Mitigation of radiation-induced premature frailty and cognitive decline by ablation of senescent cells

Abstract

A fundamental characteristic of radiotherapy is induction of cellular senescence and presentation of a senescence associated secretory phenotype (SASP). Of clinical importance, the initial accumulation of senescent cells halts cancer progression. However, post-radiotherapy, the accumulation of senescent cells (SCs) negatively impacts clinical outcomes. This is because SCs with a pro-inflammatory and pro-apoptotic SASP target surrounding healthy cells. This bystander effect is alleviated when senescent cells are destroyed using senolytic, or genetical drugs. SCs have been associated with a wide range of age-related diseases, premature frailty, reduced health and lifespan. Frailty is a geriatric syndrome that reduces the host’s resilience to stressors and is associated with decline in physical and cognitive function, susceptibility to disease, prolonged hospitalisation, increased vulnerability to adverse drug effects, morbidity and early death. There are currently no treatments for these radiation-induced adverse effects and, as a result, life expectancy and quality of life is reduced for many cancer survivors. No previous studies have focused on investigating gender specific impact of senolytic drugs or genetical intervention after radiation-induced frailty in mice. This study investigates whether SC removal can ameliorate the clinical impact of radiotherapy in mice and whether these effects are gender-specific. Additionally, this study considers the impact of single and multiple dose treatment regimens with senolytic or pharmacogenetic drugs and the ability to alleviate premature radiation-induced frailty, physical and cognitive decline and impact on lifespan in male and female mice after 5-7 month old mice received fractionated whole body irradiation. The results demonstrate that female mice are more sensitive to radiation than male mice, displaying greater levels of premature frailty, cognitive decline and expression of SC markers as well as reduced lifespan as compared to irradiated males. Irradiated male and female mice treated with senolytic drugs or pharmacogenetic interventions were also examined. Late genetic clearance with AP20187 rescued premature frailty, physical and cognitive decline and, in irradiated female mice, extended lifespan without altering prevalence of pathologies. Strikingly, a single dose of dasatinib and quercetin treatment one month post-irradiation prevented premature frailty and physical dysfunction, extended median lifespan and reduced number of pathologies in irradiated female mice. These results indicate intervention- and gender-specific elimination of SCs may rescue cognitive decline and radiation-induced frailty and, thus, promote health and extend lifespan. This is consistent with current views that interventions that reduce SC levels present a potential opportunity to counteract the major side effects associated with radiotherapy and, indeed, a single dose of treatment is sufficient to confer lasting benefits in both genders.