Senotherapeutics for Healthy Ageing of Its Broad Efficacy

CORRESPONDENCE LINK TO ORIGINAL ARTICLE careful consideration when defining a senolytic or senomorphic drug and the likelihood Senotherapeutics for healthy ageing of its broad efficacy. Once evidence is found for senolytic activ- Laura J. Niedernhofer and Paul D. Robbins ity of a compound in vitro, it is even more difficult to document potential senolytic activity in vivo (TABLE 1). Demonstrating that The recent manuscript by Childs et al. in The natural compounds fisetin3, a quercetin- a compound reduces the number of SA-ß-gal+ Nature Reviews Drug Discovery1 thoroughly related flavonoid, and piperlongumine also cells or the level of p16ink4a expression, such as reviewed the important role senescent cells exhibit evidence of senolytic or senomorphic through the use of p16ink4a–luciferase reporter play in driving ageing and age-related dis- activity in certain cell types in vitro. Clinically mice, does not definitively demonstrate kill- eases. The review also highlighted the clinical used compounds targeting the co-chaperone ing, let alone selective killing, of senescent importance of developing senotherapeutic heat shock protein 90 (HSP90) were also iden- cells. Also, since senolytics are cell type-spe- approaches to selectively kill senescent cells tified as a novel class of potential senolytics, cific, the lack of an effect on a specific tissue (senolytics) or to suppress the senescence- able to induce apoptosis of senescent murine doesn’t preclude senolytic activity in other associated secretory phenotype (SASP) that and human cells in vitro and improve health- tissues. Even more rigorous approaches, such drives sterile inflammation associated with span in vivo4. Finally, the FDA-approved as the injection of labelled senescent cells fol- ageing (senomorphics), in order to extend histone deacetylase inhibitor panobinostat lowed by drug treatment, only serve to docu- healthspan and potentially lifespan. Clearly, induces apoptosis of senescent tumour cells ment that the putative senolytic is functioning senotherapeutic approaches can revolution- in vitro. Clearly, there are multiple SCAP tar- in vivo similar to in vitro, that is, by killing ize how age-related diseases and ultimately gets and thus it is highly likely that additional that specific type of transplanted senescent how ageing itself can be treated. Given how classes of potential senolytics will be identi- cell. Eventually, improved methods for colo- quickly the field of senotherapeutics is mov- fied through bioinformatic analyses and drug- calization of apoptosis and senescence in vivo ing towards clinical trials, we would like to screening approaches. at the single cell level, such as through the use expand upon several important issues regard- Several classes of senomorphics — drugs of cytometry by time-of-flight (CyTOF) or ing the current and future development of that suppress markers of senescence or their dual fluorescent reporters, will be needed to senotherapeutics. This is particularly impor- secretory phenotype without inducing apopto- define a compound as senolytic. tant since the nascent field of senotherapeu- sis — have also been identified. Senomorphics One current tactic to provide evidence tics is faced with the challenge of establishing include inhibitors of IkB kinase (IKK) and that a compound has senolytic activity is the important standards and criteria for docu- nuclear factor (NF)-kB5, free radical scaven- ‘hit-and-run’ approach, for example, the one- menting a compound’s or a combination of gers and Janus kinase (JAK) pathway inhibi- time treatment of mice with dasatinib and compounds’ function as advertised, that is, as tors6. Even rapamycin acts as a senomorphic quercetin following hind-leg irradiation3. senotherapeutics. by reducing the SASP. Some compounds, for Here, a single administration of dasatinib It is established that senescent cells play a example fisetin, have senomorphic effects on plus quercetin yielded a therapeutic benefit causative role in ageing and age-related dis- some cell types while having senolytic activity that endured for months in terms of tread- ease. Therefore, the development of drugs that on others, at least in vitro3. mill performance, consistent with a senolytic specifically kill senescent cells is envisioned to It is important to note that definitively mechanism in which disease-causing cells are have significant therapeutic effects on slow- demonstrating that a drug is senolytic or killed. In general, if a short course of treating ageing phenotypes, treating age-related senomorphic is challenging and should be ment yields a sustained reduction in senes- comorbidities and improving resiliency. approached critically. Simply measuring cence, it is likely acting in a senolytic