Fight Aging!

Now that senescent cells are conclusively demonstrated to be highly influential in the progression of degenerative aging, and broad reversal of aspects of aging is regularly demonstrated in mice via the use of various senolytic therapies, there is considerably more interest and funding in the research community for investigations of the fundamental biochemistry of senescent cells. Senescent cells are generated constantly in all tissues, and are primed for self-destruction via apoptosis. The vast majority either self-destruct or are destroyed by the immune system, quite soon after their creation. Those that linger in tissues to cause aging and age-related disease are in some way resistant to apoptosis, and the mechanisms involved in that resistance are of great relevance to the development of future senolytic therapies, treatments capable of selectively destroying senescent cells.

Increasing evidence suggests that senescent cells are primed to apoptosis due to unresolved chronic stresses, and this might favor the efficacy of known senolytic drugs. In oncology, two-step therapeutic strategies aim to first induce cancer cells into senescence via cytotoxic drugs and then to exploit the vulnerability of senescent cancer cells to apoptosis by using senolytics. However, given the deleterious roles of senescent cells, and the negative systemic side effects associated to chemotherapy, these strategies should be best approached with caution. Recently, the use of genetic screens and compound libraries has yielded aurora kinase inhibitors as powerful inducers of senescence in cancer cells (independent of p53). Importantly, senescent cancer cells also acquired vulnerability to the anti-apoptotic Bcl-2 inhibitor ABT-263 regardless of how senescence was induced. Further research is needed to assess the effects of aurora kinase inhibition in normal cells, as opposed to chemotherapy, in combination with senolytic drugs.

Redundant mechanisms aid cell death prevention in both senescent and cancer cells, as observed with anti-apoptotic Bcl-2 family homologs. Nevertheless, as senescent cells may rely more on anti-apoptotic players compared to normal cells that are free of intracellular stressors, targeting anti-apoptotic players may still represent a viable therapeutic strategy. Moreover, different apoptotic mechanisms exist across different cell types and senescent programs, and these differences may be exploited to allow preferential elimination of a specific subtype of senescent cells. In this respect, targeting a defined senescent subtype that is relevant to a specific pathology may be more desirable and with less side effects than simultaneously targeting all types of senescent cells.

It is important to note that senescent cells rely on multiple levels of regulation in order to achieve apoptosis resistance. The concurrent targeting of multiple and indirectly related anti-apoptotic pathways (SCAPs) may therefore result in increased sensitivity of senescent cells without incurring in toxicities for normal proliferating or quiescent cells. A combinatorial approach to senescent cell clearance is exemplified by the concomitant treatment of dasatinib and quercetin. Targeting SCAP networks, as opposed to single targets, may enable lowering the therapeutic dosage of each drug, therefore decreasing off- and on-target side effects associated to single drugs.

Despite an increased resistance to certain apoptotic stimuli, senescent cells may be more susceptible to various forms of metabolic targeting. Senescent cell hypercatabolism can be pharmacologically exploited for the elimination of senescent cells by means of synthetic lethal approaches such as glycolysis inhibition, autophagy inhibition, and mitochondrial targeting. Synthetic lethal metabolic targeting could therefore be used alone or in combination with SCAP inhibitors for increased selectivity.

Finally, additional strategies alternative to apoptosis induction may be employed to alleviate the deleterious phenotypes associated to senescent cells. For instance, the use of SASP modulators may prevent the establishment of a chronic SASP and dampen the negative side-effects of senescent cell persistence without the need for their removal from tissues. Similarly, the use of selective inhibitors for specific SASP components, such as neutralizing antibodies, may allow a tailoring of the SASP by only targeting SASP components thought to play a negative role in the tissue micro-environment while preserving the beneficial ones. Lastly, enhancing the natural clearance of senescent cells by the immune system could be another way of overcoming apoptosis resistance. The use of immune modulators or artificially increasing the number of immune effector cells may effectively restore senescence surveillance, and decrease the senescent cell burden.

Link: https://doi.org/10.1016/j.jmb.2019.05.036