Christian Sell, PhD, is an associate professor of biochemistry and molecular biology and the director of the Aging Initiative at Drexel University College of Medicine.
Dr. Sell was awarded an R01 grant for his project “The Novel Longevity Enhancing Pathways Regulated by mTOR.” Inhibitors of the mTOR pathway are among the most promising interventions to target age-related dysfunction. However, there is a critical need to further define the pro-longevity effects to facilitate clinical development of mTOR inhibitors. The overarching goal of this research program is to develop a mechanistic understanding of novel downstream targets of rapamycin, in order to facilitate safer and more effective strategies to promote healthy aging. Cellular senescence occurs in both somatic and stem cell populations and contributes to age-related dysfunction, and Dr. Sell’s laboratory has shown that mTOR inhibition using rapamycin can prevent entry into the senescent state. The mTOR pathway also regulates senescence and pluripotency in a variety of stem cell populations. The central hypothesis of the application is that mTOR inhibition by rapamycin prevents senescence and enhances pluripotency by increasing the lncRNA H19. The rationale for this hypothesis is Dr. Sell’s observation that rapamycin increases levels of the non-coding RNA (lncRNA) H19. He has found that levels of H19 decrease during senescence and in pluripotent cells. H19 plays a central role during development, differentiation and maintenance of adult stem cell populations. Rapamycin increases H19 levels, prevents senescence and maintains pluripotency. The results suggest that increasing H19 levels in response to mTOR inhibition may play a dual role, inhibiting senescence while simultaneously increasing pluripotency in adult stem cell populations. The proposed work will provide transformative data regarding a novel mechanism for lifespan extension and improvement of late-life function in multiple tissues.
Dr. Sell’s primary research focus is the basic biology of aging. His laboratory investigates the intersection between neuroendocrine signaling, cellular metabolism and senescence. Due to the high potential for clinical impact of mTOR inhibitors, Dr. Sell focuses on both understanding the fundamental processes regulated by mTOR, which are critical to longevity, and on exploring the clinical applications for mTOR inhibition to improve late-life function. His studies on cellular senescence and the impact of rapamycin have contributed to the understanding of this important process, now thought to be a major driver of aging. His laboratory was the first to identify hyperactivation of the mTOR pathway during senescence and to demonstrate that rapamycin prevents cellular senescence in human cells.