Intermittent Senolytic Treatment with Dasatinib and Quercetin Produces Benefits in Non-Human Primates
Researchers here report on the outcome of six months of monthly senolytic therapy in cynomolgus macaques. The results are broadly positive, as one might expect from the established human data. Dasatinib is a chemotherapeutic drug, but senolytic dosing is not sustained as is the case in the treatment of cancer, and side-effects are much reduced as a result. It remains to be seen as to what the optimal dose and dose schedule for this treatment will be. Researchers are trying a range of options, and arguably the human trials conducted by the Mayo Clinic are using too low a dose. Time will tell, but there is a need for more clinical trials, and an opportunity for philanthropists to step in and run few-hundred individual, affordable, safe clinical trials of this cheap senolytic treatment to provide support for physicians to use the therapy off-label for many age-related conditions.
Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported.
Age-, weight-, sex-, and glycemic control-matched NHPs (D + Q, n = 9; vehicle [VEH] n = 7) received two consecutive days of D + Q (5 mg/kg + 50 mg/kg) monthly for 6 months, where in month six, a 10% CR was implemented in both D + Q and VEH NHPs to induce equal weight reductions. D + Q reduced senescence marker gene expressions in adipose tissue and circulating PAI-1 and MMP-9. Improvements were observed in immune cell types with significant anti-inflammatory shifts and reductions in microbial translocation biomarkers, despite stable microbiomes. Blood urea nitrogen showed robust improvements with D + Q. CR resulted in significant positive body composition changes in both groups with further improvement in immune cell profiles and decreased GDF15, and the interaction of D + Q and CR dramatically reduced glycosylated hemoglobin A1c.
This work indicates that 6 months of intermittent D + Q exposure is safe and may combat inflammaging via immune benefits and improved intestinal barrier function. We also saw renal benefits, and with CR, improved metabolic health. These data are intended to provide direction for the design of larger controlled intervention trials in older patients.
The 5mg/kg dosing of D used would equal 400mg for an 80 Kg human (me) sized animal, an aggressive dose presuming these primates process D similar to humans. Although the study claims 'no negative effects', I am skeptical the animals were not stressed at that dose. I personally begin to experience stress at 240mg D.
senolytics. The question I have about senolytics is...say you have a rusty car. You can remove the rust, but how long can that be expected to work? Eventually, functional structural steel must be replaced. For humans, how are the stem cells to be replaced? Isn't that the problem? How are the epigenetics to be restored? And does silencing the deleterious portions of the genome with histones and methylation really accomplish what we want to accomplish? Don't we truly need gene therapy? What's with all the junk DNA? Why keep that?
@JohnD
In molar equivalence, the dose must be divided by three between monkeys and humans (and divided by twelve) from mice to humans.