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 review the clinical potential of senolytic drugs on aging

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.

The Clinical Potential of Senolytic Drugs