Telomere and Telomerase Dynamics in Human T Lymphocytes

Advanced cancer is characterized by a phenotype that permits cells to divide indefinitely while cellular aging is characterized by cells ceasing to divide. It is believed that senescence may have evolved as an anti-cancer protection mechanism in long-lived species such as humans. Therefore, cancer and aging are essentially opposite ends of the same problem. Telomeres are the cellular aging-clock that determines a cell's capability of proliferation. When normal cells divide, telomeres gets progressively shorter. When telomeres reach a critical short length, cells stop dividing. To compensate for the loss of telomeres, telomerase is a ribonucleoprotein enzyme complex that elongates telomeres, but its expression is restricted to certain subsets of cell types. Investigating how telomerase is regulated in normal cells may provide insights and new approaches to block telomerase activity in cancer cells or to re-activate telomerase in aging cells. Immune cells play central roles in defending humans from pathogens, infections, and malignant cells. Immunotherapy has shown great potential in cancer treatment and has gained increasing public attention. Thus, a better understanding of how to increase the proliferation efficiency of normal immune cells, especially in older individuals whose immune stem-like cells may becoming less efficient is important. Due to the accessibility of blood from volunteers, immune cells are a model system to investigate healthy aging. For my doctoral research, I decided to study telomeres and telomerase dynamics in immune cells. Using novel techniques in telomere length analysis and telomerase activity measurements developed in our lab, I discovered that a subset of CD28+ T cells show robust telomerase activity and the ability to maintain telomere lengths during stimulated cell proliferation. In a centenarian study, T cells from a subset of centenarians showed stronger telomerase activation compared with many younger individuals. RNA-seq analysis revealed distinct differences between high performance centenarians and other age groups. Finally, we developed novel techniques using ddPCR for quantitating mitochondrial DNA numbers per cell and validated the differences we found in centenarian samples. Altogether, my doctoral project has added value to our current knowledge of how telomerase is regulated during immune responses and revealed its importance in longevity studies.