Mechanisms and Regulation of Cellular Senescence

Abstract

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.

Keywords: DNA damage signaling; aging; cell cycle arrest; cellular senescence; epigenetic and chromatin changes; metabolism alteration; mitochondrial dysfunction; senescence-associated secretory phenotype; transcriptome signature.

Figure 1

Schematic diagram of cell cycle arrest in senescent cells. In replicative senescence that results from chronic low-level macromolecular damage, cells mainly stop in the G2 phase of the cell cycle because post-replicative telomere attrition preferentially triggers the DNA damage response (DDR) at the G2/M transition. Upon damage resolution, through repair or proper post-replicative processing, checkpoint recovery allows a subset of these cells to pass through mitosis. However, at the next G1 phase, the daughter cells irreversibly exit the cell cycle in a diploid (2N DNA content) state after mitosis if new DNA breaks are generated. Conversely, a prolonged DNA damage signal emanating from severe DNA lesions leads to exit in the G2 phase, APC/C CDH1 is prematurely activated as a consequence of p21 accumulation, and these cells by-pass mitosis resulting in tetraploidy (4N DNA content) and permanent G1 arrest. CycB1, cyclin B1; APC/C, anaphase-promoting complex/cyclosome.

Figure 2

Summary of the most common senescence inducers and alterations observed at initiation, developing, and late senescence. CCFs, cytoplasmic chromatin fragments; cGAS-STING, cyclic GMP–AMP synthase-stimulator of interferon genes; DDR, DNA damage response; ROS, reactive oxygen species; SA-βGal, senescence-associated β galactosidase; SASP, senescence-associated secretory phenotype.

Figure 3

Overview of the mechanisms by which DNA damage promotes senescence. DNA damage (through telomere dysfunction and replicative stress) can result in cellular senescence, mitochondrial dysfunction, autophagy defects, and metabolic changes. These functional alterations are all interconnected and generate positive feedback signals that induce more DNA damage. This creates a cycle that contributes to stabilize the senescence-related cell cycle exit. AMPK, adenosine monophosphate-activated protein kinase; ETC, electron transport chain; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype.

Figure 4

SASP signaling controls the beneficial and detrimental functions of senescent cells. Senescent cells through their secretome are actively engaged in cell-to-cell communications and extracellular matrix remodeling within the tissue microenvironment. The scheme depicts how senescent cells communicate via soluble factors, the release of extracellular vesicles (exosomes), cell–cell contacts, formation of cytoplasmic bridges, interactions with the extracellular matrix, and secretion of metabolites. It also lists some of the SASP-associated functions. A transient SASP is beneficial, while a chronic SASP causes negative outcomes. NK cells, natural killer cells; SASP, senescence-associated secretory phenotype.