A new paper published yesterday is perhaps the fourth in a recent series of similar commentaries and reviews from a variety of research groups involved in the study of senescent cells. Each declares in its own way that senolytic therapies, approaches capable of selectively destroying senescent cells in old tissues, are a development of great importance in aging research. Senolytics have the near-future potential to produce sweeping change and improvement in the treatment of age-related conditions. The degree to which removal of senescent cells is better than the vast majority of present day medicine is hard to overstate. Accumulation of senescent cells is one of the root causes of aging, and removing these cells is a form of rejuvenation, capable of partially turning back the progression of most of the common age-related medical conditions.
Senescent cells well illustrate the SENS view of aging as an accumulation of unrepaired damage, generated as a side-effect of the normal operation of metabolism. Senescent cells are generated in large numbers in our tissues, day in and day out, but near all are destroyed, either by their own programmed cell death mechanisms or by the immune system. A tiny, tiny fraction of these cells evade this fate, however, and linger. Senescent cells generate a range of signals - the senescence-associated secretory phenotype, SASP - that corrode nearby tissue structures, change surrounding cell behavior, and generate an inflammatory response in the immune system. This is all beneficial in the short term and in small numbers, and senescent cells play a temporary role in steering embryonic development, or in regeneration of wounds, or in suppression of potentially cancerous cells. The problem arises in the long term, as growing numbers of lingering senescent cells continually run their program of inflammation and corrosion.
In recent years, studies have definitively linked senescent cells to age-related fibrosis, a major cause of organ dysfunction, to the progression of inflammatory conditions such as osteoarthritis and atherosclerosis, to the failing function of lungs, and to a range of other measures of age-related decline. Removing senescent cells from old mice has been shown to partially reverse the progression of many of these conditions. Since the mechanisms of cellular senescence are very similar in mice and humans, the hope is that the benefits of senolytics in old people will be significant. Since human studies have commenced in a variety of venues, we will find out in the next few years just how transformative this new approach to the treatment of aging might be.
Researchers are moving closer to realizing the clinical potential of drugs that have previously been shown to support healthy aging in animals. In a review article aging experts say that, if proven to be effective and safe in humans, these drugs could be "transformative" by preventing or delaying chronic conditions as a group instead of one at a time. The drugs being tested are called senolytic agents, because they target senescent cells. These are cells that have stopped dividing and secrete toxic chemicals that damage adjacent cells. Accumulation of senescent cells, which increases with age, is associated with chronic conditions, including diabetes, cardiovascular disease, most cancers, dementia, arthritis, osteoporosis, and frailty.
In a recent study researchers confirmed that the first senolytic drugs to be discovered effectively clear senescent cells while leaving normal cells unaffected. The study also describes a new screening platform for finding additional senolytic drugs that will more optimally target senescent cells. The platform, together with additional human cell assays, identified and confirmed a new category of senolytic drugs, which are called HSP90 inhibitors. The platform will help researchers quickly identify additional drugs that target aging processes, which he says will be useful as they move closer to clinical intervention. "We've moved rapidly in the last few years, and it's increasingly looking like senolytic drugs, including the recently discovered HSP90 inhibitors, are having an impact on a huge range of diseases. We will need to continue to test whether there are more optimal drugs or drug combinations to broaden the range of senescent cell types targeted."
As senolytic drugs and drug combinations are discovered, researchers then will need to test them in clinical trials. The review article, "The Clinical Potential of Senolytic Drugs," acknowledges the unique challenges of these trials in the field of aging, including the difficulty of testing long-term end points, such as life span and health span - the healthy, productive years of life. Outcomes such as effects on median or maximum lifespan cannot be tested feasibly in humans. That's why researchers are using new clinical trial paradigms, which include testing the effects of senolytic drugs on co-morbidity, accelerated aging like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. The authors also call out a need for additional geriatricians with research training to lead future clinical trials.
Chronological aging is the leading predictor of the major chronic diseases that account for the bulk of morbidity, mortality, and health costs worldwide. Furthermore, age-related chronic diseases, geriatric syndromes, and disabilities tend to cluster within individuals, leading to multimorbidity. These observations support the concept that fundamental aging processes not only cause aging phenotypes, but also predispose to chronic diseases and the geriatric syndromes. Thus, it has been predicted that therapeutically targeting these processes can delay, prevent, or alleviate age-related chronic diseases and disabilities as a group, instead of one at a time-the "geroscience hypothesis."
