Mikhail Kolonin
Professor
The University of Texas Health Science Center at Houston
McGovern Medical School
Institute of Molecular Medicine
Center for Metabolic and Degenerative Diseases
Our group studies mechanisms underlying aging-related diseases and develops new approaches to target them. We have focused on the role of pathogenic senescent cells, accumulation of which promotes aging, and which is accelerated by excessive caloric intake. In obesity, progenitor cells over-proliferate and undergo replicative senescence due to premature telomere shortening. We created mice lacking telomerase in endothelial cells, senescence in which causes blood vessel leakiness and tissue hypoxia. This animal model recapitulates the hallmarks of aging, including impaired cognitive function, reduced muscle endurance, and adipose tissue metabolism abnormality. Importantly, we discovered that this resulting multi-organ dysfunction, characteristic of aging, arises irrespective of telomere attrition.
Our data indicate that telomerase-deficient cells have dysfunctional mitochondria, which results in increased dependence on glycolysis in both senescent cells and other cells of the tissue. The effects of senescence in various types of cells on cancer progression is another interest of our group. We found that senescent endothelial cell accumulation promotes metastatic dissemination. Cancer-associated fibroblasts (CAFs) are another cell population of interest, which underlies carcinoma progression. Our group has discovered that adipose stromal cells (ASCs) from fat tissue, mobilized in obesity, contribute to a population of CAFs increasing cancer aggressiveness. Based on our unpublished studies, we conclude that therapeutic approaches to target ASC-derived CAFs may be effective in combination with immunotherapy. In another project, we have studied GLP1 receptor agonists (GLP1RAs), such as Ozempic, which induce weight loss. We discovered that Interleukin-6 (IL6) is a cytokine whose expression is transiently induced by treatment with GLP1RAs.
While chronically elevated IL6 signaling can be pathogenic, acute metronomic IL6 administration improves glucose clearance. According to our data, transient IL6 receptor (IL6R) signaling on perivascular cells and adipocytes is required for GLP1RA-induced adipose tissue thermogenesis and anti-diabetic effects. GLP1RAs also have other poorly understood anti-aging effects, which we are investigating.
We are also performing unbiased screens for molecules activating telomerase expression and molecules targeting senescent cells. Finally, we are developing peptide-based probes targeting metastatic cancer cells that can be used for non-invasive imaging and therapy delivery.
Education & Training
Ph.D. - Wayne State University - 2000