Human Data on Epigenetic Age Following Senolytic Treatment
In today's open access paper, researchers report on the results of a small clinical trial of senolytic treatments to clear senescent cells in human patients. The treatment produced a short term increase in epigenetic age as measured via immune cells in a blood sample, not the hoped-for result. Bear in mind that one of the senolytic treatments used in this small study, dasatinib and quercetin, has been shown to clear senescent cells in at least some tissues in earlier human studies. Given the well-established role of lingering senescent cells in degenerative aging, at least in mice, why the treatment produced no lasting decrease in epigenetic age in this study is an interesting question.
Firstly, it is entirely possible that current epigenetic clocks are insensitive to the contribution of senescent cells to degenerative aging. Some clocks have demonstrated insensitivity to other factors in the past, such as physical fitness or chronic inflammation. The results may also reflect changes in immune cell population sizes and behaviors rather than anything more significant about aging; this is ever the challenge when looking at epigenetic age in blood samples. It is also possible that the limited data on whether established senolytic treatments clear senescent cells in humans as well as they do in mice is in error, and we'll have to wait for different therapies, those currently under development, to reach clinical trials in order to learn more.
Lastly, it is possible that many of the patients used in the study may not have been old enough to have sizable burdens of senescent cells. With an average age of ~60 and lowest age of 40-something in the study group, it is reasonably to think that something like half of the participants may not have exhibited a sizable burden of senescent cells. Research is never simple!
Given the potential role of senescence in aging, senolytic drugs have emerged as promising candidates for extending lifespan. Some initially identified senolytics were Dasatinib, Quercetin, and Fisetin. These molecules were drugs or natural products already used for other indications in humans, including anti-cancer therapies.
Dasatinib is a tyrosine kinase inhibitor approved by the FDA to treat myeloid leukemia. Quercetin is a flavonoid compound that induces apoptosis in senescent endothelial cells. Combined treatment with Dasatinib and Quercetin (DQ) has been demonstrated to decrease senescent cell burden in humans in multiple tissues; improve pulmonary and physical function along with survival in mice while lessening their age-dependent intervertebral disc degeneration; and reduce senescence and inflammatory markers in non-human primates. In human studies, patients with idiopathic pulmonary fibrosis, a senescence associated disease, improved 6-minute walk distance, walking speed, chair rise ability and short physical performance battery after 9 doses of oral DQ over 3 weeks.
Fisetin is another flavonoid compound that has gained recognition for its anti-proliferative, anti-inflammatory, and anti-metastatic properties. Fisetin has the potential to reduce senescence markers in multiple tissues in murine and human subjects. Administration of Fisetin to old mice restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan. Notably, a comparative study has highlighted Fisetin as the safest and most potent natural senolytic among the tested compounds.
This study aimed to assess the effects of Dasatinib and Quercetin (DQ) senolytic treatment on DNA methylation (DNAm), epigenetic age, and immune cell subsets. In a Phase I pilot study, 19 participants received DQ for 6 months, with DNAm measured at baseline, 3 months, and 6 months. The age range of these individuals that were considered in the first study analyses were between 43.0 and 86.6.
Significant increases in epigenetic age acceleration were observed in first-generation epigenetic clocks and mitotic clocks at 3 and 6 months, along with a notable decrease in telomere length. However, no significant differences were observed in second and third-generation clocks. Building upon these findings, a subsequent investigation evaluated the combination of DQ with Fisetin (DQF), a well-known antioxidant and antiaging senolytic molecule. After one year, 19 participants (including 10 from the initial study) received DQF for 6 months, with DNAm assessed at baseline and 6 months. Remarkably, the addition of Fisetin to the treatment resulted in non-significant increases in epigenetic age acceleration, suggesting a potential mitigating effect of Fisetin on the impact of DQ on epigenetic aging.
Furthermore, our analyses unveiled notable differences in immune cell proportions between the DQ and DQF treatment groups, providing a biological basis for the divergent patterns observed in the evolution of epigenetic clocks. These findings warrant further research to validate and comprehensively understand the implications of these combined interventions.
So, this study shows Quercetin+Dasatinib seems to be not working as predicted. Not encouraging, yet main effect of senescent cells should be chronic inflammation, which hardly influences on telomeres, for example. Maybe, there are some certain parameters related to inflammation should be checked.
Disappointing. It looks like they had a relatively short-term follow-up (6 months post-treatment), small numbers (N=19 DQ, N=9 "new" DQF), and did not seem to actually assess levels of senescent cells in blood and tissues - hard to interpret the findings given the limited sample size and no "positive controls" (eg, confirming senolytic activity).