The biological processes that underlie aging phenotypes and are active at the nidus of most chronic diseases include chronic, low-grade, "sterile" (absence of known pathogens) inflammation; macromolecular and organelle dysfunction (e.g., changes in DNA, such as telomere erosion, unrepaired damage, mutations, polyploidy, proteins - e.g., aggregation, misfolding, autophagy - carbohydrates, lipids, or mitochondria); stem and progenitor cell dysfunction; and accumulation of senescent cells. These four processes are linked; that is, in general, interventions that target one process also attenuate the others. For example, DNA damage causes increased senescent cell burden and mitochondrial and stem or progenitor cell dysfunction. Conversely, reducing senescent cell burden can lead to less inflammation, less macromolecular dysregulation, and enhanced function of stem and progenitor cells.
To remove senescent cells pharmacologically from wild type animals, "senolytic" agents, including small molecules, peptides, and antibodies, are being developed. Since the article describing the first senolytic agents was published in 2015, progress in identifying additional senolytic agents and their effects has been rapid. In that first article, a hypothesis-driven senolytic agent discovery paradigm was implemented. Senescent cells are resistant to apoptosis, despite the SASP factors they release, which should trigger apoptosis. Indeed, pro-apoptotic pathways are up-regulated in senescent cells, yet these cells resist apoptosis. The hypothesis was therefore tested that senescent cells depend on pro-survival pathways to defend against their own pro-apoptotic signaling.
Using bioinformatic approaches based on the ribonucleic acid (RNA) and protein expression profiles of senescent cells, five senescent-cell anti-apoptotic pathways (SCAPs) were identified. That SCAPs are required for senescent cell viability was verified in RNA interference studies, in which levels of key proteins in these pathways were reduced. Through this approach, survival proteins were identified as the Achilles' heel of senescent cells. Knocking down expression of these proteins causes death of senescent but not nonsenescent cells. The SCAPs discovered so far have been used to identify putative senolytic targets.
The first senolytic agents discovered using this hypothesis-driven approach were dasatinib and quercetin. Ten months later, the third senolytic drug, navitoclax, a BCL-2 pro-survival pathway inhibitor, was reported. Since then, a growing number of senolytics have been reported. Yet more senolytics are in development, and additional potential SCAPs are being identified. The SCAPs required for senescent cell resistance to apoptosis vary according to cell type. The Achilles' heels, for example, of senescent human primary adipose progenitors differ from those of a senescent human endothelial cell strain, indicating that agents targeting a single SCAP may not eliminate all types of senescent cells. The senolytics that have been tested across a wide range of senescent cell types have all exhibited a degree of cell type specificity. For example, navitoclax is senolytic in a cell culture-acclimated human umbilical vein endothelial cell strain but is not effective against senescent primary human fat cell progenitors.
Senolytics do not have to be continuously present to exert their effect. Brief disruption of pro-survival pathways is adequate to kill senescent cells. Thus, senolytics can be effective when administered intermittently. For example, dasatinib and quercetin have an elimination half-life of a few hours, yet a single short course alleviates effects of radiation-induced senescent cell creation in vivo for at least 7 months. The frequency of senolytic treatment will depend on rates of senescent cell re-accumulation, which probably varies according to conditions that induce cellular senescence. Advantages of intermittent administration include less opportunity to develop side effects, the feasibility of administering senolytic drugs during periods of relatively good health, and less risk of off-target effects caused by continuous exposure to drugs. Another advantage of senolytics is that cell division-dependent drug resistance is unlikely to occur, because senescent cells do not divide and therefore cannot acquire advantageous mutations, unlike the situation in treating cancers or infectious agents.
The introduction of effective senolytics or other agents that target fundamental aging processes into clinical practice could be transformative. These drugs may be critical to increasing healthspan and delaying, preventing, or alleviating the multiple chronic diseases that account for the bulk of morbidity, mortality, and health costs in developed and developing societies. They could also delay or treat the geriatric syndromes, including sarcopenia, frailty, immobility, and cognitive impairment, as well as age-related loss of physiological resilience, in a way not imaginable until recently. These agents could transform geriatric medicine from being a discipline focused mainly on tertiary or quaternary prevention into one with important primary preventive options centered on a solid science foundation equivalent to, or even better than, that of other medical specialties.
Senolytics might prevent or delay chronic diseases as a group, instead of one at a time in presymptomatic or at-risk individuals. Furthermore, if what can be achieved in preclinical aging animal models can be achieved in humans, it may be feasible to alleviate dysfunction even in frail individuals with multiple comorbidities, a group that until recently was felt to be beyond the point of treatment other than palliative and supportive measures. Although considerable care must be taken, particularly until clinical trials are completed and the potential adverse effects of senolytic drugs are understood fully, it is conceivable that the rapidly emerging repertoire of senolytic agents might transform medicine as we know it.