Targeting normal and cancer senescent cells as a strategy of senotherapy

Abstract

Senotherapy is an antiageing strategy. It refers to selective killing of senescent cells by senolytic agents, strengthening the activity of immune cells that eliminate senescent cells or alleviating the secretory phenotype (SASP) of senescent cells. As senescent cells accumulate with age and are considered to be at the root of age-related disorders, senotherapy seems to be very promising in improving healthspan. Genetic approaches, which allowed to selectively induce death of senescent cells in transgenic mice, provided proof-of-concept evidence that elimination of senescent cells can be a therapeutic approach for treating many age-related diseases. Translating these results into humans is based on searching for synthetic and natural compounds, which are able to exert such beneficial effects. The major challenge in the field is to show efficacy, safety and tolerability of senotherapy in humans. The question is how these therapeutics can influence senescence of non-dividing post-mitotic cells. Another issue concerns senescence of cancer cells induced during therapy as there is a risk of resumption of senescent cell division that could terminate in cancer renewal. Thus, development of an effective senotherapeutic strategy is also an urgent issue in cancer treatment. Different aspects, both beneficial and potentially detrimental, will be discussed in this review.

Introduction

In the modern world the population of very old people is increasing and we have realized that successful intervention in the lifespan is possible. A desirable outcome of such intervention would be ageing free of age-related diseases, such as metabolic and cardiovascular disease, neurodegeneration, cancer and many others. Geroscience aims to understand the relationship between ageing, chronic age-related diseases (ARDs) and geriatric syndromes (GSs) and assumes that ageing and ARDs/GSs share a common set of basic biological mechanisms (Franceschi et al., 2018). It has been suggested that these mechanisms include cell senescence. Indeed, recently it has been proposed that elimination of senescent cells in genetically modified mice can rejuvenate the organism (Childs et al., 2015). The just coined term “senotherapy” refers to the process of body rejuvenation by pharmacological treatment with senolytic drugs selectively eradicating senescent cells (Sturmlechner et al., 2017; Zhu et al., 2015).

Section snippets

Cellular senescence

The term “cellular senescence”, introduced almost 60 years ago, referred to the limited capacity of cell population to divide in culture (Hayflick and Moorhead, 1961), which later on has been attributed to telomere shortening (Harley et al., 1990). Since then, it has been observed that not only telomere shortening, but also oncogenes and some sorts of stress were able to stop cell divisions and induce cell senescence. These phenomena were termed OIS (oncogene-induced senescence) (Kuilman et

Transgenic mouse models used in senotherapy

In recent years, several transgenic mouse models have been developed that make possible the visualization, assessment and eradication of senescent cells in vivo. In these models the promoter of p16INK4A gene was used to drive the expression of genes encoding proteins, which induce death of senescent cells upon administration of small molecules (transgene activator). Beside death-inducing product of the transgene also expression of fluorescent proteins can be regulated by p16INK4A promoter in

Senolytics in vitro and in vivo

Senescent cells are resistant to apoptosis. On the other hand some SASP factors are pro-apoptotic. Moreover, pro-apoptotic pathways were shown to be up-regulated in senescent cells (Zhu et al., 2015), To solve this paradox the hypothesis was tested that senescent cells depend on pro-survival pathways, which inhibit apoptosis, in order to defend themselves against their own pro-apoptotic SASP. Using bioinformatics approaches based on the RNA and protein expression profiles of senescent cells,

Senotherapy in alleviation of age-related diseases

The results obtained in mouse transgenic models and upon treatment with senolytics give hope that many age-related diseases in humans can be cured. The potential outcome of senotherapy is outlined on Fig. 1 and detailed description of the results obtained in animal experiments, both genetic and pharmacological, are presented in Table 1. Their number is growing quite rapidly. Some of these results are discussed below.

Senotherapeutic approach to treat cancer and to alleviate side-effects of anticancer therapy

Increasing age is one of the strongest risk factors for cancer development. On the other hand, cell senescence is an important barrier to cancer development as it protects against spreading cells with harmful mutations.

At the end of the previous century Serrano and colleagues showed that in vitrooverexpression of the Ras oncogene in normal cells leads to senescence (OIS, oncogene induced senescence), while transfection of immortalized cells with the same oncogene facilitates cell transformation

Autophagy in senotherapy

Autophagy is a catabolic process, in which proteins, other macromolecules, and organelles are degraded and recycled, thus providing metabolites to maintain energy supply in the cell. It also prevents “waste” accumulation in a tissue. Three main types of autophagic processes have been described to date: macroautophagy, microautophagy, and chaperone-mediated autophagy (Gomez-Sintes et al., 2016). As macroautophagy has been the best recognized type of autophagy, the term autophagy usually refers

Questions and remarks

Pharmacological and nutraceutical elimination of senescent cells from the body seems to be very promising in postponing ageing and age-related diseases. However, results obtained so far originate mainly from animal and tissue culture studies, even though the first human pilot study has been successfully completed (Justice et al., 2019). Namely, fourteen patients with stable mild severe idiopathic pulmonary fibrosis (IPF) were treated with 9 oral doses of D + Q over 3 weeks. Physical function

Funding

This study was supported by National Science Centre grants: UMO-2016/21/B/NZ3/00370 (to ABZ), UMO 2014/15/B/NZ3/01150 (to GM) and UMO-2015/17/B/NZ3/03531(to ES)

Declaration of Competing Interest

The authors confirm no conflict of interest

Acknowledgements

The authors thanks Karolina Mosieniak for preparing the picture

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