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1.
Nat Commun ; 12(1): 720, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526781

RESUMO

Cellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.


Assuntos
Senescência Celular/fisiologia , Retículo Endoplasmático/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Longevidade/fisiologia , Mitocôndrias/metabolismo , Animais , Cálcio/metabolismo , Retículo Endoplasmático/ultraestrutura , Feminino , Fibroblastos , Células HEK293 , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Masculino , Camundongos , Camundongos Knockout , Microscopia Confocal , Mitocôndrias/ultraestrutura , RNA Interferente Pequeno , Período Refratário Eletrofisiológico , Análise de Célula Única
2.
Life Sci ; 272: 119196, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617857

RESUMO

Senescent cancer cells contribute to tumor refractoriness. The removal of senescent cells after chemotherapy prevents or delays cancer relapse. Our study showed that GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy)-4-H-chromen-4-one), a potential anticancer drug, eliminated senescent MEFs (Mouse embryonic fibroblasts) and drug-induced senescent breast cancer cells. GL-V9 induced apoptosis in senescent MDA-MB-231 cells. Mechanistically, it alkalized lysosomes and increased the abundance of mitochondria as well as ROS (Reactive oxygen species). The senolytic effect of GL-V9 was also observed in epirubicin-treated mammary tumors in MMTV-PyMT mice. Our data thus indicated that GL-V9 is a promising senolytic drug which could be used to improve the outcome of cancer chemotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Senescência Celular/efeitos dos fármacos , Flavonoides/farmacologia , Envelhecimento/fisiologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/fisiologia , China , Feminino , Flavonoides/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Espécies Reativas de Oxigênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445766

RESUMO

Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases.


Assuntos
Senescência Celular/fisiologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Triptofano/metabolismo , Animais , Antioxidantes/metabolismo , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
4.
Science ; 371(6526): 265-270, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446552

RESUMO

Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (GLS1) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.


Assuntos
Envelhecimento/metabolismo , Senescência Celular/fisiologia , Glutaminase/metabolismo , Tecido Adiposo/enzimologia , Envelhecimento/genética , Amônia/metabolismo , Animais , Sobrevivência Celular , Senescência Celular/genética , Genes Essenciais , Glutaminase/genética , Humanos , Concentração de Íons de Hidrogênio , Pulmão/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pele/enzimologia
5.
Aging (Albany NY) ; 13(1): 1294-1313, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33406502

RESUMO

Although several evidence has suggested the impact of exercise on the prevention of aging phenotypes, few studies have been conducted on the mechanism by which exercise alters the immune-cell profile, thereby improving metabolism in senile obesity. In this study, we confirmed that 4-week treadmill exercise sufficiently improved metabolic function, including increased lean mass and decreased fat mass, in 88-week-old mice. The expression level of the senescence marker p16 in the white adipose tissue (WAT) was decreased after 4-weeks of exercise. Exercise induced changes in the profiles of immune-cell subsets, including natural killer (NK) cells, central memory CD8+ T cells, eosinophils, and neutrophils, in the stromal vascular fraction of WAT. In addition, it has been shown through transcriptome analysis of WAT that exercise can activate pathways involved in the interaction between WAT and immune cells, in particular NK cells, in aged mice. These results suggest that exercise has a profound effect on changes in immune-cell distribution and senescent-cell scavenging in WAT of aged mice, eventually affecting overall energy metabolism toward a more youthful state.


