Pub Date : 2024-02-26DOI: 10.1007/s10522-024-10093-y
Abstact
With advancing age, the incidence of sarcopenia increases, eventually leading to a cascade of adverse events. However, there is currently a lack of effective pharmacological treatment for sarcopenia. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin demonstrates anti-fibrotic capabilities in various organs. This study aims to determine whether empagliflozin can improve skeletal muscle fibrosis induced by sarcopenia in naturally aging mice. A natural aging model was established by feeding male mice from 13 months of age to 19 months of age. A fibrosis model was created by stimulating skeletal muscle fibroblasts with TGF-β1. The Forelimb grip strength test assessed skeletal muscle function, and expression levels of COL1A1, COL3A1, and α-SMA were analyzed by western blot, qPCR, and immunohistochemistry. Additionally, levels of AMPKα/MMP9/TGFβ1/Smad signaling pathways were examined. In naturally aging mice, skeletal muscle function declines, expression of muscle fibrosis markers increases, AMPKα expression is downregulated, and MMP9/TGFβ1/Smad signaling pathways are upregulated. However, treatment with empagliflozin reverses this phenomenon. At the cellular level, empagliflozin exhibits similar anti-fibrotic effects, and these effects are attenuated by Compound C and siAMPKα. Empagliflozin exhibits anti-fibrotic effects, possibly associated with the AMPK/MMP9/TGFβ1/Smad signaling pathways.
{"title":"The SGLT2 inhibitor empagliflozin inhibits skeletal muscle fibrosis in naturally aging male mice through the AMPKα/MMP9/TGF-β1/Smad pathway","authors":"","doi":"10.1007/s10522-024-10093-y","DOIUrl":"https://doi.org/10.1007/s10522-024-10093-y","url":null,"abstract":"<h3>Abstact</h3> <p>With advancing age, the incidence of sarcopenia increases, eventually leading to a cascade of adverse events. However, there is currently a lack of effective pharmacological treatment for sarcopenia. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin demonstrates anti-fibrotic capabilities in various organs. This study aims to determine whether empagliflozin can improve skeletal muscle fibrosis induced by sarcopenia in naturally aging mice. A natural aging model was established by feeding male mice from 13 months of age to 19 months of age. A fibrosis model was created by stimulating skeletal muscle fibroblasts with TGF-β1. The Forelimb grip strength test assessed skeletal muscle function, and expression levels of COL1A1, COL3A1, and α-SMA were analyzed by western blot, qPCR, and immunohistochemistry. Additionally, levels of AMPKα/MMP9/TGFβ1/Smad signaling pathways were examined. In naturally aging mice, skeletal muscle function declines, expression of muscle fibrosis markers increases, AMPKα expression is downregulated, and MMP9/TGFβ1/Smad signaling pathways are upregulated. However, treatment with empagliflozin reverses this phenomenon. At the cellular level, empagliflozin exhibits similar anti-fibrotic effects, and these effects are attenuated by Compound C and siAMPKα. Empagliflozin exhibits anti-fibrotic effects, possibly associated with the AMPK/MMP9/TGFβ1/Smad signaling pathways.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139968080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-04DOI: 10.1007/s10522-024-10094-x
Gustavo Borges, Yahya Benslimane, Lea Harrington
Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases.
{"title":"A CRISPR base editing approach for the functional assessment of telomere biology disorder-related genes in human health and aging","authors":"Gustavo Borges, Yahya Benslimane, Lea Harrington","doi":"10.1007/s10522-024-10094-x","DOIUrl":"https://doi.org/10.1007/s10522-024-10094-x","url":null,"abstract":"<p>Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139677882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-09-22DOI: 10.1007/s10522-023-10064-9
Kento Takaya, Toru Asou, Kazuo Kishi
Accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling due to aging-related secretory phenotypes have been hypothesized to cause age-related skin aging, which results in wrinkles and loss of skin elasticity, thus compromising appearance attractiveness. However, the rejuvenating effects of removing senescent cells from the human skin and the efficacy of related therapeutic agents remain unclear. Here, we investigated the effects of fisetin, a potential anti-aging component found in various edible fruits and vegetables, on senescent human dermal fibroblasts (HDFs) and aging human skin. Senescence was induced in primary HDFs using long-term passaging and treatment with ionizing radiation, and cell viability was assessed after treatment with fisetin and a control component. A mouse/human chimeric model was established by subcutaneously transplanting whole skin grafts from aged individuals into nude mice, which were treated intraperitoneally with fisetin or control a component for 30 d. Skin samples were obtained and subjected to senescence-associated-beta-galactosidase staining; the extent of aging was evaluated using western blotting, reverse transcription-quantitative PCR, and histological analysis. Fisetin selectively eliminated senescent dermal fibroblasts in both senescence-induced cellular models; this effect is attributable to cell death induction by caspases 3, 8, and 9-mediated endogenous and exogenous apoptosis. Fisetin-treated senescent human skin grafts showed increased collagen density and decreased senescence-associated secretory phenotypes (SASP), including matrix metalloproteinases and interleukins. No apparent adverse events were observed. Thus, fisetin could improve skin aging through selective removal of senescent dermal fibroblasts and SASP inhibition, indicating its potential as an effective novel therapeutic agent for combating skin aging.
