Circadian reprogramming in cellular senescence

The National Institute on Aging awarded The University of Texas Health Science Center at San Antonio $379,988 on March 3, 2026, under the Aging Research program (CFDA 93.866) to investigate circadian reprogramming in cellular senescence.

The research addresses the bidirectional relationship between aging and circadian rhythms by examining how the molecular clock regulates cellular senescence and how cellular senescence drives circadian dysfunction with age. The project will determine how the molecular clock contributes to cellular senescence, define the rhythm of senescent cells, and investigate mechanisms linking circadian disruption to elevated disease risk in aging populations. Preliminary data indicates that expression of prominent cellular senescence drivers depends on BMAL1 (a core clock component) and that P21 (a cell-cycle protein driving senescence) is upregulated at night in a rhythm disrupted by circadian misalignment. The research will test whether circadian clock regulation of senescence and senescence-driven circadian dysfunction explain the coincidence of increased cellular senescence markers and disrupted circadian behaviors with age in mouse models.

The award funds a fellowship to train the principal investigator toward becoming an independent investigator in circadian aging at an academic institution. Performance occurs in San Antonio, Texas, with a completion date of August 31, 2028. This is a National Research Service Award (individual postdoctoral fellowship), consistent with the program's support for postdoctoral training typically capped at three years.

Abstract

Aging and age-related diseases have become a public health crisis. Circadian rhythms become dysfunctional with age and disrupted circadian rhythms result in elevated risk for diseases that are associated with aging. The proposal aims to improve our understanding of the BI-directional relationship between aging and circadian rhythms. This fellowship application will help train the candidate toward the goal of becoming an independent investigator at an academic institution in the field of circadian aging. A major driver of age-related disease is cellular senescence. There is literature evidence to suggest circadian disruptions result in elevated in cellular senescence. Interestingly, there is also evidence that senescent cells display circadian dysfunction. Mechanisms that govern these processes are incompletely understood and require further investigation to delineate. Our preliminary data suggests expression levels of prominent players in the cellular senescence program are dependent on expression of BMAL1, a core clock component. Further, we have identified that P21, a cell-cycle protein also responsible for driving cellular senescence is highly upregulated at night, but this rhythm is disrupted with circadian misalignment, suggesting the clock is responsible for regulating its expression. We have also identified that both senescence status and treatment with exogenous sasp factors can robustly alter clock protein, PER2 expression rhythms over time. Finally, we have identified that increased markers of cellular senescence and disrupted circadian behaviors coincide with increased age in mice. Taken together, we hypothesize that the molecular clock regulates cellular senescence and that cellular senescence drives circadian dysfunction with age. To test this, we designed these aims: aim 1: determine how the molecular clock contributes to cellular senescence. Aim 2: define the rhythm of senescent cells and determine how they influence the rhythm and circadian functions of neighboring non-senescent cells. We will use both in vivo and in vitro approaches to strategically manipulate the molecular clock and cellular senescence to disentangle their effects on one-another. Using state-of-the-art single-cell imaging techniques and innovative treatment strategies, this proposal will fill in significant gaps in our understanding of mechanisms driving age-associated disease. Further, the candidate will also undertake a rigorous training program at UT health SAN antonio designed to enhance critical thinking and presentation skills, scientific productivity, and successful entrance into a position as an independent researcher at an academic institution. The proposed studies are significant because they will explicate a currently understudied reciprocal relationship between circadian rhythms and cellular senescence. A better understanding of the underlying biological processes that drive aging will undoubtedly provide insight toward development of therapeutic interventions capable of ameliorating an array of diseases. This proposal will also support the scientific endeavors and training of a young scientist with significant potential to run her own state-of-the art research program in the future.