The Path to the Clinic for First Generation Senolytic Therapies

Senolytic therapies selectively destroy lingering senescent cells in old tissues, improving health as a result. Senescent cells, while never very large in absolute numbers, even in late life, actively maintain a degraded state of tissue and organ function via secretions that provoke chronic inflammation, detrimental alterations to the behavior of normal cells, and harmful remodeling of tissue structure, such as the development of fibrosis. A large number of animal studies have demonstrated rapid rejuvenation and reversal of aspects of specific age-related conditions to result from clearance of senescent cells. The best of the early senolytic approaches, small molecule drugs and plant extracts that sabotage senescent cell resistance to apoptosis, such as the dasatinib and quercetin combination, manage to destroy as many as half of the senescent cells in a given tissue, with the degree of clearance varying widely between therapies and tissues.

Given the animal data, which is far and away the most robust and impressive of all of the approaches to the treatment of aging attempted to date, there is an enthusiasm for human clinical trials. Unfortunately, these early small molecule drugs are largely off-patent or close to it, and so near all of the sizeable funding in the field goes towards the development of new, patentable senolytic therapies rather than the validation of existing low-cost treatments that might be more rapidly brought to the clinic. Still, a number of clinical trials of early, low-cost senolytic drugs are ongoing, as noted by the authors of today's open access paper. In the years ahead, those will be joined by the second generation senolytic therapies under development, hopefully at least marginally better as a result of the effort put into their development, and what has been learned to date about the ways in which early senolytics work. This is all moving far too slowly, however!

Cellular senescence and senolytics: the path to the clinic

The elimination of senescent cells has emerged as a plausible therapeutic strategy for preventing, delaying, or alleviating multiple diseases and age-related dysfunction. Promising results of senolytics in preclinical models suggest therapeutic and preventive opportunities for delaying multimorbidity and increasing healthspan. A key priority should be the identification of reliable, sensitive and specific gerodiagnostics - biomarkers to quantify senescent cell abundance, the senescence-associated secretory phenotype (SASP), and senolysis as well as other pillars of aging.

Fundamental aging mechanisms can be grouped into so-called hallmarks or 'pillars' of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence. The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction and loss of resilience. The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others. For example, interventions that target cellular senescence tend to attenuate other fundamental aging mechanisms leading to reduced inflammation, attenuated exhaustion of progenitors, decreased fibrosis, alleviated mitochondrial dysfunction, and a partially restored microbiome in experimental animal models of aging and chronic diseases

Based on promising results in preclinical models, over 20 clinical trials of senolytic therapies are completed, ongoing or planned. Because side effects of senolytics in humans are not yet fully known, and to maximize benefit-risk ratios, the first clinical trials are underway in patients with serious health conditions, such as diabetic kidney disease, Alzheimer's disease, frailty and idiopathic pulmonary fibrosis (IPF). The first in-human trial of senolytics (dasatinib and quercetin, D + Q), the Hematopoietic Stem Cell Transplant Survivors Study, is still underway (NCT02652052; first patient dosed on 1 April 2016). The first senolytic clinical trial published was an open-label pilot study in which 14 patients with IPF were treated with intermittent D + Q on 3 days per week for 3 weeks. Results suggested that senolytics improved physical function in these frail patients. Furthermore, post hoc analysis of a study involving 20 patients with IPF showed that urine levels of the 'geroprotective' factor α-Klotho were higher after oral D + Q than before treatment. In an open-label phase 1 pilot study in 9 patients with diabetic kidney disease, a 3-day course of oral D + Q was sufficient to decrease adipose tissue senescent cell burden, inflammation, fibrosis and circulating SASP factors for at least 11 days after the last dose of senolytics, indicating target engagement and suggesting that an intermittent dosing regimen may be effective in humans.

These early data warrant evaluation in larger randomized, double-blind, placebo-controlled trials for senescence-associated disorders and diseases, some of which are underway


I think Mayo Clinic is running a clinical trial with Dasatinib and Quercitin. Does anybody know anything about it?

Posted by: Josep at August 19th, 2022 12:06 PM
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