In one of the first studies of its kind, the popular senolytic combination, administered systematically for six months, produced several health benefits in these animals. Some effects were enhanced by calorie restriction [1].
Coup de grace for the cells
The combination of the drug dasatinib and the flavonoid quercetin, also known as D+Q, is one of the most popular senolytics (compounds that induce death in senescent cells). It has been the subject of several preclinical studies and a few clinical trials, showing a lot of promise [2]. However, there are limited data on the safety and efficacy of long-term systemic administration of D+Q in humans or human-like animal models.
This new study attempts to fill the gap. The scientists treated 16 middle-aged male and female cynomolgus macaques with D+Q for six months. The drug was administered orally on two consecutive days once a month. In the last month, the animals were also subjected to a slight caloric restriction (10%) to reveal any potential synergistic effects, as the caloric restriction itself is a powerful anti-aging therapy [3].
Reduced senescence
As expected, the treatment led to a significant reduction in cellular senescence which was measured in the subcutaneous tissue three months after the start of the experiment. In parallel, markers of apoptosis (cell death) increased, indicating effective senolysis.
Interestingly, three diabetic monkeys were included in each group. In the study group, they showed the greatest senolysis, about three times more than their non-diabetic counterparts. While the number of diabetic subjects was too low for the statistical analysis, the trend suggests that diabetic individuals may benefit more from a senolytic treatment.
Less inflammation and other benefits
D+Q treatment also produced some anti-inflammatory effects, with significant or borderline significant changes in blood cell composition. Calorie restriction further reduced inflammation, and little synergy between the two treatments was observed. The researchers speculate that the somewhat ambiguous results could be explained by the activity of macrophages that clear out dying senescent cells.
One of the highly conserved features of aging is the degradation of the intestinal barrier, which leads to the entry of microbes and other pathogens into the bloodstream. D+Q treatment led to a significant improvement in markers of intestinal barrier integrity. This effect was enhanced by calorie restriction. No significant changes in microbiome composition were observed.
Renal function also appeared to benefit from senolytic treatment. Blood urea nitrogen (BUN), a common indicator of kidney health, was significantly improved. This time, however, the calorie restriction didn’t add any benefits.
On the metabolic front, D+Q alone failed to produce any significant benefit, although there was a trend toward a reduction in the abdominal:subcutaneous fat ratio; belly fat is thought to be more unhealthy. Calorie restriction, on the other hand, has been predictably brilliant, with very significant reductions in body weight, waist circumference, and increases in lean body mass percentage. It also reduced triglycerides and fasting blood sugar. However, an interesting synergistic effect was observed between the two treatments in improving hemoglobin A1C (HbA1c), an important metric of average glucose levels over a period of time.
Given the results of this study, we believe these data provide preliminary evidence supporting the safe implementation of a human clinical study, possibly focusing on diabetic kidney disease in middle-to-late-life adults. We believe that intermittent D+Q combined with low-percentage calorie restriction would significantly and safely improve inflammation, blood glucose, and renal outcomes associated with aging-related metabolic dysfunction.
While this study did not lead to dramatic results, it demonstrated the feasibility and safety of systemic administration of D+Q over a period of time relevant to human clinical trials. It has also led to additional benefits beyond a lower burden of senescent cells, such as less inflammation. Finally, it showed an intriguing synergy between a senolytic treatment and reasonably manageable calorie restriction that is worth exploring further.
Literature
[1] Ruggiero, AD, Vemuri, R., Blawas, M. et al. (2023). Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: Implications for senolytic clinical trial design. GeroScience.
[2] Hickson, LJ, Prata, LGL, Bobart, SA, Evans, TK, Giorgadze, N., Hashmi, SK, … & Kirkland, JL (2019). Senolytics reduce senescent cells in humans: preliminary report from a clinical study of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine, 47, 446-456.
[3] Masoro, E. J. (2005). Overview of calorie restriction and aging. Mechanisms of Aging and Development, 126(9), 913-922.
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