Can senolytics influence frailty? Shedding light on preclinical study results

 Cellular senescence is a process in which the cell cycle irreversibly stops due to various reasons, such as oxidative stress, oncogene expression, mitochondrial dysfunction, and others. Senescent cells have been associated with aging and have been shown to accumulate in tissues, causing age-related diseases, like neurocognitive disorders and physical conditions.

Frailty is a multifaceted concept that includes physical, cognitive, and social domains. It is defined as increased sensitivity to stress factors and can be used as an indicator of health in the elderly population. Frailty is usually measured by a scale known as the frailty index (FI), a quantitative measure of health-related deficit that humans display. Higher scores correspond to poorer outcomes, like physical disability, cognitive disorders, and mortality.

Evidence from literature highlights that senolytic medications like dasatinib and quercetin (D+Q) combination helps in clearing senescent cells, which translates into positive outcomes in aged organs. Dasatinib is an anti-cancer medication, while quercetin is a flavonoid with antioxidant, anti-inflammatory, and supposed anti-cancer activities. These agents temporarily disable the anti-apoptotic pathways that protect senescent cells, inducing cell death. Ota and Kodoma initiated an experiment on a senescence-accelerated mouse prone 10 (SAMP10) mouse model to understand better the value of combining both agents to tackle frailty. This mouse model was chosen due to its shorter lifespan and age-related brain atrophy under normal conditions.

Their investigation revealed that mice given D+Q had lower FI scores at 38 weeks of age than their counterparts who received the vehicle control. Additionally, the grip strength was stronger, the distance traveled in the open field was higher, and the spontaneous alteration rate (a test that shows the tendency to explore, higher results are better) was more pronounced in the group receiving D+Q compared to control. These outcomes indicate that treatment with D+Q enhances physical, cognitive, and FI scores in the SAMP10 mouse model. Histological analysis revealed that the proportion of senescence-associated beta-galactosidase positive cells was lower in the D+Q group compared to its vehicle counterpart. Additionally, p16Ink4a expression (a protein highly expressed in senescent cells) was lower in the D+Q group. The authors concluded that dasatinib and quercetin might possess protective properties against frailty.

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