becomes increasingly popular. Altered iron homeostasis leads to increased iron accumulation in specific brain areas, explaining the clinical picture of AD patients. Moreover, growing evidence sustains the significant impact of iron metabolism in relationship to other pathological processes encountered in the AD-affected brain, such as the amyloidogenic pathway, chronic inflammation, or oxidative stress. In this context, this mini-review aims to summarize the novel data from the continuously expanding literature on this topic in a didactic manner. Thus, in the first part, the authors briefly highlight the most relevant aspects related to iron absorption, transport, regulation, and elimination at the cerebral level, focusing on the role of the blood-brain barrier and the newer concept of ferroptosis. Subsequently, currently available iron chelation therapies are discussed, including an overview of the most relevant clinical trials on this topic. In the final part, based on the latest results from <i>in vitro</i> and <i>in vivo</i> studies, new research directions are suggested to enhance the development of effective antidementia therapies.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10433644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10047670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-14eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1217054
Kamal Awad, Neelam Ahuja, Ahmed S Yacoub, Leticia Brotto, Simon Young, Antonios Mikos, Pranesh Aswath, Venu Varanasi
In this review, we explore the application of novel biomaterial-based therapies specifically targeted towards craniofacial bone defects. The repair and regeneration of critical sized bone defects in the craniofacial region requires the use of bioactive materials to stabilize and expedite the healing process. However, the existing clinical approaches face challenges in effectively treating complex craniofacial bone defects, including issues such as oxidative stress, inflammation, and soft tissue loss. Given that a significant portion of individuals affected by traumatic bone defects in the craniofacial area belong to the aging population, there is an urgent need for innovative biomaterials to address the declining rate of new bone formation associated with age-related changes in the skeletal system. This article emphasizes the importance of semiconductor industry-derived materials as a potential solution to combat oxidative stress and address the challenges associated with aging bone. Furthermore, we discuss various material and autologous treatment approaches, as well as in vitro and in vivo models used to investigate new therapeutic strategies in the context of craniofacial bone repair. By focusing on these aspects, we aim to shed light on the potential of advanced biomaterials to overcome the limitations of current treatments and pave the way for more effective and efficient therapeutic interventions for craniofacial bone defects.
{"title":"Revolutionizing bone regeneration: advanced biomaterials for healing compromised bone defects.","authors":"Kamal Awad, Neelam Ahuja, Ahmed S Yacoub, Leticia Brotto, Simon Young, Antonios Mikos, Pranesh Aswath, Venu Varanasi","doi":"10.3389/fragi.2023.1217054","DOIUrl":"10.3389/fragi.2023.1217054","url":null,"abstract":"<p><p>In this review, we explore the application of novel biomaterial-based therapies specifically targeted towards craniofacial bone defects. The repair and regeneration of critical sized bone defects in the craniofacial region requires the use of bioactive materials to stabilize and expedite the healing process. However, the existing clinical approaches face challenges in effectively treating complex craniofacial bone defects, including issues such as oxidative stress, inflammation, and soft tissue loss. Given that a significant portion of individuals affected by traumatic bone defects in the craniofacial area belong to the aging population, there is an urgent need for innovative biomaterials to address the declining rate of new bone formation associated with age-related changes in the skeletal system. This article emphasizes the importance of semiconductor industry-derived materials as a potential solution to combat oxidative stress and address the challenges associated with aging bone. Furthermore, we discuss various material and autologous treatment approaches, as well as <i>in vitro</i> and <i>in vivo</i> models used to investigate new therapeutic strategies in the context of craniofacial bone repair. By focusing on these aspects, we aim to shed light on the potential of advanced biomaterials to overcome the limitations of current treatments and pave the way for more effective and efficient therapeutic interventions for craniofacial bone defects.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10376722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9973644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-06eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1176706
Derik L Davis, Ranyah Almardawi, Brock A Beamer, Alice S Ryan, Michael L Terrin
The impact of shoulder pain on health-related quality of life and physical function among community-dwelling older adults (>60 years) not seeking medical care is not well understood. Forty-four community-dwelling older adult volunteers with low comorbidity were stratified into two groups by the presence (n = 18) or absence (n = 26) of shoulder pain. Participants completed the 36-Item Short Form and American Shoulder and Elbow Surgeon surveys and received shoulder range of motion and magnetic resonance imaging testing. Participants with shoulder pain perceived more difficulty accomplishing usual tasks secondary to their physical and emotion health and displayed inferior shoulder function, relative to participants without shoulder pain. This study suggests that shoulder pain reduces quality of life and physical function in the population of community-dwelling older adults not seeking medical evaluation for their symptoms.