{"title":"Fisetin, a potential skin rejuvenation drug that eliminates senescent cells in the dermis.","authors":"Kento Takaya, Toru Asou, Kazuo Kishi","doi":"10.1007/s10522-023-10064-9","DOIUrl":"10.1007/s10522-023-10064-9","url":null,"abstract":"<p><p>Accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling due to aging-related secretory phenotypes have been hypothesized to cause age-related skin aging, which results in wrinkles and loss of skin elasticity, thus compromising appearance attractiveness. However, the rejuvenating effects of removing senescent cells from the human skin and the efficacy of related therapeutic agents remain unclear. Here, we investigated the effects of fisetin, a potential anti-aging component found in various edible fruits and vegetables, on senescent human dermal fibroblasts (HDFs) and aging human skin. Senescence was induced in primary HDFs using long-term passaging and treatment with ionizing radiation, and cell viability was assessed after treatment with fisetin and a control component. A mouse/human chimeric model was established by subcutaneously transplanting whole skin grafts from aged individuals into nude mice, which were treated intraperitoneally with fisetin or control a component for 30 d. Skin samples were obtained and subjected to senescence-associated-beta-galactosidase staining; the extent of aging was evaluated using western blotting, reverse transcription-quantitative PCR, and histological analysis. Fisetin selectively eliminated senescent dermal fibroblasts in both senescence-induced cellular models; this effect is attributable to cell death induction by caspases 3, 8, and 9-mediated endogenous and exogenous apoptosis. Fisetin-treated senescent human skin grafts showed increased collagen density and decreased senescence-associated secretory phenotypes (SASP), including matrix metalloproteinases and interleukins. No apparent adverse events were observed. Thus, fisetin could improve skin aging through selective removal of senescent dermal fibroblasts and SASP inhibition, indicating its potential as an effective novel therapeutic agent for combating skin aging.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41095565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-09-19DOI: 10.1007/s10522-023-10066-7
Mariano Almirón, Federico H Gomez, Pablo Sambucetti, Fabian M Norry
Heat-induced hormesis in longevity is the increase in life span resulting from the previous exposure to a mild heat stress early in life. Here we examined heat-induced hormesis of Drosophila buzzatii in five mass-mating populations, which were derived from five wild populations along an elevation gradient from 202 to 1855 m above sea level in North-Western Argentina. Five day old flies were exposed to 37.5 °C for 90 min to induce hormesis and its possible variation across altitudinal populations. This heat treatment strongly extended longevity in lowland-derived flies from the most heat-resistant population only. Both heat-induced effects on longevity and heat-knockdown time (heat-stress sensitivity) were negatively correlated to altitude of population of origin. Hormesis was positively correlated to heat-knockdown time across populations. These results indicate that variation in heat-induced hormesis can not be considered as independent of heat-stress sensitivity (or heat-knockdown time) in populations of insects.
