Researchers here discuss the path to the clinic for the first batch of senolytic drugs, compounds that nudge senescent cells into self-destruction. Senescent cells accumulate with age, and secrete signals that disrupt tissue function and produce chronic inflammation. Their growing presence is one of the root causes of aging, and their effects on surrounding cells contribute to many age-related diseases. Researchers have demonstrated extended life and reversal of measures of aging in rodents through the targeted removal of senescent cells; the sooner this class of treatment makes it to the clinic the better.
Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions.
The first senolytic drugs, compounds that selectively eliminate senescent cells by causing apoptosis, were discovered using a hypothesis-driven approach. This approach was based on the observation that senescent cells are resistant to apoptosis, suggesting senescent cells have up-regulated pro-survival pathways that protect them from their own pro-apoptotic SASP. Up-regulation of these Senescent Cell Anti-apoptotic Pathways (SCAPs) might be related to senescence-associated mitochondrial dysfunction (SAMD). An essential part of SAMD appears to be a decrease in mitochondrial membrane potential related to mitochondrial membrane permeabilization. SAMD could explain why senescent cells depend on upregulated pro-survival pathways and why they are more sensitive to drugs that interfere with these SCAP pathways than non-senescent cells.
The first SCAPs were identified through expression profiling of senescent vs. non-senescent human cells and confirmed in RNA interference studies. Drugs that target these SCAPs were tested for senolytic activity. The tyrosine kinase inhibitor, dasatinib (D) and the flavonoid, quercetin (Q), were shown to induce apoptosis in senescent cells. Ten months later, two groups simultaneously reported that navitoclax (N; ABT-263), which targets components of the Bcl 2 pathway, is senolytic. Recently, the specific BCL-XL inhibitors A1331852 and A1155463, were found to be senolytic. Fisetin, related to Q, was discovered to be senolytic. Fisetin is an especially promising candidate because of its favorable side-effect profile. Piperlongumine, which is also related to Q, was noted to be senolytic in vitro in some senescent cell types. None of the individual agents reported so far selectively induces apoptosis of all senescent cell types. N, A1155463, and possibly A1331852 appear to be more toxic than D, Q, piperlongumine, or fisetin. A number of additional senolytic drugs are currently being developed. Some of the most promising senolytic agents are already being moved through preclinical studies towards clinical application.
To conduct clinical trials with senolytics, it will be important to have ways to track changes in senescent cell burden. It might be feasible to do so using biopsies, blood assays, other body fluids, and imaging, but more research on developing and optimizing assays needs to be done and reported. Complicating matters, the definition of cellular senescence is somewhat vague, particularly since several potentially pro-inflammatory cell types, such as macrophages or osteoclasts as well as pre-cancerous or cancer cells share many characteristics of senescent cells and could arguably be the same as what are currently regarded as being senescent cells. Few tissue assays are very sensitive or specific for senescent cells. Work needs to be done to establish, optimize, and validate these assays. Novel assays, such as of the microvesicles shed into blood or urine by senescent cells, need to be developed and optimized for use in clinical trials of senolytic drugs.
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. 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.
There is a possibility that senolytics and SASP inhibitors could be transformative, substantially benefiting the large numbers on patients with chronic diseases and enhancing healthspan. That said, as this is a very new treatment paradigm, there are many obstacles to overcome. Treatments that appear to be highly promising in mice frequently fail once clinical trials start, with lack of effectiveness in humans compared to mice related to the unique aspects of human biology, unforeseen side-effects, and a host of other issues. At least one reassuring advantage of targeting cellular senescence is the conservation of fundamental aging mechanisms such as senescence across mammalian species. In diseases like Alzheimer's dementia, atherosclerosis, or non-injury-related osteoarthritis, which do not occur naturally in mice, translation from genetically- or surgically-induced mouse models of these conditions to humans is more likely to fail than conditions that are more evolutionarily conserved, such as aging. Furthermore, unlike the situation for developing drugs to eliminate infectious agents or cancer cells, not every senescent cell needs to be eliminated to have beneficial effects. Unlike microbes or cancer cells, senescent cells do not divide, decreasing risk of developing drug resistance and, possibly, speed of recurrence. With respect to risk of side-effects, single or intermittent doses of senolytics appear to alleviate at least some age- or senescence-related conditions in mice. This suggests that intermittent treatment may eventually be feasible in humans.
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