{"title":"Shoulder pain, health-related quality of life and physical function in community-dwelling older adults.","authors":"Derik L Davis, Ranyah Almardawi, Brock A Beamer, Alice S Ryan, Michael L Terrin","doi":"10.3389/fragi.2023.1176706","DOIUrl":"10.3389/fragi.2023.1176706","url":null,"abstract":"<p><p>The impact of shoulder pain on health-related quality of life and physical function among community-dwelling older adults (>60 years) not seeking medical care is not well understood. Forty-four community-dwelling older adult volunteers with low comorbidity were stratified into two groups by the presence (<i>n</i> = 18) or absence (<i>n</i> = 26) of shoulder pain. Participants completed the 36-Item Short Form and American Shoulder and Elbow Surgeon surveys and received shoulder range of motion and magnetic resonance imaging testing. Participants with shoulder pain perceived more difficulty accomplishing usual tasks secondary to their physical and emotion health and displayed inferior shoulder function, relative to participants without shoulder pain. This study suggests that shoulder pain reduces quality of life and physical function in the population of community-dwelling older adults not seeking medical evaluation for their symptoms.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9860896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-03eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1192149
Chi Zhang, Dongmei Wang, Robin Dowell, Rui Yi
Aging is defined as the functional decline of tissues and organisms, leading to many human conditions, such as cancer, neurodegenerative diseases, and hair loss. Although stem cell exhaustion is widely recognized as a hallmark of aging, our understanding of cell state changes-specifically, the dynamics of the transcriptome and open chromatin landscape, and their relationship with aging-remains incomplete. Here we present a longitudinal, single-cell atlas of the transcriptome and open chromatin landscape for epithelia cells of the skin across various hair cycle stages and ages in mice. Our findings reveal fluctuating hair follicle stem cell (HF-SC) states, some of which are associated with the progression of the hair cycle during aging. Conversely, inner bulge niche cells display a more linear progression, seemingly less affected by the hair cycle. Further analysis of the open chromatin landscape, determined by single-cell Assay for Transposase-Accessible Chromatin (ATAC) sequencing, demonstrates that reduced open chromatin regions in HF-SCs are associated with differentiation, whereas gained open chromatin regions in HF-SCs are linked to the transcriptional control of quiescence. These findings enhance our understanding of the transcriptional dynamics in HF-SC aging and lay the molecular groundwork for investigating and potentially reversing the aging process in future experimental studies.
{"title":"Single cell analysis of transcriptome and open chromatin reveals the dynamics of hair follicle stem cell aging.","authors":"Chi Zhang, Dongmei Wang, Robin Dowell, Rui Yi","doi":"10.3389/fragi.2023.1192149","DOIUrl":"10.3389/fragi.2023.1192149","url":null,"abstract":"<p><p>Aging is defined as the functional decline of tissues and organisms, leading to many human conditions, such as cancer, neurodegenerative diseases, and hair loss. Although stem cell exhaustion is widely recognized as a hallmark of aging, our understanding of cell state changes-specifically, the dynamics of the transcriptome and open chromatin landscape, and their relationship with aging-remains incomplete. Here we present a longitudinal, single-cell atlas of the transcriptome and open chromatin landscape for epithelia cells of the skin across various hair cycle stages and ages in mice. Our findings reveal fluctuating hair follicle stem cell (HF-SC) states, some of which are associated with the progression of the hair cycle during aging. Conversely, inner bulge niche cells display a more linear progression, seemingly less affected by the hair cycle. Further analysis of the open chromatin landscape, determined by single-cell Assay for Transposase-Accessible Chromatin (ATAC) sequencing, demonstrates that reduced open chromatin regions in HF-SCs are associated with differentiation, whereas gained open chromatin regions in HF-SCs are linked to the transcriptional control of quiescence. These findings enhance our understanding of the transcriptional dynamics in HF-SC aging and lay the molecular groundwork for investigating and potentially reversing the aging process in future experimental studies.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9839798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-30eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1213228