Assuntos
Tecido Adiposo Branco/metabolismo , Metabolismo Energético/fisiologia , Sistema Imunitário/fisiologia , Condicionamento Físico Animal , Esforço Físico/fisiologia , Envelhecimento , Animais , Senescência Celular/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Esforço Físico/imunologia
6.
Biochem J ; 478(1): 179-196, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33346336

RESUMO

Human body temperature limits below 40°C during heat stroke or fever. The implications of prolonged exposure to the physiologically relevant temperature (40°C) on cellular mechanobiology is poorly understood. Here, we have examined the effects of heat stress (40°C for 72 h incubation) in human lung adenocarcinoma (A549), mouse melanoma (B16F10), and non-cancerous mouse origin adipose tissue cells (L929). Hyperthermia increased the level of ROS, γ-H2AX and HSP70 and decreased mitochondrial membrane potential in the cells. Heat stress impaired cell division, caused G1 arrest, induced cellular senescence, and apoptosis in all the tested cell lines. The cells incubated at 40°C for 72 h displayed a significant decrease in the f-actin level and cellular traction as compared with cells incubated at 37°C. Also, the cells showed a larger focal adhesion area and stronger adhesion at 40°C than at 37°C. The mitotic cells at 40°C were unable to round up properly and displayed retracting actin stress fibers. Hyperthermia down-regulated HDAC6, increased the acetylation level of microtubules, and perturbed the chromosome alignment in the mitotic cells at 40°C. Overexpression of HDAC6 rescued the cells from the G1 arrest and reduced the delay in cell rounding at 40°C suggesting a crucial role of HDAC6 in hyperthermia mediated responses. This study elucidates the significant role of cellular traction, focal adhesions, and cytoskeletal networks in mitotic cell rounding and chromosomal misalignment. It also highlights the significance of HDAC6 in heat-evoked senile cellular responses.


Assuntos
Senescência Celular/fisiologia , Citoesqueleto/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Desacetilase 6 de Histona/metabolismo , Fibras de Estresse/metabolismo , Acetilação , Actinas/metabolismo , Apoptose/fisiologia , Adesão Celular/fisiologia , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Forma Celular , Tamanho Celular , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Desacetilase 6 de Histona/genética , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Microtúbulos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
7.
Gene ; 765: 145116, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32896589

RESUMO

In contrast to most mammals including human, fish cell lines have long been known to be immortal, with little sign of cellular senescence, despite the absence of transformation. Recently, our laboratory reported that DNA demethylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induces telomere-independent cellular senescence and senescence-associated secretory phenotype (SASP) in an immortal fish cell line, EPC (Epithelioma papulosum cyprini). However, it is not known how fish derived cultured cells are usually resistant to aging in vitro. In this study, we focused on Ras, which carries out the main role of Ras-induced senescence (RIS), and investigated the role of Ras in the regulation of senescence in EPC cells. Our results show that 5-Aza-dC induced the expression of the ras (hras, kras, nras) gene in EPC cells. EPC cells overexpressing HRas or its constitutively active form (HRasV12) showed p53-dependent senescence-like growth arrest and senescence-associated ß-galactosidase (SA-ß-gal) activity with a large and/or flat morphology characteristic of cell senescence. On the other hand, the SASP was not induced. These results imply that the increased expression of HRas contributes to early senescence in EPC cells, but it alone may not be sufficient for the full senescence, even if HRas is aberrantly activated. Thus, the limited mechanism of RIS may play a role in the senescence-resistance of fish cell lines.


Assuntos
Senescência Celular/genética , Genes ras/genética , Genes ras/fisiologia , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Senescência Celular/fisiologia , Peixes/genética , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética
8.
J Frailty Aging ; 10(1): 2-9, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33331615

RESUMO

Telomeres are repetitive nucleotide sequences that together with the associated sheltrin complex protect the ends of chromosomes and maintain genomic stability. Evidences from various organisms suggests that several factors influence telomere length regulation, such as telomere binding proteins, telomere capping proteins, telomerase, and DNA replication enzymes. Recent studies suggest that micronutrients, such as vitamin D, folate and vitamin B12, are involved in telomere biology and cellular aging. In particular, vitamin D is important for a range of vital cellular processes including cellular differentiation, proliferation and apoptosis. As a result of the multiple functions of vitamin D it has been speculated that vitamin D might play a role in telomere biology and genomic stability. In this study, our main goal is investigating the relationship between telomerase enzyme and vitamin D. Findings of this study suggest that higher vitamin D concentrations, which are easily modifiable through nutritional supplementation, are associated with longer LTL, which underscores the potentially beneficial effects of this hormone on aging and age-related diseases. Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. Significant Low levels of telomerase activity create short telomeres, which in turn signal exit from the cell cycle resulting in cell senescence and apoptosis. In follow-up examination, the patients who remained vitamin D deficient tended to have shorter telomeres than those patients whose 25-hydroxyvitamin D levels were depleted. Increasing 25-hydroxyvitamin D levels in patients with SLE may be beneficial in maintaining telomere length and preventing cellular aging. Moreover, anti-telomere antibody levels may be a promising biomarker of SLE status and disease activity.