{"title":"Heat-induced hormesis in longevity is linked to heat-stress sensitivity across laboratory populations from diverse altitude of origin in Drosophila buzzatii.","authors":"Mariano Almirón, Federico H Gomez, Pablo Sambucetti, Fabian M Norry","doi":"10.1007/s10522-023-10066-7","DOIUrl":"10.1007/s10522-023-10066-7","url":null,"abstract":"<p><p>Heat-induced hormesis in longevity is the increase in life span resulting from the previous exposure to a mild heat stress early in life. Here we examined heat-induced hormesis of Drosophila buzzatii in five mass-mating populations, which were derived from five wild populations along an elevation gradient from 202 to 1855 m above sea level in North-Western Argentina. Five day old flies were exposed to 37.5 °C for 90 min to induce hormesis and its possible variation across altitudinal populations. This heat treatment strongly extended longevity in lowland-derived flies from the most heat-resistant population only. Both heat-induced effects on longevity and heat-knockdown time (heat-stress sensitivity) were negatively correlated to altitude of population of origin. Hormesis was positively correlated to heat-knockdown time across populations. These results indicate that variation in heat-induced hormesis can not be considered as independent of heat-stress sensitivity (or heat-knockdown time) in populations of insects.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41100264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-10-21DOI: 10.1007/s10522-023-10062-x
Elena Yushkova
The Argonaute family genes (piwi and aub) involved in the production of small RNAs are responsible for the regulation of many cellular processes, including the suppression of genome instability, modulation of gene activity, and transposable elements. Dysfunction of these genes and the associated activation of transposable elements adversely affect reproductive development and quality of life. The role of transposons in contrast to retrotransposons and their interaction with genes of the Argonaute family in aging processes have not been studied. This study considers a scenario in which the piwi and aub genes in the presence of functional hobo transposons can modify the effects from the level of DNA damage to lifespan. The simultaneous presence of mutation (piwi or aub) and hobo (regardless of size) in the genome has practically no effect or (less often) leads to a decrease in the level of DNA damage in ovarian cells. A high level of sterility and low ovarian reserve were noted mainly with a combination of mutations and full-sized hobo elements. The combination of these two genetic factors negatively affects the fertility of young females and embryonic survival. Isolated cases of restoration of reproductive functions with age were noted but only in females that had low fertility in the early period of life. The presence of hobo transposons contributed to an increase in the lifespan of both mutant and non-mutant females. Dysfunction of the piwi and aub genes (without hobo) can reduce the lifespan of both sexes. Together, each mutation and hobo transposons act antagonistically/additively (in females) and synergistically/antagonistically (in males) to change the lifespan. In parameters of locus-specific instability, hobo activation was more pronounced in piwi gene dysfunction. The results obtained complement data on the study of new functions of Argonaute family genes and their interactions with transposable elements in the aging process.
{"title":"Interaction effect of mutations in the genes (piwi and aub) of the Argonaute family and hobo transposons on the integral survival parameters of Drosophila melanogaster.","authors":"Elena Yushkova","doi":"10.1007/s10522-023-10062-x","DOIUrl":"10.1007/s10522-023-10062-x","url":null,"abstract":"<p><p>The Argonaute family genes (piwi and aub) involved in the production of small RNAs are responsible for the regulation of many cellular processes, including the suppression of genome instability, modulation of gene activity, and transposable elements. Dysfunction of these genes and the associated activation of transposable elements adversely affect reproductive development and quality of life. The role of transposons in contrast to retrotransposons and their interaction with genes of the Argonaute family in aging processes have not been studied. This study considers a scenario in which the piwi and aub genes in the presence of functional hobo transposons can modify the effects from the level of DNA damage to lifespan. The simultaneous presence of mutation (piwi or aub) and hobo (regardless of size) in the genome has practically no effect or (less often) leads to a decrease in the level of DNA damage in ovarian cells. A high level of sterility and low ovarian reserve were noted mainly with a combination of mutations and full-sized hobo elements. The combination of these two genetic factors negatively affects the fertility of young females and embryonic survival. Isolated cases of restoration of reproductive functions with age were noted but only in females that had low fertility in the early period of life. The presence of hobo transposons contributed to an increase in the lifespan of both mutant and non-mutant females. Dysfunction of the piwi and aub genes (without hobo) can reduce the lifespan of both sexes. Together, each mutation and hobo transposons act antagonistically/additively (in females) and synergistically/antagonistically (in males) to change the lifespan. In parameters of locus-specific instability, hobo activation was more pronounced in piwi gene dysfunction. The results obtained complement data on the study of new functions of Argonaute family genes and their interactions with transposable elements in the aging process.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49673916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-11-02DOI: 10.1007/s10522-023-10072-9