Katherine A Collins, Fabrisia Ambrosio, Renee J Rogers, Wei Lang, Eric B Schelbert, Kelliann K Davis, John M Jakicic
Introduction: Klotho is a protein associated with protection from aging-related diseases and health conditions. Obesity is associated with lower Klotho concentrations. Thus, this secondary analysis of adults with obesity examined 1) the change in serum Klotho concentration in response to a behavioral weight loss intervention by the magnitude of weight loss achieved; and 2) the association among serum Klotho concentration and weight, body composition, and cardiorespiratory fitness. Methods: Participants were randomized to either diet alone (DIET), diet plus 150 min of physical activity per week (DIET + PA150), or diet plus 250 min of physical activity per week (DIET + PA250). Participants [n = 152; age: 45.0 ± 7.9 years; body mass index (BMI): 32.4 ± 3.8 kg/m2] included in this secondary analysis provided blood samples at baseline, 6-, and 12 months, and were classified by weight loss response (Responder: achieved ≥10% weight loss at 6 or 12 months; Non-responder: achieved <5% weight loss at both 6 and 12 months). Serum Klotho was measured using a solid-phase sandwich enzyme-linked immunosorbent assay (ELISA). Analyses of covariance (ANCOVA's) were used to examine changes in weight, body composition, cardiorespiratory fitness, and Klotho concentration by weight loss response across the 12-month weight loss intervention. Results: Responders had a greater reduction in measures of weight and body composition, and a greater increase in cardiorespiratory fitness, compared to Non-Responders (p < 0.05). Change in Klotho concentration differed between Responders and Non-Responders (p < 0.05), with the increase in Klotho concentration from baseline to 6 months for Responders being statistically significant. The 6-month change in Klotho concentration was inversely associated with the 6-month change in weight (rs = -0.195), BMI (rs = -0.196), fat mass (rs = -0.184), and waist circumference (rs = -0.218) (p-values <0.05). Discussion: Findings provide evidence within the context of a behavioral intervention, with and without exercise, that change in Klotho concentration is significantly different between adults with weight loss ≥10% compared to <5% across 12 months. These findings suggest that weight loss and reduction in fat mass may be favorably associated with the change in Klotho concentration. This may reduce the risk of negative health consequences associated with accelerated aging in middle-aged adults.
介绍:Klotho是一种与预防衰老相关疾病和健康状况相关的蛋白质。肥胖与Klotho浓度降低有关。因此,这项对肥胖成人的二级分析检查了:1)通过体重减轻的幅度来响应行为减肥干预时血清Klotho浓度的变化;2)血清Klotho浓度与体重、体成分和心肺功能的关系。方法:参与者被随机分为单独饮食组(diet)、饮食加每周150分钟体力活动组(diet + PA150)或饮食加每周250分钟体力活动组(diet + PA250)。参与者[n = 152;年龄:45.0±7.9岁;体重指数(BMI): 32.4±3.8 kg/m2]纳入该二次分析,提供基线、6个月和12个月的血液样本,并根据体重减轻反应进行分类(反应者:在6或12个月体重减轻≥10%;结果:与无应答者相比,应答者在体重和身体组成方面有更大的减少,心肺健康有更大的增加(p < 0.05)。反应者与无反应者的Klotho浓度变化差异有统计学意义(p < 0.05),反应者的Klotho浓度从基线到6个月的增加有统计学意义。6个月的Klotho浓度变化与6个月的体重(r s = -0.195)、BMI (r s = -0.196)、脂肪量(r s = -0.184)和腰围(r s = -0.218)变化呈负相关(p值讨论:研究结果在行为干预的背景下提供了证据,有和没有运动,与体重减轻≥10%的成年人相比,Klotho浓度的变化显著不同
{"title":"Change in circulating klotho in response to weight loss, with and without exercise, in adults with overweight or obesity.","authors":"Katherine A Collins, Fabrisia Ambrosio, Renee J Rogers, Wei Lang, Eric B Schelbert, Kelliann K Davis, John M Jakicic","doi":"10.3389/fragi.2023.1213228","DOIUrl":"10.3389/fragi.2023.1213228","url":null,"abstract":"<p><p><b>Introduction:</b> Klotho is a protein associated with protection from aging-related diseases and health conditions. Obesity is associated with lower Klotho concentrations. Thus, this secondary analysis of adults with obesity examined 1) the change in serum Klotho concentration in response to a behavioral weight loss intervention by the