Assuntos
Senescência Celular/fisiologia , Telômero/metabolismo , Vitamina D/sangue , Vitamina D/metabolismo , Envelhecimento/sangue , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Humanos , Telomerase/genética , Telomerase/metabolismo , Telômero/genética
9.
Nat Commun ; 11(1): 4979, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020468

RESUMO

Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes. However, the mechanisms and factors that control the negative effects of senescence while retaining its benefits are still elusive. Here, we show that the rasGAP SH3-binding protein 1 (G3BP1) is required for the activation of the senescent-associated secretory phenotype (SASP). During senescence, G3BP1 achieves this effect by promoting the association of the cyclic GMP-AMP synthase (cGAS) with cytosolic chromatin fragments. In turn, G3BP1, through cGAS, activates the NF-κB and STAT3 pathways, promoting SASP expression and secretion. G3BP1 depletion or pharmacological inhibition impairs the cGAS-pathway preventing the expression of SASP factors without affecting cell commitment to senescence. These SASPless senescent cells impair senescence-mediated growth of cancer cells in vitro and tumor growth in vivo. Our data reveal that G3BP1 is required for SASP expression and that SASP secretion is a primary mediator of senescence-associated tumor growth.


Assuntos
Senescência Celular/fisiologia , DNA Helicases/metabolismo , Neoplasias/patologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Células A549 , Animais , Carcinogênese , Linhagem Celular , Movimento Celular , Citocinas/metabolismo , DNA Helicases/antagonistas & inibidores , DNA Helicases/deficiência , Humanos , Inflamação , Camundongos , Neoplasias/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/deficiência , RNA Helicases/antagonistas & inibidores , RNA Helicases/deficiência , Proteínas com Motivo de Reconhecimento de RNA/antagonistas & inibidores , Proteínas com Motivo de Reconhecimento de RNA/deficiência , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo
10.
Nat Commun ; 11(1): 4289, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855397

RESUMO

Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, thereby aggravating transplant outcomes. Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.


Assuntos
DNA Mitocondrial/efeitos adversos , Dasatinibe/farmacologia , Inflamação/prevenção & controle , Transplante de Órgãos/métodos , Quercetina/farmacologia , Adulto , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Ácidos Nucleicos Livres , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Citocinas/metabolismo , DNA Mitocondrial/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Transplante de Coração/efeitos adversos , Transplante de Coração/métodos , Humanos , Inflamação/etiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Doadores de Tecidos
11.
Am J Physiol Endocrinol Metab ; 319(2): E447-E454, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32691630

RESUMO

The aim of the present study was to determine if the training status decreases inflammation, slows down senescence, and preserves telomere health in skeletal muscle in older compared with younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies (n = 34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS), and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence-associated ß-galactosidase (SA-ß-Gal) staining, and quantitative (q)RT-PCR. Independently of the endurance training status, TIF levels (+35%, P < 0.001) and the percentage of SA-ß-Gal-positive cells (+30%, P < 0.05) were higher in cultured satellite cells of older compared with younger subjects. p16 (4- to 5-fold) and p21 (2-fold) mRNA levels in skeletal muscle were higher with age but unchanged by the training status. Aging induced higher CD68 mRNA levels in human skeletal muscle (+102%, P = 0.009). Independently of age, both trained groups had lower IL-8 mRNA levels (-70%, P = 0.011) and tended to have lower TNF-α mRNA levels (-40%, P = 0.10) compared with the sedentary subjects. All together, we found that the endurance training status did not slow down senescence in skeletal muscle and satellite cells in older compared with younger subjects despite reduced inflammation in skeletal muscle. These findings highlight that the link between senescence and inflammation can be disrupted in skeletal muscle.


