HSCI Retreat 2020 Abstract 9

Targeting Immune Checkpoint as a Novel Strategy for Anti-Aging Intervention 

Yuting Tan,* Angelique Onorati, Zhixun Dou
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA, USA
* Presenting and corresponding author: ytan0@mgh.harvard.edu 

Submitted: Jun 11, 2020; Published online: Jul 27, 2020



Cellular senescence is one of the hallmarks of aging. Senescence triggers chronic inflammation in aged tissues, which plays a causative role in many age-associated diseases. Senescent cells accumulate in aged tissues and shorten healthy lifespan in mice. Clearance of senescent cells delays age-associated disorders in mouse models and preclinical studies of a variety of diseases. This instigates the efforts to develop senolytic drugs to remove senescent cells from aged tissues. However, senolytics have documented side effects and toxicity to healthy cells, limiting their applications in the elderly. Senescent cells are subjected to immune surveillance. A broad spectrum of immune cells can be recruited to tissues to mediate clearance of senescent cells. However, senescent cells accumulate in aged tissues, without being cleared by the immune system. The underlying mechanisms for the failed immunosurveillance is unknown. My preliminary results indicate that senescent cells upregulate PD-L1, a ligand for PD-1, which is a major inhibitory receptor on immune cells. This upregulation is dependent on cGAS-STING and STAT activity. Inhibition of PD-L1/PD-1 can incur the hair-regrowth in aged mice. I hypothesize that senescence employs a similar mechanism as cancer to inhibit the immune system, and that targeting the PD-L1 pathway in senescent cells can restore immune-mediated clearance. I will conduct drug and genetic screen to identify novel agents that can downregulate PD-L1 on senescent cells to promote immunosurveillance. This will introduce a pioneering concept to target senescent cells, with potential of developing novel therapies to delay aging and ameliorate age-associated functional decline.