Setting aside the mice genetically engineered to destroy senescent cells, the combination of dasatinib and quercetin is the oldest of the senolytic treatments used in animal studies. Senolytic therapies are those that selectively destroy senescent cells in old tissues in order to produce rejuvenation, turning back the progression of numerous age-related conditions. Unusually for early stage research, these initial senolytics are actually quite effective, considered in the grand scheme of things. Thus they have moved directly to human trials in some cases. The first data on their ability to produce the same outcomes in humans as in mice emerged this year, and more data will continue to roll out over the next few years as the first trials run and complete. The results reported in today's open access paper provide an important demonstration for those not yet convinced that the animal data is relevant.
Meanwhile, the older members of the self-experimentation community have been using dasatinib, quercetin, and a few other senolytics for a few years now on the strength of the animal data and the whisper network of positive outcomes. Further, groups such as the Age Reversal Network are attempting to build physician networks and support for off-label use of senolytics.
While senescent cells are important in a range of beneficial processes, from cancer suppression, to the Hayflick limit, to wound healing, their presence is temporary in all such cases. Near all are destroyed, either by programmed cell death or by the immune system. Lingering senescent cells, on the other hand, are an entirely different story: they are in fact an important cause of aging and age-related dysfunction. They secrete a potent and inflammatory mix of signals that rouses the immune system to destructive chronic inflammation, degrades surrounding tissue structure and function, and encourages other cells to also become senescent.
The more lingering senescent cells present in the body, the worse the outcome for health, and their numbers steadily and inexorably grow with age. The silver lining here is that senescent cells actively maintain a degraded, aberrant state of metabolism, regeneration, and tissue function. If they are removed, rejuvenation takes place quite rapidly. In some cases, surprising levels of rejuvenation, with features of aging that might have been thought irreversible, and that no existing medicine can much affect, vanishing as the tissue environment becomes less aged and dysfunctional. The world at large will begin to wake up to the true potential here as trials continue, but it remains a tragedy that hundreds of millions of people worldwide could have their quality of life significantly improved overnight, if they only knew. But it isn't happening. Dasatinib and quercetin are both mass produced and cheap, easily obtained, easily used. Too little is being done to bring this treatment to the masses who could benefit.
In a small safety and feasibility clinical trial, researchers have demonstrated for the first time that senescent cells can be removed from the body using drugs termed "senolytics". The result was verified not only in analysis of blood but also in changes in skin and fat tissue senescent cell abundance. Senescent cells are malfunctioning cells that accumulate with aging and in organs affected by chronic diseases. Senescent cells can remain in the body and contribute to multiple diseases as well as features of aging, ranging from heart disease to frailty, dementias, osteoporosis, diabetes, and kidney, liver, and lung diseases.
For three days the nine participants received a combination dose of dasatinab and quercetin. Though the drugs cleared the body in a couple of days, effects on reducing senescent cells were evident for at least 11 days. The researchers say this shows the senolytic drug combination significantly decreases senescent cell burden in humans. Senescent cells are characteristic in end-stage kidney failure as well as diabetes-related kidney disease. By removing the cells from mice, researchers had previously found that senolytics alleviate insulin resistance, cell dysfunction, and other processes that cause disease progression and complications. While more research is needed on the impact of senolytics on diseases and disorders of aging, the researchers say the results of occasional dosing reduces risks from having to give drugs continuously.
By definition, the target of senolytics is senescent cells, not a molecule or a single biochemical pathway. The first senolytic drugs, Dasatinib (D) and Quercetin (Q), were discovered using a mechanism-based approach instead of the random high-throughput screening usually used for drug discovery. Because senescent cells can take weeks to months to develop and do not divide, and because even eliminating only 30% of senescent cells can be sufficient to alleviate dysfunction in preclinical studies, D + Q is as effective in mice if administered intermittently, for example every 2 weeks to a month, as continuously, even though D and Q have elimination half-lives of only 4 and 11 hours, respectively. This is consistent with the point that, since the target of senolytics is senescent cells, these drugs do not need to be continuously present in the circulation in the same way as drugs whose mechanism of action is to occupy a receptor, modulate an enzyme, or act on a particular biochemical pathway, at least in mice. Intermittently administering D + Q effectively circumvents any potential off-target effects due to continuous receptor occupancy or modulation of an enzyme or biochemical pathway.
Based on the many promising studies of D + Q in mice, the experience gained from the use of D in humans for over 20 years, and the fact that Q is a natural product present in many foods such as apples, we initiated clinical trials of these agents. The first-in-human clinical trial of senolytics was a brief course of D + Q for patients with idiopathic pulmonary fibrosis, which resulted in statistically significant improvements in physical function in 14 subjects with this relentlessly progressive, debilitating, and ultimately fatal cellular senescence-driven disease. Although alleviation of this cellular senescence-related phenotype was demonstrated in that pioneering trial in tandem with trends for decreased senescence-associated secretory phenotype (SASP) factors, and others found decreased SASP factors in a trial of continuous D administration in the skin of subjects with systemic sclerosis, so far, there has been no direct demonstration of senescent cell clearance by senolytic drugs in peer-reviewed published human clinical trials.
To test whether intermittent D + Q is effective in targeting senescent cells in humans, we administered a single 3 day course of oral D + Q and assayed senescent cell abundance 11 days after the last dose in subjects with diabetic kidney disease, the most common cause of end-stage kidney failure and which is characterized by increased senescent cell burden. We found D + Q alleviates insulin resistance, proteinuria, and renal podocyte dysfunction caused by high fat diet-induced or genetic obesity in mice. We also found that even Q alone can prevent high fat diet-induced increases in markers of senescence, renal fibrosis, decreases in renal oxygenation, and increased creatinine in mice, although Q alone did not prevent insulin resistance. Diabetes and chronic kidney disease (CKD) in humans therefore represent conditions that may benefit from D + Q therapy-induced alleviation of tissue dysfunction and disease progression, which is being tested as the clinical trial reported here continues. In this interim report of findings from that trial, we found the single brief course of D + Q attenuated adipose tissue and skin senescent cell burden, decreased resulting adipose tissue macrophage accumulation, enhanced adipocyte progenitor replicative potential, and reduced key circulating SASP factors.