Assuntos
Envelhecimento/fisiologia , Treino Aeróbico , Inflamação/prevenção & controle , Músculo Esquelético/fisiologia , Resistência Física/fisiologia , Homeostase do Telômero/fisiologia , Idoso , Senescência Celular/genética , Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Humanos , Masculino , Músculo Esquelético/química , Músculo Esquelético/citologia , RNA Mensageiro/análise , Células Satélites de Músculo Esquelético/fisiologia , Células Satélites de Músculo Esquelético/ultraestrutura , Telômero/fisiologia , Telômero/ultraestrutura , Adulto Jovem , beta-Galactosidase/análise
12.
PLoS One ; 15(7): e0234255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726311

RESUMO

'Normal aging' in the brain refers to age-related changes that occur independent of disease, in particular Alzheimer's disease. A major barrier to mapping normal brain aging has been the difficulty in excluding the earliest preclinical stages of Alzheimer's disease. Here, before addressing this issue we first imaged a mouse model and learn that the best MRI measure of dendritic spine loss, a known pathophysiological driver of normal aging, is one that relies on the combined use of functional and structural MRI. In the primary study, we then deployed the combined functional-structural MRI measure to investigate over 100 cognitively-normal people from 20-72 years of age. Next, to cover the tail end of aging, in secondary analyses we investigated structural MRI acquired from cognitively-normal people, 60-84 years of age, who were Alzheimer's-free via biomarkers. Collectively, the results from the primary functional-structural study, and the secondary structural studies revealed that the dentate gyrus is a hippocampal region differentially affected by aging, and that the entorhinal cortex is a region most resistant to aging. Across the cortex, the primary functional-structural study revealed and that the inferior frontal gyrus is differentially affected by aging, however, the secondary structural studies implicated other frontal cortex regions. Together, the results clarify how normal aging may affect the brain and has possible mechanistic and therapeutic implications.


Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Senescência Celular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Mapeamento Encefálico/métodos , Disfunção Cognitiva/fisiopatologia , Espinhas Dendríticas/patologia , Giro Denteado/patologia , Córtex Entorrinal/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Pessoa de Meia-Idade
13.
Life Sci ; 257: 118055, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634429

RESUMO

AIMS: Human adipose derived mesenchymal stem cells (hAD-MSCs) as the most promising target for cell therapy and regenerative medicine, face senescence as a major drawback resulting in their limited proliferation and differentiation potentials. To evaluate the efficacy of miR-34a silencing as an anti-senescence strategy in hAD-MSCs, in this study common hallmarks of senescence were assessed after transient inhibition of miR-34a in hAD-MSCs. MATERIALS AND METHODS: The expression levels of miR-34a in hAD-MSCs at different passages were evaluated by real-time quantitative PCR. hAD-MSCs at passage 2 and passage 7 were transfected with miR-34a inhibitor. Doubling time assay, colony forming assay, and cell cycle analysis were performed to evaluate cell proliferation rate. The activity of senescence associated ß-galactosidase (SA-ß-gal) was assessed by histochemical staining. Moreover, the senescence associated molecular alterations including that of pro-senescence (P53, P21 and P16) and anti-senescence (SIRT1, HTERT and CD44) genes were examined by quantitative RT-PCR and western blot assays. To evaluate the differentiation potentials of MSCs, following adipogenic and osteogenic induction, the expression levels of lineage specific markers were analyzed by qPCR. KEY FINDINGS: Our results showed that inhibition of miR-34a enhances the proliferation, promotes the adipogenic and osteogenic differentiation potency, reduces the senescence associated-ß gal activity, and reverses the senescence associated molecular alterations in hAD-MSCs. SIGNIFICANCE: In this study, we showed that inhibition of miR-34a reduces the cellular senescence through the activation of SIRT1. Our findings support the silencing of miR-34a as an anti-senescence approach to improve the therapeutic potentials of hAD-MSCs.


