RESUMO
BACKGROUND: Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. METHODS: Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. RESULTS: Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. CONCLUSIONS: Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.
Assuntos
Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Isquemia/fisiopatologia , Rim/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Quinases Ativadas por p21/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Doença Crônica , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p19/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Dasatinibe/farmacologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/fisiologia , Transição Epitelial-Mesenquimal , Expressão Gênica , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Humanos , Isquemia/etiologia , Rim/irrigação sanguínea , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteopontina/genética , Inibidores de Proteínas Quinases/farmacologia , Obstrução da Artéria Renal/complicações , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Análise de Sequência de RNA , Análise de Célula Única , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Regulação para Cima , Quinases Ativadas por p21/genéticaRESUMO
Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.
Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Envelhecimento/metabolismo , Glicoproteínas de Membrana/metabolismo , NAD/biossíntese , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Envelhecimento/imunologia , Animais , Transplante de Medula Óssea , Senescência Celular , Células HEK293 , Humanos , Inflamação/imunologia , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mononucleotídeo de Nicotinamida/metabolismo , FenótipoRESUMO
Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD.
Assuntos
Envelhecimento , Doenças Cardiovasculares , Sistema Cardiovascular , Senescência Celular , Idoso , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , HumanosRESUMO
Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.
Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Proliferação de Células/fisiologia , Senescência Celular/fisiologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Pontos de Checagem do Ciclo Celular/fisiologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis.
Assuntos
Aterosclerose/patologia , Senescência Celular , Células Espumosas/patologia , Animais , Aterosclerose/genética , Quimiocinas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Citocinas/metabolismo , Camundongos , Camundongos Transgênicos , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Receptores de LDL/genética , Túnica Íntima/patologiaRESUMO
Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Saúde , Longevidade/fisiologia , Adipócitos/citologia , Adipócitos/patologia , Adipócitos/fisiologia , Animais , Apoptose , Separação Celular , Transformação Celular Neoplásica/patologia , Células Epiteliais/citologia , Células Epiteliais/patologia , Feminino , Rim/citologia , Rim/patologia , Rim/fisiologia , Rim/fisiopatologia , Lipodistrofia/patologia , Masculino , Camundongos , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Especificidade de Órgãos , Células-Tronco/citologia , Células-Tronco/patologia , Fatores de TempoRESUMO
Pain in cancer therapy is a common condition and there is a need for new options in therapeutic management. While phytochemicals have been proposed as one pain management solution, knowledge of their utility is limited. The objective of this study was to perform a systematic review of the biomedical literature for the use of phytochemicals for management of cancer therapy pain in human subjects. Of an initial database search of 1,603 abstracts, 32 full-text articles were eligible for further assessment. Only 7 of these articles met all inclusion criteria for this systematic review. The average relative risk of phytochemical versus control was 1.03 [95% CI 0.59 to 2.06]. In other words (although not statistically significant), patients treated with phytochemicals were slightly more likely than patients treated with control to obtain successful management of pain in cancer therapy. We identified a lack of quality research literature on this subject and thus were unable to demonstrate a clear therapeutic benefit for either general or specific use of phytochemicals in the management of cancer pain. This lack of data is especially apparent for psychotropic phytochemicals, such as the Cannabis plant (marijuana). Additional implications of our findings are also explored.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Manejo da Dor/estatística & dados numéricos , Dor/epidemiologia , Dor/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Causalidade , Comorbidade , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Neoplasias/diagnóstico , Dor/diagnóstico , Manejo da Dor/métodos , Prevalência , Resultado do TratamentoRESUMO
In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence-inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence-associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor-promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non-neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment.
Assuntos
Envelhecimento/genética , Apoptose , Carcinogênese/genética , Senescência Celular , Envelhecimento/metabolismo , Animais , Carcinogênese/metabolismo , Humanos , Transdução de Sinais , Estresse FisiológicoRESUMO
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.