Lower Dose Senolytics Fail to Prevent Cognitive Decline in Female Rats
Researchers here evaluate the effects of a longer term dosing schedule of a few different senolytic drugs in rats, 5 days on and 14 days off repeated for 7 months. The dose of dasatinib and quercetin used is about half of that shown to be effective in clearance of senescent cells in mice and people, but those higher doses have typically not been used as frequently or for as long. That this fails to affect cognitive decline in female rats is a data point, to contrast with other studies in which senolytic therapies have slowed cognitive decline or produced benefits in animal models of neurodegenerative conditions. Determining dosage is a hard problem generally, and this is still a work in progress for first generation senolytic therapies such as the combination of dasatinib and quercetin. Near all such effort in the field is directed towards new senolytics under development by biotech companies.
There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats.
Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the water maze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.
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