Assuntos
Diferenciação Celular/fisiologia , Senescência Celular/fisiologia , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Sirtuína 1/genética , Adipogenia/fisiologia , Tecido Adiposo/citologia , Inativação Gênica , Humanos , Receptores de Hialuronatos/genética , Osteogênese/fisiologia , Telomerase/genética
14.
Ann Rheum Dis ; 79(10): 1370-1380, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32665267

RESUMO

OBJECTIVE: Previous work has established that the deacetylase sirtuin-1 (SIRT1) is cleaved by cathepsin B in chondrocytes subjected to proinflammatory stress, yielding a stable but inactive N-terminal (NT) polypeptide (75SIRT1) and a C-terminal (CT) fragment. The present work examined if chondrocyte-derived NT-SIRT1 is detected in serum and may serve as an investigative and exploratory biomarker of osteoarthritis (OA). METHODS: We developed a novel ELISA assay to measure the ratio of NT to CT of SIRT1 in the serum of human individuals and mice subjected to post-traumatic OA (PTOA) or age-dependent OA (ADOA). We additionally monitored NT/CT SIRT1 in mice subject to ADOA/PTOA followed by senolytic clearance. Human chondrosenescent and non-senescent chondrocytes were exposed to cytokines and analysed for apoptosis and NT/CT SIRT1 ratio in conditioned medium. RESULTS: Wild-type mice with PTOA or ADOA of moderate severity exhibited increased serum NT/CT SIRT1 ratio. In contrast, this ratio remained low in cartilage-specific Sirt1 knockout mice despite similar or increased PTOA and ADOA severity. Local clearance of senescent chondrocytes from old mice with post-traumatic injury resulted in a lower NT/CT ratio and reduced OA severity. While primary chondrocytes exhibited NT/CT ratio increased in conditioned media after prolonged cytokine stimulation, this increase was not evident in cytokine-stimulated chondrosenescent cells. Finally, serum NT/CT ratio was elevated in humans with early-stage OA. CONCLUSIONS: Increased levels of serum NT/CT SIRT1 ratio correlated with moderate OA in both mice and humans, stemming at least in part from non-senescent chondrocyte apoptosis, possibly a result of prolonged inflammatory insult.


Assuntos
Biomarcadores/sangue , Osteoartrite/patologia , Sirtuína 1/sangue , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Senescência Celular/fisiologia , Condrócitos/metabolismo , Condrócitos/patologia , Humanos , Camundongos , Osteoartrite/sangue
15.
Clin Interv Aging ; 15: 695-714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32546988

RESUMO

Skeletal muscle aging manifests as a decline in muscle quantity and quality that accelerates with aging, increasing the risk of sarcopenia. Sarcopenia is characterized by a loss of muscle strength and mass, and contributes to adverse health outcomes in older adults. Intervention studies have shown that sarcopenia may be treated by higher protein intake in combination with resistance exercise (RE). In comparison, less is known about the role of whole protein-containing foods in preventing or treating sarcopenia. Liquid milk contains multiple nutrients and bioactive components that may be beneficial for muscle, including proteins for muscle anabolism that, alone or with RE, may have myoprotective properties. However, there is a lack of evidence about the role of milk and its effects on muscle aging. This narrative review considers evidence from three observational and eight intervention studies that used milk or fortified milk, with or without exercise, as an intervention to promote muscle health and function in older adults (aged 50-99 years). The observational studies showed no association between higher habitual milk consumption and muscle-related outcomes. The results of intervention studies using fortified milk in relation to elements of sarcopenia were also negative, with further inconclusive results from the studies using a combination of (fortified) milk and exercise. Although milk contains nutrients that may be myoprotective, current evidence does not show beneficial effects of milk on muscle health in older adults. This could be due to high habitual protein intakes (>1.0 g/kg BW/d) in study participants, differences in the type of milk (low-fat vs whole) and timing of milk consumption, length of interventions, as well as differences in the sarcopenia status of participants in trials. Adequately powered intervention studies of individuals likely to benefit are needed to test the effectiveness of a whole food approach, including milk, for healthy muscle aging.


