Cellular Quiescence, Senescence, and Cell Death in Aging and Disease

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Topic Description

Post Date: July 1, 2026

Expiration Date: July 1, 2028

Purpose

The purpose of this topic is to gain a deeper understanding of the mechanistic and functional interrelationships among quiescence, senescence, regulated cell death, and other cell-fate decisions. Moving beyond classification, this initiative seeks to uncover the molecular logic governing cell fate under stress and during aging -- knowledge essential for the rational design of next-generation therapeutics targeting aging and age-related diseases (ARD).

Background

Despite remarkable progress in cellular senescence research, much of the past decade has focused on defining the extraordinary heterogeneity of senescent cells, shaped by inducing stressors, tissue of origin, and organismal age, leading to the concept of distinct “senotypes.” While this groundbreaking work has transformed the field, fundamental mechanistic questions remain unresolved.

A central premise of this initiative is that quiescence, senescence, and apoptosis represent interconnected, yet distinct, states of cell-cycle withdrawal. Whether these states constitute separate endpoints, exist along a continuum, or reflect probabilistic outcomes of cell-cycle re-entry remains unknown. Furthermore, how aging reshapes these decision pathways, and whether they can be therapeutically redirected remains a major gap in aging and disease. 

By elucidating how stressed cells choose between repair, quiescence, senescence, or death, and how these processes are altered by aging, this topic aims to establish a mechanistic foundation for precision therapeutics. Ultimately, these efforts will accelerate strategies to prevent or delay ARD and extend healthspan.

Participating ICOs

National Institute on Aging (NIA)

Research Areas of Interest may include, but are not limited to, the following:

  • Determining whether quiescence and senescence represent discrete cell fates or exist on a continuum of cell-cycle withdrawal, and whether these states are reversible or probabilistic.
  • Defining molecular factors that determine whether stressed cells undergo senescence versus apoptosis.
  • Identifying cell fate decisions that can be selectively promoted or redirected during aging and ARD, including potential consequences of manipulating these processes.
  • Investigating how aging and the hallmarks of aging influence cell fate determination.
  • Examining cell fate decisions in brain aging, including mechanisms in post-mitotic neurons and glial populations (astrocytes, microglia, oligodendrocytes, endothelial cells) and their roles in vulnerability and resilience.
  • Evaluating how senolytics affect quiescent and reprogramming cell populations, and whether these mechanisms differ from canonical elimination of senescent cells.
ICO Scientific Contact:
András Orosz Ph.D
[email protected]

Amanda Dibattista Ph.D.
[email protected]

Irina Sazonova Ph.D.
[email protected]

National Cancer Institute (NCI)

NCI supports projects to decipher molecular and cellular mechanisms governing ranges of cell state and individual or combined roles in cancer initiation, progression, therapy response, and tissue heterogeneity in primary and metastatic sites. Priorities include:

  • Define regulatory mechanisms of cell cycle exit/re-entry in quiescent, senescent, stem, progenitor and dormant tumor or stromal cells
  • Elucidate epigenetic/heterochromatic, chromatin architecture, genomic instability, transcriptional, metabolic, proteostatic and organelle dynamics-mediated cell state regulation
  • Characterize cell fate transitions and heterogeneity driven by quiescence, senescence, dormancy, stemness, and proliferative states, including senescence-associated secretory phenotype-mediated reprogramming of cells or microenvironments in tumor evolution, barrier functions and pre-metastatic niche formation
  • Define distinct or overlapping mechanisms of varied cell states of cancer or stromal cell death and related pathways
ICO Scientific Contact:
Cheryl Cero, Ph.D. (Cancer Cell Biology)
[email protected]

Ruibai Luo, Ph.D. (Cancer Cell Biology)
[email protected]

Tapan Bera, Ph.D. (Tumor Biology and Microenvironment)
[email protected]

Natalia Mercer, Ph.D. (Tumor Biology and Microenvironment)
[email protected]

Zhihui Liu, Ph.D. (DNA and Chromosome Aberrations)
[email protected]

Joanna Watson, Ph.D. (Tumor Metastasis)
[email protected]

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