Quiescence-Origin Senescence: A New Paradigm in Cellular Aging

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.

Keywords: Rb–E2F switch threshold; dormancy state continuum; geroconversion; quiescence; quiescence deepening; senescence.

Figure 1

Quiescence-origin senescence. Conventional senescence originates from proliferating and growing cells via mTOR-mediated geroconversion, when cell growth continues aberrantly after the cell cycle is blocked in response to severe stress and damage. In comparison, quiescence-origin senescence originates from quiescent cells via quiescence deepening, accompanied by a progressively increasing Rb–E2F switch threshold in response to decreased lysosomal autophagy and increased ROS accumulation and protein aggregation. Senescent cells are irreversibly arrested under physiological conditions. Deep quiescent cells are reversible but require stronger growth stimulation and take a longer time to re-enter the cell cycle than shallow quiescent cells. The boundary between very deep quiescence and quiescence-origin senescence (the red dashed line) is blurred.