Assuntos
Envelhecimento/fisiologia , Senescência Celular/fisiologia , Proteínas do Leite/metabolismo , Músculo Esquelético/fisiologia , Sarcopenia , Idoso , Exercício Físico/fisiologia , Comportamento Alimentar , Humanos , Força Muscular , Estudos Observacionais como Assunto , Sarcopenia/fisiopatologia , Sarcopenia/prevenção & controle
16.
Geriatr Gerontol Int ; 20(6): 520-525, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32346971

RESUMO

The renin-angiotensin system (RAS) plays crucial roles in the control of blood pressure and sodium homeostasis. Moreover, RAS also acts as a key player in cell and organ senescence, mainly by activation of the classical axis of angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang II type 1 receptor via overproduction of reactive oxygen species. Overactivation of the classical RAS axis induces organ dysfunction in the vasculature, brain, kidney and skeletal muscle, resulting in atherosclerosis, stroke, chronic kidney disease and sarcopenia. Moreover, RAS has been shown to regulate lifespan, using gene-modification models. Recently, mice lacking the Ang II type 1 receptor were shown to exhibit an increase in lifespan compared with control mice. Here, the effect of RAS on age-related tissue dysfunction in several organs is reviewed, including not only the classical axis but also protective functions of RAS such as the ACE2/Ang (1-7)/Mas axis. Geriatr Gerontol Int 2020; ••: ••-••.


Assuntos
Angiotensina II/metabolismo , Senescência Celular/fisiologia , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/fisiologia , Envelhecimento/fisiologia , Angiotensina I/metabolismo , Animais , Humanos , Longevidade , Camundongos , Estresse Oxidativo/fisiologia , Fragmentos de Peptídeos/metabolismo , Ratos , Transdução de Sinais
17.
Med Sci Monit ; 26: e920520, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32188838

RESUMO

BACKGROUND Freshly isolated mouse embryonic fibroblasts (MEFs) have great proliferation capacity but quickly enter senescent state after several rounds of cell cycle, a process called premature senescence. Cellular senescence can be induced by various stresses such as telomere erosion, DNA damage, and oncogenic signaling. But the contribution of other molecules, such as growth factors, to cellular senescence is incompletely understood. This study aimed to compare the gene expression difference between non-senescent and senescent MEFs to identify the key molecule(s) involved in the spontaneous senescence of MEFs. MATERIAL AND METHODS Primary MEFs were isolated from E12.5 pregnant C57/BL6 mice. The cells were continuously cultured in Dulbecco's Modified Eagle Medium for 9 passages. SA-ß-Gal staining was used as an indicator of cell senescence. The supernatant from primary MEFs (P1 medium) or Passage 6 MEFs (P6 medium) were used to culture freshly isolated MEFs to observe the effects on cell senescence state. Gene expression profiles of primary and senescent MEFs were investigated by RNA-Seq to find the key genes involved in cell senescence. Adipocyte differentiation assay was used to evaluate the stemness of MEFs cultured in FGF2-stimulated medium. RESULTS The senescence of MEFs cultured in the P1 medium was alleviated when compared to the P6 medium. Downregulation of FGF2 expression was revealed by RNA-Seq and further confirmed by real-time quantitative polymerase chain reaction and western blot. FGF2-stimulated medium also had anti-senescence function and could maintain the differentiation ability of MEFs. CONCLUSIONS The premature senescence of MEFs was at least partially caused by FGF2 deficiency. Exogenous FGF2 could alleviate the senescent phenotype.