magnitude of weight loss achieved; and 2) the association among serum Klotho concentration and weight, body composition, and cardiorespiratory fitness. <b>Methods:</b> Participants were randomized to either diet alone (DIET), diet plus 150 min of physical activity per week (DIET + PA150), or diet plus 250 min of physical activity per week (DIET + PA250). Participants [<i>n</i> = 152; age: 45.0 ± 7.9 years; body mass index (BMI): 32.4 ± 3.8 kg/m<sup>2</sup>] included in this secondary analysis provided blood samples at baseline, 6-, and 12 months, and were classified by weight loss response (Responder: achieved ≥10% weight loss at 6 or 12 months; Non-responder: achieved <5% weight loss at both 6 and 12 months). Serum Klotho was measured using a solid-phase sandwich enzyme-linked immunosorbent assay (ELISA). Analyses of covariance (ANCOVA's) were used to examine changes in weight, body composition, cardiorespiratory fitness, and Klotho concentration by weight loss response across the 12-month weight loss intervention. <b>Results:</b> Responders had a greater reduction in measures of weight and body composition, and a greater increase in cardiorespiratory fitness, compared to Non-Responders (<i>p</i> < 0.05). Change in Klotho concentration differed between Responders and Non-Responders (<i>p</i> < 0.05), with the increase in Klotho concentration from baseline to 6 months for Responders being statistically significant. The 6-month change in Klotho concentration was inversely associated with the 6-month change in weight (<i>r</i> <sub>s</sub> = -0.195), BMI (<i>r</i> <sub>s</sub> = -0.196), fat mass (<i>r</i> <sub>s</sub> = -0.184), and waist circumference (<i>r</i> <sub>s</sub> = -0.218) (<i>p</i>-values <0.05). <b>Discussion:</b> Findings provide evidence within the context of a behavioral intervention, with and without exercise, that change in Klotho concentration is significantly different between adults with weight loss ≥10% compared to <5% across 12 months. These findings suggest that weight loss and reduction in fat mass may be favorably associated with the change in Klotho concentration. This may reduce the risk of negative health consequences associated with accelerated aging in middle-aged adults.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10347392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-29eCollection Date: 2023-01-01DOI: 10.3389/fragi.2023.1175601
Hoau-Yan Wang, Zhe Pei, Kuo-Chieh Lee, Boris Nikolov, Tamara Doehner, John Puente, Nadav Friedmann, Lindsay H Burns
Introduction: Implicated in both aging and Alzheimer's disease (AD), mammalian target of rapamycin (mTOR) is overactive in AD brain and lymphocytes. Stimulated by growth factors such as insulin, mTOR monitors cell health and nutrient needs. A small molecule oral drug candidate for AD, simufilam targets an altered conformation of the scaffolding protein filamin A (FLNA) found in AD brain and lymphocytes that induces aberrant FLNA interactions leading to AD neuropathology. Simufilam restores FLNA's normal shape to disrupt its AD-associated protein interactions. Methods: We measured mTOR and its response to insulin in lymphocytes of AD patients before and after oral simufilam compared to healthy control lymphocytes. Results: mTOR was overactive and its response to insulin reduced in lymphocytes from AD versus healthy control subjects, illustrating another aspect of insulin resistance in AD. After oral simufilam, lymphocytes showed normalized basal mTOR activity and improved insulin-evoked mTOR activation in mTOR complex 1, complex 2, and upstream and downstream signaling components (Akt, p70S6K and phosphorylated Rictor). Suggesting mechanism, we showed that FLNA interacts with the insulin receptor until dissociation by insulin, but this linkage was elevated and its dissociation impaired in AD lymphocytes. Simufilam improved the insulin-mediated dissociation. Additionally, FLNA's interaction with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), a negative regulator of mTOR, was reduced in AD lymphocytes and improved by simufilam. Discussion: Reducing mTOR's basal overactivity and its resistance to insulin represents another mechanism of simufilam to counteract aging and AD pathology. Simufilam is currently in Phase 3 clinical trials for AD dementia.
