Senolytics and senostatics as adjuvant tumour therapy.

Susan Short,Edward Fielder,Thomas Von Zglinicki,Satomi Miwa

doi:10.1016/j.ebiom.2019.01.056

Abstract

Cell senescence is a driver of ageing, frailty, age-associated disease and functional decline. In oncology, tumour cell senescence may contribute to the effect of adjuvant therapies, as it blocks tumour growth. However, this is frequently incomplete, and tumour cells that recover from senescence may gain a more stem-like state with increased proliferative potential. This might be exaggerated by the induction of senescence in the surrounding niche cells. Finally, senescence will spread through bystander effects, possibly overwhelming the capacity of the immune system to ablate senescent cells. This induces a persistent system-wide senescent cell accumulation, which we hypothesize is the cause for the premature frailty, multi-morbidity and increased mortality in cancer survivors.Senolytics, drugs that selectively kill senescent cells, have been developed recently and have been proposed as second-line adjuvant tumour therapy. Similarly, by blocking accelerated senescence following therapy, senolytics might prevent and potentially even revert premature frailty in cancer survivors.Adjuvant senostatic interventions, which suppress senescence-associated bystander signalling, might also have therapeutic potential. This becomes pertinent because treatments that are senostatic in vitro (e.g. dietary restriction mimetics) persistently reduce numbers of senescent cells in vivo, i.e. act as net senolytics in immunocompetent hosts.

Highlights

Cell senescence is a driver of ageing, frailty, age-associated disease and functional decline
This induces a persistent system-wide senescent cell accumulation, which we hypothesize is the cause for the premature frailty, multi-morbidity and increased mortality in cancer survivors
Based on evidence, discussed below, that senescence may be relevant in promoting frailty after brain radiotherapy and data supporting senescence in glioma cells after both radiation and chemotherapy, we suggest that brain tumours represent an excellent clinical model in which to investigate senescence as a therapeutic target

Summary

Cell senescence

Cell senescence has originally been identified as the irreversible and reproducible loss of proliferative capacity of human somatic cells in culture [16]. Organism-wide, resulting in persistent physical dysfunction [46] These consequences of senescent cell transplantation became evident at a time point when practically all transplanted senescent cells had already been cleared from the recipient tissues [39,46], indicating that senescence-induced bystander senescence is a significant cause for accumulation of senescent cells in vivo. This was confirmed comparing accumulation rates of native senescent hepatocytes in ‘normal’ and multiple immunocompromised mice during ageing and under dietary restriction [39]. Ablation of senescent cells should not just reduce senescent cell numbers but in addition reduce rates of senescent cell accumulation to a youthful state (Fig. 1)

Senolytics versus senostatics

Anti-senescence as adjuvant tumour therapy

Findings

Outstanding questions