Abstract
Cellular senescence, traditionally viewed as a consequence of proliferating and growing cells overwhelmed by extensive stresses and damage, has long been recognized as a critical cellular aging mechanism. Recent research, however, has revealed a novel pathway termed “quiescence-origin senescence”, where cells directly transition into senescence from the quiescent state, bypassing cell proliferation and growth. This opinion paper presents a framework conceptualizing a continuum between quiescence and senescence with quiescence deepening as a precursor to senescence entry. We explore the triggers and controllers of this process and discuss its biological implications. Given that the majority of cells in the human body are dormant rather than proliferative, understanding quiescence-origin senescence has significant implications for tissue homeostasis, aging, cancer, and various disease processes. The new paradigm in exploring this previously overlooked senescent cell population may reshape our intervention strategies for age-related diseases and tissue regeneration.
1. Introduction
Cellular senescence, a state of permanent cell cycle arrest, has been a focal point of biomedical research for decades [1]. It is typically triggered when growing cells are overwhelmed by extensive stresses and damage, such as telomere erosion, oncogene activation, oxidative stress, and DNA damage, to a degree beyond their repair capacity [2,3]. Cells enter senescence and permanently halt proliferation to avoid deleterious consequences like malignant tumorigenesis and fibrotic response [4,5]. The hallmarks of senescent cells include permanent cell cycle arrest, senescence-associated secretory phenotype (SASP), macromolecular damage, deregulated metabolism [6], and often enlarged cell size and other morphological changes [2,7]. This conventional view has shaped our understanding of senescence primarily as an extreme stress response in proliferating and growing cells.
In contrast, cellular quiescence is a reversible state of cell cycle arrest. Under physiological growth-limiting conditions, such as mitogen withdrawal or contact inhibition, cells exit the cell cycle and enter quiescence [8]. Quiescent cells are typically associated with low metabolic activity and reduced cell size and do not exhibit obvious deleterious phenotypes associated with senescence, such as SASP and severe damage [8,9]. Upon restoration of growth-permissive conditions (e.g., reintroducing growth factors or alleviating contact inhibition), quiescent cells can resume proliferation, which is a key distinction from senescent cells [8,9]. Quiescence is considered a physiological state that allows cells to maintain cellular viability and integrity under growth-limiting conditions, playing a crucial role in tissue homeostasis and stem cell maintenance [9,10]. This mechanism is proposed to safeguard cells from senescence [11,12].
Recent research in the past decade, however, has begun to challenge this traditional paradigm by demonstrating that senescence can originate directly from quiescent cells in various contexts [13,14,15,16]. This phenomenon, which we term “quiescence-origin senescence”, suggests a fluid continuum between quiescence and senescence with profound implications for tissue homeostasis, aging, and disease processes. Notably, proliferating cells account for less than 1% of the thirty-seven trillion cells in the human body at any given time [17], suggesting that quiescence-origin senescence may underlie a large proportion of previously overlooked or misclassified senescent cells.
This brief review synthesizes recent findings to provide a new framework for understanding senescence from the perspective of cell dormancy–state plasticity, aiming to stimulate further related research into novel intervention strategies for age-related diseases, cancer, and regenerative medicine.