导言:雷帕霉素哺乳动物靶标(mTOR)与衰老和阿尔茨海默病(AD)都有关系,它在 AD 大脑和淋巴细胞中过度活跃。在胰岛素等生长因子的刺激下,mTOR 监控着细胞的健康和营养需求。作为一种治疗注意力缺失症的小分子候选口服药物,simufilam 针对的是注意力缺失症患者大脑和淋巴细胞中的支架蛋白丝胶蛋白 A (FLNA)的构象改变,这种改变会诱发 FLNA 的异常相互作用,从而导致注意力缺失症的神经病理学。辛氟拉姆能恢复 FLNA 的正常形状,从而破坏其与 AD 相关的蛋白质相互作用。方法:与健康对照淋巴细胞相比,我们测量了口服辛非兰前后AD患者淋巴细胞中的mTOR及其对胰岛素的反应。结果:与健康对照组相比,AD 患者淋巴细胞中的 mTOR 过度活跃,对胰岛素的反应降低,这从另一个方面说明了 AD 患者的胰岛素抵抗。口服辛氟苯胺后,淋巴细胞的基础 mTOR 活性恢复正常,胰岛素诱发的 mTOR 复合物 1、复合物 2 和上下游信号元件(Akt、p70S6K 和磷酸化的 Rictor)的 mTOR 激活得到改善。在机制方面,我们发现 FLNA 与胰岛素受体相互作用,直到被胰岛素解离,但在 AD 淋巴细胞中,这种联系会增强,其解离作用会减弱。辛氟拉姆改善了胰岛素介导的解离作用。此外,在AD淋巴细胞中,FLNA与mTOR的负调控因子--染色体10上缺失的磷酸酶和同源蛋白(PTEN)的相互作用减弱,而辛氟苯胺能改善这种相互作用。讨论降低mTOR的基础过度活性及其对胰岛素的抗性是辛氟司林对抗衰老和AD病理的另一种机制。目前,辛氟拉姆正处于治疗AD痴呆症的3期临床试验阶段。
{"title":"Simufilam suppresses overactive mTOR and restores its sensitivity to insulin in Alzheimer's disease patient lymphocytes.","authors":"Hoau-Yan Wang, Zhe Pei, Kuo-Chieh Lee, Boris Nikolov, Tamara Doehner, John Puente, Nadav Friedmann, Lindsay H Burns","doi":"10.3389/fragi.2023.1175601","DOIUrl":"10.3389/fragi.2023.1175601","url":null,"abstract":"<p><p><b>Introduction:</b> Implicated in both aging and Alzheimer's disease (AD), mammalian target of rapamycin (mTOR) is overactive in AD brain and lymphocytes. Stimulated by growth factors such as insulin, mTOR monitors cell health and nutrient needs. A small molecule oral drug candidate for AD, simufilam targets an altered conformation of the scaffolding protein filamin A (FLNA) found in AD brain and lymphocytes that induces aberrant FLNA interactions leading to AD neuropathology. Simufilam restores FLNA's normal shape to disrupt its AD-associated protein interactions. <b>Methods:</b> We measured mTOR and its response to insulin in lymphocytes of AD patients before and after oral simufilam compared to healthy control lymphocytes. <b>Results:</b> mTOR was overactive and its response to insulin reduced in lymphocytes from AD versus healthy control subjects, illustrating another aspect of insulin resistance in AD. After oral simufilam, lymphocytes showed normalized basal mTOR activity and improved insulin-evoked mTOR activation in mTOR complex 1, complex 2, and upstream and downstream signaling components (Akt, p70S6K and phosphorylated Rictor). Suggesting mechanism, we showed that FLNA interacts with the insulin receptor until dissociation by insulin, but this linkage was elevated and its dissociation impaired in AD lymphocytes. Simufilam improved the insulin-mediated dissociation. Additionally, FLNA's interaction with Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN), a negative regulator of mTOR, was reduced in AD lymphocytes and improved by simufilam. <b>Discussion:</b> Reducing mTOR's basal overactivity and its resistance to insulin represents another mechanism of simufilam to counteract aging and AD pathology. Simufilam is currently in Phase 3 clinical trials for AD dementia.</p>","PeriodicalId":73061,"journal":{"name":"Frontiers in aging","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9829509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}