Assuntos
Senescência Celular/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fibroblastos/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Dano ao DNA , Embrião de Mamíferos/metabolismo , Feminino , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
18.
Am J Pathol ; 190(6): 1164-1171, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32194054

RESUMO

Chronic kidney disease (CKD), commonly fostering nonrenal complications, themselves more life threatening than renal pathology, remains enigmatic. Despite more than a century of intense research, therapeutic options to halt or reverse renal disease are rather limited. Recently, similarity between manifestations of progressive CKD and aging kidney has attracted investigative attention that revealed senescent cells and secreting proinflammatory and profibrotic mediators in all renal compartments, even at young age, in patients with kidney maladies. The overlapping features of these categories have been noticed previously and are briefly summarized herein. I propose two hypothetical scenarios for interactive association of kidney diseases and cell senescence, both culminating in progressive deterioration of renal function. Persistence of senescent cells is considered as a critical contributor to this association; and the mechanisms explaining persistence, such as activation of cell cycle regulators, anti-apoptotic stimuli, metabolic aberrations, and their interactions, are discussed. The mutual encroachment of underlying kidney disease and cell senescence bring about the conclusion that both entities merge along the natural history of the disease. This putative interpretation of vicarious relation between cell senescence and CKD may expand the arsenal of pharmacotherapy to include the judicious use of senotherapeutics in the management of renal disease.


Assuntos
Senescência Celular/fisiologia , Rim/patologia , Insuficiência Renal Crônica/patologia , Humanos
19.
Med Sci Monit ; 26: e921887, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32191680

RESUMO

BACKGROUND Recent studies have suggested that hepatocyte senescence could contribute to hepatic steatosis and its progression in nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism causing hepatocyte senescence in this pathological condition is still unclear. A thorough understanding of the mechanism could provide a new target for therapeutic intervention. The purpose of this study was to investigate the role of p66shc in hepatocyte senescence and hepatocyte damage in NAFLD progression. MATERIAL AND METHODS We examined the expression levels of hepatic p66shc and senescence markers in rats and humans with NAFLD, and we assessed the effect of p66shc knockdown or overexpression on senescence and steatosis in human liver cells. RESULTS In this study, we showed that increased hepatic p66shc expression was consistent with upregulated expression of the following senescence markers in NAFLD rats: heterochromatin protein-1-beta (HP1ß), p16, p21, and p53. Furthermore, senescence and steatosis could be induced in hepatoblastoma cell line (HepG2) cells when cells were stimulated with a low concentration of H2O2, and this effect was significantly alleviated by knockdown of p66shc. However, overexpression of p66shc could promote senescence and steatosis in L02 cells. Finally, increased hepatic p66shc protein levels correlated with enhanced expression of the senescence marker p21 and mirrored the degree of disease severity in NAFLD patients. CONCLUSIONS Our findings indicated that the increase in hepatocyte senescence and steatosis in NAFLD may be caused by the upregulation of p66shc expression, implying that strategies for p66shc-mediated regulation of hepatocyte senescence may provide new therapeutic tools for NAFLD.


Assuntos
Senescência Celular , Fígado Gorduroso/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Senescência Celular/fisiologia , Progressão da Doença , Fígado Gorduroso/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src
20.
Nat Commun ; 11(1): 1545, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210226

RESUMO

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.


Assuntos
Núcleo Celular/metabolismo , Reprogramação Celular/fisiologia , Senescência Celular/fisiologia , RNA Mensageiro/metabolismo , Rejuvenescimento/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Animais , Células Cultivadas , Condrócitos , Metilação de DNA/fisiologia , Células Endoteliais , Epigênese Genética/fisiologia , Feminino , Fibroblastos , Perfilação da Expressão Gênica , Humanos , Microscopia Intravital , Masculino , Camundongos , Pessoa de Meia-Idade , Células Musculares , Cultura Primária de Células , Células-Tronco , Adulto Jovem
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