Antero Salminen
Disruption of the extracellular matrix (ECM) and an accumulation of fibrotic lesions within tissues are two of the distinctive hallmarks of the aging process. Tissue fibroblasts are mesenchymal cells which display an impressive plasticity in the regulation of ECM integrity and thus on tissue homeostasis. Single-cell transcriptome studies have revealed that tissue fibroblasts exhibit a remarkable heterogeneity with aging and in age-related diseases. Excessive stress and inflammatory insults induce the differentiation of fibroblasts into myofibroblasts which are fusiform contractile cells and abundantly secrete the components of the ECM and proteolytic enzymes as well as many inflammatory mediators. Detrimental stresses can also induce the transdifferentiation of certain mesenchymal and myeloid cells into myofibroblasts. Interestingly, many age-related stresses, such as oxidative and endoplasmic reticulum stresses, ECM stiffness, inflammatory mediators, telomere shortening, and several alarmins from damaged cells are potent inducers of myofibroblast differentiation. Intriguingly, there is convincing evidence that the signaling pathways stimulated by the AMP-activated protein kinase (AMPK) are potent inhibitors of myofibroblast differentiation and accordingly AMPK signaling reduces fibrotic lesions within tissues, e.g., in age-related cardiac and pulmonary fibrosis. AMPK signaling is not only an important regulator of energy metabolism but it is also able to control cell fate determination and many functions of the immune system. It is known that AMPK signaling can delay the aging process via an integrated signaling network. AMPK signaling inhibits myofibroblast differentiation, e.g., by suppressing signaling through the TGF-β, NF-κB, STAT3, and YAP/TAZ pathways. It seems that AMPK signaling can alleviate age-related tissue fibrosis and degeneration by inhibiting the differentiation of myofibroblasts.
{"title":"AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration.","authors":"Antero Salminen","doi":"10.1007/s10522-023-10072-9","DOIUrl":"10.1007/s10522-023-10072-9","url":null,"abstract":"<p><p>Disruption of the extracellular matrix (ECM) and an accumulation of fibrotic lesions within tissues are two of the distinctive hallmarks of the aging process. Tissue fibroblasts are mesenchymal cells which display an impressive plasticity in the regulation of ECM integrity and thus on tissue homeostasis. Single-cell transcriptome studies have revealed that tissue fibroblasts exhibit a remarkable heterogeneity with aging and in age-related diseases. Excessive stress and inflammatory insults induce the differentiation of fibroblasts into myofibroblasts which are fusiform contractile cells and abundantly secrete the components of the ECM and proteolytic enzymes as well as many inflammatory mediators. Detrimental stresses can also induce the transdifferentiation of certain mesenchymal and myeloid cells into myofibroblasts. Interestingly, many age-related stresses, such as oxidative and endoplasmic reticulum stresses, ECM stiffness, inflammatory mediators, telomere shortening, and several alarmins from damaged cells are potent inducers of myofibroblast differentiation. Intriguingly, there is convincing evidence that the signaling pathways stimulated by the AMP-activated protein kinase (AMPK) are potent inhibitors of myofibroblast differentiation and accordingly AMPK signaling reduces fibrotic lesions within tissues, e.g., in age-related cardiac and pulmonary fibrosis. AMPK signaling is not only an important regulator of energy metabolism but it is also able to control cell fate determination and many functions of the immune system. It is known that AMPK signaling can delay the aging process via an integrated signaling network. AMPK signaling inhibits myofibroblast differentiation, e.g., by suppressing signaling through the TGF-β, NF-κB, STAT3, and YAP/TAZ pathways. It seems that AMPK signaling can alleviate age-related tissue fibrosis and degeneration by inhibiting the differentiation of myofibroblasts.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10794430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71420348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-09-14DOI: 10.1007/s10522-023-10063-w
Rachana Trivedi, Bailey Knopf, Sharlene Rakoczy, Gunjan D Manocha, Holly Brown-Borg, Donald A Jurivich
Brain aging is a major risk factor for cognitive diseases such as Alzheimer's disease (AD) and vascular dementia. The rate of aging and age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs and depend upon regenerative capacity and ability to manage damaged proteins and proteotoxicity. To answer these questions, we assessed age-dependent changes in brain stress responses with normally aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, and its regulation. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi-factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.
