Dissecting Cell Cycle Arrest Phenotypes in Aging and Age-Associated Diseases

/Abstract The quiescence-senescence continuum hypothesis posits that cellular quiescence, a reversible state of cell cycle arrest, and senescence, an irreversible form of arrest, exist along a dynamic continuum rather than as distinct, mutually exclusive states. In this model, quiescent cells, which typically enter a dormant phase in response to environmental cues such as nutrient deprivation or growth factor withdrawal, can transition into senescence if exposed to chronic stress or DNA damage. This hypothesis suggests that cellular states are fluid and context-dependent, where the same molecular pathways involved in maintaining quiescence may be co-opted or altered to induce senescence. A key difference between the two is that while quiescent cells retain the ability to re-enter the cell cycle when conditions improve, senescent cells adopt a permanent arrest accompanied by the secretion of pro-inflammatory signals, contributing to aging and tissue dysfunction. Understanding this continuum has profound implications for aging research, as it highlights the potential reversibility of cellular fates and the fine molecular balances that determine a cell’s transition between growth, rest, and aging. In this project, we will investigate which hallmarks of senescence are shared with quiescent cells, explore the quiescent cell secretome, and examine various quiescent states that may be linked to stress-induced changes associated with aging and disease in tissue-resident quiescent cells. Project Number: 1R21AG095984-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: NICOLA NERETTI | Institution: BROWN UNIVERSITY, PROVIDENCE, RI | Award Amount: $438,625 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CDB-H (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11382065