Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice

Abstract

Cancer survivors suffer from progressive frailty, multimorbidity and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sub-lethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow up was for one year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial ROS production via NOX4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.

Mitochondrial dysfunction in cell senescence and aging

“…However, the concentrations needed for complex I inhibition are considerably higher than those achievable by therapeutic intervention in vivo. It appears that metformin reduces ROS and SASP in senescent cells in vivo mainly by suppressing the activity of cytoplasmic NADPH oxidases, specifically NOX4 (70).…”

Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA Damage

“…The molecular basis for this heterogeneous response is unclear, and future work will be required to better define the underlying mechanisms, which represent a general challenge for predicting the clinically relevant biology of complex tumors during both their development and their response to treatment (Chapman et al, 2014; Kemper et al, 2015; Marusyk et al, 2014; Morrissy et al, 2016; Quintana et al, 2010; Zhao, Hemann, & Lauffenburger, 2014). Nonetheless, our finding of distinct early and late roles for JNK and Erk in senescence progression is of clear clinical utility, given the recent interest in the use of senolytics and SASP inhibitors for the treatment of cancer (Fielder et al, 2022; Short, Fielder, Miwa, & von Zglinicki, 2019; L. Wang, Lankhorst, & Bernards, 2022). For example, administering a JNK or Mek inhibitor days or weeks after chemotherapy could favorably lower IL-6 and IL-8 levels secreted by treatment-induced senescent cells, and thus decrease the IL-6/IL-8-mediated signaling events in the tumor microenvironment that favor cancer progression (Coppé et al, 2008; Goulet et al, 2019; Ruhland et al, 2016; Wu et al, 2019); conversely, administering these inhibitors at the same time as chemotherapy could drive cells towards proliferation rather than senescence due to the early cell fate decision-making role of JNK and Erk, resulting in tumor resistance to cytotoxic agents and hindering the efficacy of senolytic therapies later on.…”

The Hypothetical Utilisation of Entomopoxvirus to Achieve Rejuvenation through Cyclic Expression of Yamanaka Factors

“…The delivery of the AmEPV gene vector procedure would be repeated, most likely once a day for 2 consecutive days out of each week, in line with the cycle previously described in literature and the roughly 20-24h expression period for AmEPV [1,2]. The mouse's age-related phenotype can be characterised using clinically relevant longitudinal multiple parameter frailty index testing, with further tests to quantify cognitive and neuromuscular performance [10,11,12]. This assessed at regular intervals and be interspaced with the treatment protocol.…”

“…Late-adult mice can be purchased directly at 18 months from suppliers such as Charles River, although this is costly and mice may need to be kept for a further 12 or more months to monitor health and lifespan. Alternatively, accelerated ageing can be induced systemically in young mice using insults such as radiotherapy [12] and chemotherapy [13]. Alternatively, damage can be caused in specific organs with targeted treatment [14,15], or with disease-mimicking insults such as carbon tetrachloride induced liver fibrosis [16].…”