In experimental animals in which senescent cells contribute to age-related physical dysfunction such as those generated after exposure to ionizing radiation, the researchers found that PCC1 administration significantly decreased the number of senescent cells, reversed organ degeneration and led to health improvements. For mice carrying tumor xenografts, they found that PCC1 improved therapeutic outcomes when combined with traditional anticancer agents. Strikingly, they PCC1 treatment in a metronomic schedule into very old mice (aged 24-27 months old, equivalent to the human age of 75–90 years old) increased their remaining lifespan by over 60%, or extended their total lifespan by more than 9%.
Senescent cells produce distinct paracrine and endocrine signals, causing local tissue dysfunction and exerting systemic effects. Dr. SUN Yu's group at SINH demonstrated in this study that senescent cell removal by apoptosis-inducing "senolytic" agents such as PCC1, effectively limits senescent cell populations in multiple types of tissues and organs, providing benefits to the models of geriatric decline and chronic diseases. The findings support senescent cells as a pharmacologic target for alleviating effects of fundamental aging processes.
Given the increasing demand to develop targeted senotherapeutics addressing the needs of the aging and chronically-ill, the researchers proposed that the exact molecular and cellular mechanisms of PCC1 actions warrant continued investigation. "Although PCC1 delivery by intermittent programs appears to be well tolerated by mice in preclinical trials, further efforts are needed to establish safe routes adaptable for PCC1 treatments in humans, key factors have to be determined by future clinical studies," Dr. SUN said.
Working model for PCC1 in inducing apoptosis of senescent cells, a process that likely engages multiple signaling pathways. (Image by Dr. SUN Yu's group)
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