RESUMEN
Senolytics are a class of drugs that selectively remove senescent cells. Dasatinib and quercetin have been discovered, and their combination has shown various anti-ageing effects. The SAMP10 mouse strain is a model of brain ageing. Here, we investigated the effect of combination on frailty characteristics in SAMP10. By comparing SAMP10 with SAMR1 mice as normal ageing controls, we investigated some frailty characteristics. Frailty was assessed at 18-38 weeks of age with a clinical frailty index. Motor and cognitive function of these mice were evaluated using behavioral experiments. SAMP10 mice were divided into vehicle and combination, and these functions and histological changes in the brain hippocampus were investigated. Finally, the in vitro effects of combination on oxidative stress-induced senescent muscle and neuronal cells were investigated. As a result, we found that frailty index was higher in SAMP10 than SAMR1. Motor and cognitive function were worse in SAMP10 than SAMR1. Furthermore, combination therapy improved frailty, motor and cognitive function, and the senescent phenotype of the hippocampus compared with vehicle in SAMP10. In summary, SAMP10 showed more marked frailty characteristics than SAMR1, and dasatinib and quercetin attenuated them in SAMP10. From our results, senolytic therapy might contribute protective effects against frailty.
Asunto(s)
Envejecimiento/efectos de los fármacos , Antioxidantes/administración & dosificación , Senescencia Celular/efectos de los fármacos , Dasatinib/administración & dosificación , Fragilidad/tratamiento farmacológico , Quercetina/administración & dosificación , Senoterapéuticos/administración & dosificación , Envejecimiento/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Línea Celular Tumoral , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Fragilidad/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Resultado del TratamientoRESUMEN
Various stresses latently induce cellular senescence that occasionally deteriorates the functioning of surrounding tissues. Nevertheless, little is known about the appearance and function of senescent cells, caused by the implantation of beta-tricalcium phosphate (ß-TCP)-used widely in dentistry and orthopedics for treating bone diseases. In this study, two varying sizes of ß-TCP granules (<300 µm and 300-500 µm) were implanted, and using histological and immunofluorescent staining, appearances of senescent-like cells in critical-sized bone defects in the calvaria of Sprague Dawley rats were evaluated. Parallelly, bone formation in defects was investigated with or without the oral administration of senolytics (a cocktail of dasatinib and quercetin). A week after the implantation, the number of senescence-associated beta-galactosidase, p21-, p19-, and tartrate-resistant acid phosphatase-positive cells increased and then decreased upon administrating senolytics. This administration of senolytics also attenuated 4-hydroxy-2-nonenal staining, representing reactive oxygen species. Combining senolytic administration with ß-TCP implantation significantly enhanced the bone formation in defects as revealed by micro-computed tomography analysis and hematoxylin-eosin staining. This study demonstrates that ß-TCP granules latently induce senescent-like cells, and senolytic administration may improve the bone-forming ability of ß-TCP by inhibiting senescence-associated mechanisms.
Asunto(s)
Enfermedades Óseas/tratamiento farmacológico , Sustitutos de Huesos/uso terapéutico , Fosfatos de Calcio/uso terapéutico , Senescencia Celular/efectos de los fármacos , Dasatinib/administración & dosificación , Osteogénesis/efectos de los fármacos , Quercetina/administración & dosificación , Senoterapéuticos/administración & dosificación , Implantes Absorbibles , Administración Oral , Animales , Regeneración Ósea/efectos de los fármacos , Sustitutos de Huesos/química , Fosfatos de Calcio/química , Masculino , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Cráneo/diagnóstico por imagen , Cráneo/metabolismo , Cráneo/patología , Resultado del Tratamiento , Microtomografía por Rayos X/métodosRESUMEN
Persistent senescent cells (SCs) are known to underlie aging-related chronic disorders, but it is now recognized that SCs may be at the center of tissue remodeling events, namely during development or organ repair. In this study, we show that two distinct senescence profiles are induced in the context of a spinal cord injury between the regenerative zebrafish and the scarring mouse. Whereas induced SCs in zebrafish are progressively cleared out, they accumulate over time in mice. Depletion of SCs in spinal-cord-injured mice, with different senolytic drugs, improves locomotor, sensory, and bladder functions. This functional recovery is associated with improved myelin sparing, reduced fibrotic scar, and attenuated inflammation, which correlate with a decreased secretion of pro-fibrotic and pro-inflammatory factors. Targeting SCs is a promising therapeutic strategy not only for spinal cord injuries but potentially for other organs that lack regenerative competence.