Senolytics and senostatics as adjuvant tumour therapy

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.

Keywords: Cancer; Glioma; Senolytics; Senostatics; Survivor; Therapy.

Fig. 1

The bystander effect shifts the balance between generation and surveillance of senescent cells. A) In young animals, immune-mediated turnover compensates for cell-autonomous (stress-induced) generation of senescent cells as well as for a minor bystander effect. B) Temporal induction of senescence (e.g. by tumour therapy) or decreasing efficiency of immunosurveillance disturb the balance causing growth of the senescent cell fraction. The bystander feedback will aggravate the imbalance, even if immunosurveillance would not further decline with age. C) By killing a significant fraction of senescent cells, senolytics also reduce bystander signals and regenerate a steady state with low senescent cell numbers. D) Senostatics suppress the bystander effect and enable the immune system to reduce senescent cell frequencies.

Fig. 2

Senolytics complement adjuvant tumour therapy. A) Following irradiation and/or chemotherapy, senescent tumour and non-tumour (niche) cells are generated that secrete SASP factors which promote tumour growth and perpetuate senescence. B) Post-treatment with senolytics removes these sources of tumour regrowth and relapse.

Fig. 3

A testable hypothesis for the pathogenesis of therapy-induced frailty and multimorbidity. We propose that primary, therapy-induced senescence and its perpetuation by bystander effects is the root cause for accelerated ageing and thus for premature frailty, multi-morbidity and enhanced mortality in long-term cancer survivors. If correct, anti-senescence interventions (using senolytics or senostatics) should at least prevent, if not cure, this syndrome.