大脑老化是阿尔茨海默病(AD)和血管性痴呆等认知疾病的主要风险因素。衰老的速度和与年龄相关的病理变化受应激反应和修复途径的调节,而应激反应和修复途径会随着年龄的增长而逐渐衰退。然而,最近的报告表明,超常的长寿会维持甚至增强应激反应。正常衰老和超常衰老是否会导致所有器官的应激反应减弱或增强,目前尚不清楚。这个问题源于我们对生物年龄不同于计时年龄的理解,以及不同器官衰老速度不同的证据。因此,不同器官的应激反应可能不同,并取决于再生能力以及管理受损蛋白质和蛋白质毒性的能力。为了回答这些问题,我们用正常衰老的野生型小鼠和长寿侏儒小鼠评估了大脑应激反应随年龄的变化。研究结果表明,正常衰老对大脑热休克(HS)轴的激活有不利影响,转录因子 HSF1 及其调控发生了关键变化。异常衰老似乎保留并加强了大脑中激活 HSF1 的许多要素。这些结果支持这样一种可能性,即重建衰老大脑的应激反应需要一种多因素方法,以解决 HSF1 蛋白水平、其 DNA 结合以及磷酸化和蛋白质相互作用等调控要素的问题。
{"title":"Disrupted HSF1 regulation in normal and exceptional brain aging.","authors":"Rachana Trivedi, Bailey Knopf, Sharlene Rakoczy, Gunjan D Manocha, Holly Brown-Borg, Donald A Jurivich","doi":"10.1007/s10522-023-10063-w","DOIUrl":"10.1007/s10522-023-10063-w","url":null,"abstract":"<p><p>Brain aging is a major risk factor for cognitive diseases such as Alzheimer's disease (AD) and vascular dementia. The rate of aging and age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs and depend upon regenerative capacity and ability to manage damaged proteins and proteotoxicity. To answer these questions, we assessed age-dependent changes in brain stress responses with normally aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, and its regulation. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi-factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10794279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10234968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frailty syndrome denotes a decreased capacity of the body to maintain the homeostasis and stress of the internal environment, which simultaneously increases the risk of adverse health outcomes in older adults, including disability, hospitalization, falls, and death. To promote healthy aging, we should find strategies to cope with frailty. However, the pathogenesis of frailty syndrome is not yet clear. Recent studies have shown that the diversity, composition, and metabolites of gut microbiota significantly changed in older adults with frailty. In addition, several frailty symptoms were alleviated by adjusting gut microbiota with prebiotics, probiotics, and symbiosis. Therefore, we attempt to explore the pathogenesis of frailty syndrome in older people from gut microbiota and summarize the existing interventions for frailty syndrome targeting gut microbiota, with the aim of providing timely and necessary interventions and assistance for older adults with frailty.
{"title":"Gut microbiota influence frailty syndrome in older adults: mechanisms and therapeutic strategies.","authors":"Xiao-Ming Wang, Lu Fan, Chen-Chen Meng, Yun-Jiao Wang, Li-E Deng, Zhuo Yuan, Jun-Ping Zhang, Yan-Yang Li, Shi-Chao Lv","doi":"10.1007/s10522-023-10082-7","DOIUrl":"10.1007/s10522-023-10082-7","url":null,"abstract":"<p><p>Frailty syndrome denotes a decreased capacity of the body to maintain the homeostasis and stress of the internal environment, which simultaneously increases the risk of adverse health outcomes in older adults, including disability, hospitalization, falls, and death. To promote healthy aging, we should find strategies to cope with frailty. However, the pathogenesis of frailty syndrome is not yet clear. Recent studies have shown that the diversity, composition, and metabolites of gut microbiota significantly changed in older adults with frailty. In addition, several frailty symptoms were alleviated by adjusting gut microbiota with prebiotics, probiotics, and symbiosis. Therefore, we attempt to explore the pathogenesis of frailty syndrome in older people from gut microbiota and summarize the existing interventions for frailty syndrome targeting gut microbiota, with the aim of providing timely and necessary interventions and assistance for older adults with frailty.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139039459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01DOI: 10.1007/s10522-023-10089-0
Suresh I S Rattan
About a year ago, members of the editorial board of Biogerontology were requested to respond to a query by the editor-in-chief of the journal as to what one question within their field of ageing research still needs to be asked and answered. This editorial is inspired by the wide range and variety of questions, ideas, comments and suggestions received in response to that query. The seven knowledge gaps identified in this article are arranged into three main categories: evolutionary aspects of longevity, biological survival and death aspects, and heterogeneity in the progression and phenotype of ageing. This is not an exhaustive and exclusive list, and may be modified and expanded. Implications of these knowledge gaps, especially in the context of ongoing attempts to develop effective interventions in ageing and longevity are also discussed.
