The Forever Healthy Foundation publishes a series of conservative risk-benefit analyses of presently available interventions that might prove beneficial in addressing aspects of aging. These range widely in proven effectiveness, quality of animal evidence, and theoretical utility. Some do not in any way attack the known root causes of aging. Some are still pending any sort of rigorous human trial data. Some have plenty of human data that strongly indicates small, unreliable effects at best. It is nonetheless a useful exercise to make clear which are which. In a world in which the “anti-aging” industry propagates all sorts of nonsense to sell their snake-oil products, there is a comparative lack of good, unbiased analysis of approaches that might actually work to some degree, coupled with a responsible attitude towards uncertainty and risk.
The latest publication in the Forever Healthy series covers what is probably the best of the few presently available rejuvenation therapies, the use of dasatinib and quercetin in combination as a senolytic treatment. Senolytics selectively destroy senescent cells. These cells accumulate with age, and their presence actively maintains an inflammatory, dysfunctional state of metabolism, contributing meaningfully to the progression of degenerative aging and age-related disease. In animal models, senolytic therapies produce impressive results in turning back the manifestations of a wide range of age-related diseases. It is not hyperbole to say that this data is far, far better, more reliable, and more robust than the equivalent data for any other intervention targeting aging in old animals. Several small human trials have either been conducted and are underway for dasatinib and quercetin, and the published results to date are promising but not yet conclusive.
Risk-Benefit Analysis of Dasatinib + Quercetin as a Senolytic Therapy
When a cell reaches the end of its life or becomes damaged beyond repair it normally either kills itself or signals the immune system to remove it. Unfortunately, every so often this mechanism fails. The cell stays around indefinitely and starts poisoning its environment. Over time, more and more of these harmful, death resistant, senescent cells accumulate. Senescent cells are thought to be one of the main drivers of aging and age-related diseases.
Senolytics are drugs that selectively remove senescent cells by disabling the mechanisms that allow them to survive. Dasatinib (D), a well-established medication used in the treatment of cancer and quercetin (Q), a flavonoid common in plants were among the first senolytics to be discovered. As they have been shown to affect different types of senescent cells, they are often employed in combination.
Studies in rodents have shown that clearing senescent cells can prevent, delay, or alleviate multiple age-related diseases and extend the healthy lifespan by up to 35%. Based on the promising results in animal testing, it is supposed that intermittent dosing of D+Q also leads to the elimination of senescent cells in humans with the accompanying health and rejuvenation benefits. As the first clinical trials in humans have been completed and interest in the practical application of D+Q is increasing, Forever Healthy seeks to assess the risks, benefits, and therapeutic protocols of using D+Q as a senolytic therapy.
Currently, there are only results from 3 trials in humans in which D+Q was evaluated as a senolytic therapy. The majority of human studies used D or Q in cancer therapy and provided information on side effects and safety.
The benefits shown in animals were significant and were observed in many organ systems. However, several of the benefits only occurred in diseased animals (i.e. diabetic mice), while the healthy control group did not benefit from the treatment.
The benefits reported in human studies are mainly focussed on senescent cell markers. So far, these markers are only hypothesized to translate to clinically meaningful effects. Few benefits had direct clinical relevance, and those were not really convincing. Additionally, 2 out of the 3 clinical studies were in patients with pre-existing disease so there is very limited information on the effect in healthy individuals. The potential risks of D are extensive and well-known through its use in the treatment of cancer. While the clinical trials that used D+Q as a senolytic therapy reported only mild to moderate adverse events, it is of note that the low number of participants in these studies might not deliver a representative result.
Furthermore, the human studies all used different treatment protocols and there is no consensus on the measurement of efficacy in clinical practice. Therefore, until there are more studies showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on a treatment protocol, it seems prudent to avoid the use of D+Q as a senolytic therapy.