manner. However, not all senescent cells are the same, a reduction in senescence markers (such In contrast, if chronic treatment is needed to expressing different senescence markers, as the expression of p16INK4A or p21CIP1 or suppress senescence markers or prevent sec- secreting different SASP factors and, more SASP factors) or in senescence-associated ondary senescence, this is more consistent importantly, using different senescent cell β-galactosidase (SA-β-gal) activity is inad- with senomorphic activity. However, more anti-apoptotic pathways (SCAPs) to resist equate to distinguish between the two mech- refined approaches are needed to rapidly apoptosis. The elimination of senescent cells anisms of action. Careful determination of demonstrate senolytic activity in vivo. Likely from multiple tissues or even a single tissue whether there is selective loss of senescent combinations of approaches may be neces- will probably require the combination of mul- cells is required. Notably, the assay selected to sary. For example, if a drug kills senescent tiple senotherapeutic drugs2. test potential therapeutics influences the out- endothelial cells, it could yield a health divi- To date, seven classes of compound with come. For example, the cell type selected and dend, but it will be very difficult to document some evidence of senolytic activity have the method used to induce senescence influ- a reduction in the expression of senescence been reported (see Supplementary Table 1), ences which SCAPs are expressed and there- markers specifically in the endothelium with- including the combination of dasatinib and fore whether a particular class of drugs (for out sophisticated reporter systems. quercetin, as well as BCL2 family inhibitors, example, BCL2 inhibitors) will be effective in Another current approach to provide identified using a bioinformatics approach killing cells. Also, the end points measured evidence that a compound potentially has for SCAPs2. In addition, a forkhead box pro- will influence interpretation (for example, senolytic activity in vivo is to compare the tein O4 (FOXO4)-interacting peptide, which senescence markers, SASP, number of viable therapeutic efficacy of the drug to outcomes blocks the association of FOXO4 with p53, cells and/or apoptosis markers) as well as what yielded by genetic ablation of senescent cells induces apoptosis of senescent human cells in control cells are used (for example, proliferat- in transgenic INK-ATTAC or p16-3MR vitro and reduces the expression of senescence ing or quiescent). Thus, the assays used and mice7,8. For example, in the bleomycin mouse markers while extending healthspan in vivo. end points measured should be taken into model of idiopathic pulmonary fibrosis, the NATURE REVIEWS | DRUG DISCOVERY www.nature.com/nrd ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. CORRESPONDENCE Table 1 | Approaches for demonstrating the mechanism of action of senotherapeutics. System for testing Class of drug New methodologies Senolytic Senomorphic p16-reporter mice and/or Short-term administration of a Chronic treatment with a • Additional transgenic reporters for measuring senescence in senolytic must yield a sustained senomorphic is required for markers of senescence such as p21 multiple tissues using multiple reduction in senescence signala a sustained suppression in • Dual reporters for apoptosis and end points (expression of p16, senescence signal senescence p21 and SASP, and/or decreased • Analysis of activity in SA-ß-gal activity) immune-deficient mice Compare pharmacological A short-term or intermittent Chronic treatment with a • Additional genetic ablation models ablation of senescent course of a senolytic yields the senomorphic is required to get the such as p21-ATTAC cells to genetic ablation same outcome as using a drug same outcome as genetic ablation • Analysis of activity in (p16-INK-ATTAC or p16-3MR to activate a transgene to ablate of senescent cells immune-deficient mice mice)b senescent cells Human tissue explants Drug treatment yields a Drug treatment yields a suppression CyTOF, in situ hybridization and harbouring senescent cells reduction in senescence markers in senescence markers (expression related approaches to colocalize (expression of p16, p21 and of p16, p21 and SASP, and/or downregulation of senescence SASP, and/or decreased SA-ß-gal decreased SA-ß-gal activity) with no with upregulation of apoptosis activity) and an increase in evidence of cell death markers as well as cell identity apoptosis markers markers Transplantation of labelled Short-term or intermittent Chronic administration of a • Transplantation of cells dually senescent cells into a host administration of a senolytic must senomorphic will suppress labelled with

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