A few years ago, a team at Mayo Clinic led by Dr. James Kirkland treated mice with the cancer drug dasatinib and the popular dietary supplement quercetin, with results suggesting that the combination was able to destroy senescent cells.
This combination was part of the first generation of drugs known as senolytics, compounds that encourage senescent cells to self destruct in a process known as apoptosis, thus reducing chronic inflammation and improving tissue regeneration. Senolytics are thought to be a possible way to address some of the aging process and could potentially support healthy longevity if the life extending results seen in previous mouse studies can be translated to humans.
A new preprinted study explores the long-term effects of exposure to dasatinib and quercetin (D+Q) on gut microbiome composition, senescent cell populations, and inflammation.
Until now, it was unknown what influence senolytics such as D+Q have on the populations and diversity of bacteria living in the gut microbiome. With 10 controls and 10 aged mice, the researchers examined the guts of the animals to determine how D+Q affected senescent cells in intestinal walls. They used the biomarkers p16 and p21, both of which are involved in the cell cycle process and whose elevated levels indicate the presence of senescent cells. Mice given D+Q had significantly reduced p16 and p21, suggesting a corresponding reduction of senescent cell activity and/or presence.
The researchers also investigated how D+Q influenced the presence of the inflammatory biomarkers Cxcl1, Il1β, Il6, Mcp1, and Tnfα. The data showed that there was a reduction of these inflammatory biomarkers in the mice given D+Q.
Finally, after analysis, the team noted that there were significant differences between the microbial signatures of the mice given D+Q and the control mice. The researchers also noted that there was a direct correlation between elevated senescence and inflammation biomarkers and particular microbial signatures.
Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16 Ink4a and p21 Cip1) and inflammation (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n=10) compared to age-matched placebo-treated mice (n=10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1β, Il6, Mcp1 and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation and microbial dysbiosis in older subjects.
Conclusion
While this is only a small study, this data suggests that senolytics may have a beneficial effect on the gut microbiome and might potentially reduce intestinal permeability and inflammation by addressing cellular senescence and modulation of the microbiome.
Literature
[1] Saccon TD, Nagpal R, Yadav H, Cavalcante MB, Nunes ADC, Schneider A, Gesing A, Hughes B, Yousefzadeh M, Tchkonia T, Kirkland JL, Niedernhofer LJ, Robbins PD, Masternak MM. Senolytic combination of Dasatinib and Quercetin alleviates intestinal senescence and inflammation and modulates the gut microbiome in aged mice. J Gerontol A Biol Sci Med Sci. 2021 Jan 6:glab002. doi: 10.1093/gerona/glab002. Epub ahead of print. PMID: 33406219.
