br Translating Senolytics into Clinical Treatments
Translating Senolytics into Clinical Treatments Healthspan, lifespan, or other very long-term potential endpoints for clinical trials of interventions that target basic aging processes, including SASP-inhibitors or senolytics, would be difficult or next to impossible to study for reasons that are obvious, as would endpoints occurring in old age as a consequence of beginning to administer a drug in adulthood or middle-age (Burd et al., 2016; Justice et al., 2016; Kirkland, 2013; Kirkland, 2016; Kirkland and Tchkonia, 2015; Kirkland and Peterson, 2009; Newman et al., 2016; Tchkonia et al., 2013; Zhu et al., 2014). Initial trials of senolytics or other agents that target fundamental aging processes will need to test effects on endpoints that can be measured weeks to a couple of years after initiating treatment. Furthermore, because the risk:benefit ratio must favor benefits for the ethical conduct of clinical trials, new interventions would have to be tested in situations in which side-effects would be considered to be acceptable. In diseases for which no effective treatment is available, some side effects may be acceptable in individuals who are already symptomatic or who are almost certain to become symptomatic within a short time. If any consequential side effects are anticipated, the treatment would also need to address a problem that would cause serious harm if left untreated. Based on these premises, a group of possible clinical trials scenarios were devised for testing senolytics and other agents that target basic aging processes by the Geroscience Network, a consortium of aging centers funded by the NIH to map procedures for translating these interventions from bench to the bedside (Burd et al., 2016; Justice et al., 2016; Kirkland, 2016; Newman et al., 2016). These clinical trials scenarios include the following:
Outstanding Questions What are the side-effects of senolytics? Apart from potentially delaying wound healing, as suggested from studies of genetic clearance of senescent buy leucine enkephalin from mice (Demaria et al., 2014), little information is available about possible side-effects of senolytics besides known side-effects of repurposed senolytic compounds when used in other contexts. Potential side-effects of senolytics as a class need to be defined. What are the best senolytic agents or combinations for treating particular conditions? Do senolytics have additive effectiveness when combined with other agents that affect fundamental aging mechanisms, such as 17α-estradiol (Stout et al., 2016), or lifestyle modifications, such as exercise (Schafer et al., 2016)? Can cells harboring latent viruses, such as HIV, be eliminated by senolytics? Host reservoir cells containing integrated viral DNA and consequently with transcription of viral DNA into RNA\'s, have activation of processes, including increased interferon, which should cause apoptosis of the host cell. However, like senescent cells, these host cells resist apoptosis, suggesting that drugs such as D+Q, BCL-2 inhibitors including N, A1331852, or A1155463, and related drugs that target SCAPs could kill these cells, much as they kill pro-inflammatory senescent cells by temporarily disabling pro-survival pathways. This could be a way to eradicate HIV, which current treatments only suppresses. Are beneficial effects of senolytics due to their causing apoptosis not only of classically senescent cells, but also cells harboring HIV, CMV, or other latent viruses, precancerous cells, cancer stem cells, or early stage cancers? Consistent with these possibilities, the senolytic drugs published so far have shown anti-cancer effects in vitro or in vivo. As many interventions that target fundamental aging processes vary in their effectiveness between sexes in mice (Austad and Bartke, 2015), effects of sex on responses to senolytic agents and SASP inhibitors needs to be determined. Does targeting FOXO4/p53 cause apoptosis of all types of senescent cells or only the subset of senescent cells that depend on the Bcl-2 family- and p53-related SCAPs originally described in (Zhu et al., 2015b)? Is FOXO4 increased in senescent cell types beyond the 3 culture-habituated fibroblast-like cell strains tested so far (Baar et al., 2017), such as senescent primary human preadipocytes or other truly primary cells that do not depend principally on the BCL-2 family SCAP to resist apoptosis (Zhu et al., 2015a; Zhu et al., 2015b)?