{"title":"Seven knowledge gaps in modern biogerontology.","authors":"Suresh I S Rattan","doi":"10.1007/s10522-023-10089-0","DOIUrl":"10.1007/s10522-023-10089-0","url":null,"abstract":"<p><p>About a year ago, members of the editorial board of Biogerontology were requested to respond to a query by the editor-in-chief of the journal as to what one question within their field of ageing research still needs to be asked and answered. This editorial is inspired by the wide range and variety of questions, ideas, comments and suggestions received in response to that query. The seven knowledge gaps identified in this article are arranged into three main categories: evolutionary aspects of longevity, biological survival and death aspects, and heterogeneity in the progression and phenotype of ageing. This is not an exhaustive and exclusive list, and may be modified and expanded. Implications of these knowledge gaps, especially in the context of ongoing attempts to develop effective interventions in ageing and longevity are also discussed.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139416275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-01Epub Date: 2023-09-14DOI: 10.1007/s10522-023-10065-8
Daigo Okada
Plasma proteins serve as biomarkers of aging and various age-related diseases. While a number of plasma proteins have been identified that increase or decrease with age, the interpretation of each protein is challenging. This is due to the nature of plasma, which is a mixture of factors secreted by many different tissues and cells. Therefore, the catalog of age-related proteins secreted by a single cell type in a single tissue would be useful for understanding tissue-specific aging patterns. In this study, the author addressed this challenge by integrative data mining of the Human Protein Atlas and the recently published result of large-scale aging proteomics research. Finally, we identified the 17 age-related proteins produced by a single tissue and a single cell type: MBL2 and HP in the liver (hepatocytes), SFTPC in the lung (type II alveolar cells), PRL and POMC in the pituitary (anterior cells), GCG, CUZD1 and CPA2 in the pancreas (pancreatic cells), MYBPC1 in skeletal muscle (myocytes), PTH in the parathyroid gland (glandular cells), LPO and AMY1A in the salivary gland (glandular cells), INSL3 in the male testis (Leydig cells), KLK3 and KLK4 in the male prostate (glandular cells), MPO and ACP5 in immune cells. This list of proteins would be potentially useful for understanding age-related changes in the plasma proteome and inter-tissue networks.
{"title":"Plasma proteins as potential biomarkers of aging of single tissue and cell type.","authors":"Daigo Okada","doi":"10.1007/s10522-023-10065-8","DOIUrl":"10.1007/s10522-023-10065-8","url":null,"abstract":"<p><p>Plasma proteins serve as biomarkers of aging and various age-related diseases. While a number of plasma proteins have been identified that increase or decrease with age, the interpretation of each protein is challenging. This is due to the nature of plasma, which is a mixture of factors secreted by many different tissues and cells. Therefore, the catalog of age-related proteins secreted by a single cell type in a single tissue would be useful for understanding tissue-specific aging patterns. In this study, the author addressed this challenge by integrative data mining of the Human Protein Atlas and the recently published result of large-scale aging proteomics research. Finally, we identified the 17 age-related proteins produced by a single tissue and a single cell type: MBL2 and HP in the liver (hepatocytes), SFTPC in the lung (type II alveolar cells), PRL and POMC in the pituitary (anterior cells), GCG, CUZD1 and CPA2 in the pancreas (pancreatic cells), MYBPC1 in skeletal muscle (myocytes), PTH in the parathyroid gland (glandular cells), LPO and AMY1A in the salivary gland (glandular cells), INSL3 in the male testis (Leydig cells), KLK3 and KLK4 in the male prostate (glandular cells), MPO and ACP5 in immune cells. This list of proteins would be potentially useful for understanding age-related changes in the plasma proteome and inter-tissue networks.</p>","PeriodicalId":8909,"journal":{"name":"Biogerontology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10224436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}