Kolonin publishes research on role of telomerase in metabolic health
The laboratory of Mikhail Kolonin, PhD, published a new report, “Caloric Restriction and Telomere Preservation in TERT Knockout Adipocyte Progenitors Does Not Rescue from Metabolic Dysfunction due to a TERT Function in Adipocyte Mitochondria” in Aging Cell, which studied the effect of dietary interventions on cell aging.
In this work, Kolonin, professor and Harry E. Bovay, Jr. Distinguished University Chair in Metabolic Disease Research at the Institute of Molecular Medicine’s Center for Metabolic and Degenerative Diseases, has been leading the efforts in using preclinical models to study cell senescence, the state of irreversible cell proliferation arrest.
The group has previously reported murine models in which telomerase revers transcriptase (TERT) is inactivated in specific cell types. Without TERT, cells undergoing repeated divisions, such as stem/progenitor cells, undergo premature telomere attrition in these models.
Previous collaborative studies showed that, in obesity, overfeeding causes excessive proliferation of adipocyte progenitor cells, which expedites their telomere shortening. The resulting proliferative cell senescence limits the generation of new lipid-storing cells (adipocytes) and causes inflammation, setting the stage for insulin resistance, and type 2 diabetes.
In the study, two dietary interventions, time-restricted feeding and caloric restriction, were tested as strategies to mitigate telomere attrition in adipocyte progenitors.
“To our surprise, while dietary interventions in the early life of preclinical models preserved telomeres, they only partially prevented metabolic dysregulation subsequently induced by high-calorie diet,” Kolonin said.
In addition to maintaining telomere length, TERT promotes cell proliferation and suppresses cell senescence through mechanisms that have remained unclear.
“Our findings from TERT knockout murine models highlight its dual role,” Kolonin said. “Beyond its canonical function in telomere maintenance, TERT is crucial for mitochondiral biogenesis and function.”
The authors found that thermogenic brown adipocytes, which rely on oxidative metabolism, particularly suffer from TERT deficiency. Their dysfunction is the primary cause of systemic metabolic defects observed.
Kolonin said that the implications of these findings are profound. They indicate that the telomere-independent roles of TERT — particularly its mitochondrial functions — are vital for sustaining metabolic health. They also suggest that adipocyte-directed TERT induction could be pursued as an approach to combat metabolic dysfunction. By harnessing TERT’s ability to support mitochondrial health and oxidative metabolism, future therapies may prevent or reverse the metabolic consequences of aging and obesity.
As research continues, the complexity of AT and its cellular constituents underscores the need for multifaceted interventions. From dietary strategies to molecular therapies, addressing both the telomere-dependent and -independent functions of TERT may pave the way for healthier aging and improved metabolic outcomes.
Co-authors from McGovern Medical School are Zhanguo Gao, PhD, senior research scientist; Yongmei Yu, research associate, and Kristin L. Eckel-Mahan, PhD, associate professor. The research is supported by the Harry E. Bovay, Jr. Foundation, Levy-Longenbaugh Fund, and the National Institutes of Health.