The role of senescent cells in ageing

Abstract

Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biological processes such as development, tissue repair, ageing and age-related disorders. New insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. A deeper understanding of the molecular mechanisms underlying the multi-step progression of senescence and the development and function of acute versus chronic senescent cells may lead to new therapeutic strategies for age-related pathologies and extend healthy lifespan.

Figures

Figure 1. Senescence-inducing stimuli and main effector pathways

A variety of cell-intrinsic and -extrinsic stresses can activate the cellular senescence program. These stressors engage various cellular signalling cascades but ultimately activate p53, p16Ink4a, or both. Stress types that activate p53 through DDR signalling are indicated with grey text and arrows (ROS elicit the DDR by perturbing gene transcription and DNA replication, as well as by shortening telomeres). Activated p53 induces p21, which induces a temporal cell-cycle arrest by inhibiting cyclin E–Cdk2. p16Ink4a also inhibits cell-cycle progression but does so by targeting cyclin D–Cdk4 and cyclin D–Cdk6 complexes. Both p21 and p16Ink4a act by preventing the inactivation of Rb, thus resulting in continued repression of E2F target genes required for S-phase onset. Upon severe stress (red arrows), temporally arrested cells transition into a senescent growth arrest through a mechanism that is currently incompletely understood. Cells exposed to mild damage that can be successfully repaired may resume normal cell-cycle progression. On the other hand, cells exposed to moderate stress that is chronic in nature or that leaves permanent damage may resume proliferation through reliance on stress support pathways (green arrows). This phenomenon (termed assisted cycling) is enabled by p53-mediated activation of p21. Thus, the p53–p21 pathway can either antagonize or synergize with p16Ink4a in senescence depending on the type and level of stress. BRAF(V600E) is unusual in that it establishes senescence through a metabolic effector pathway. BRAF(V600E) activates PDH by inducing PDP2 and inhibiting PDK1 expression, promoting a shift from glycolysis to oxidative phosphorylation that creates senescence-inducing redox stress. Cells undergoing senescence induce an inflammatory transcriptome regardless of the senescence inducing stress (coloured dots represent various SASP factors). Red and green connectors indicate ‘senescence-promoting’ and ‘senescence-preventing’ activities, respectively, and their thickness represents their relative importance. The dashed green connector denotes a ‘senescence-reversing’ mechanism.

Figure 2. Hypothetical multi-step senescence model

Mounting evidence suggests that cellular senescence is a dynamic process driven by epigenetic and genetic changes. The initial step represents the progression from a transient to a stable cell-cycle arrest through sustained activation of the p16Ink4a and/or p53–p21 pathways. The resulting early senescent cells progress to full senescence by downregulating lamin B1, thereby triggering extensive chromatin remodelling underlying the production of a SASP. Certain components of the SASP are highly conserved (grey dots), whereas others may vary depending on cell type, nature of the senescence-inducing stressor, or cell-to-cell variability in chromatin remodelling (red and green dots). Progression to deep or late senescence may be driven by additional genetic and epigenetic changes, including chromatin budding, histone proteolysis and retrotransposition, driving further transcriptional change and SASP heterogeneity (yellow, magenta, pink and blue dots). It should be emphasized that although the exact nature, number and order of the genetic and epigenetic steps occurring during senescent cell evolution are unclear, it is reasonable to assume that the entire process is prone to SASP heterogeneity. The efficiency with which immune cells (yellow) dispose of senescent cells may be dependent on the composition of the SASP. Interestingly, the proinflammatory signature of the SASP can fade due to expression of particular microRNAs late into the senescence program, thereby perhaps allowing evasion of immuno-clearance.

Figure 3. Acute and chronic senescent cells

The conceptual model in which senescent cells are subdivided into two main classes based on kinetics of senescence induction and functionality. Acute senescent cells seem to mostly be part of tightly orchestrated biological processes (that is, wound healing, tissue repair, embryonic development) to halt expansion of certain cells and/or produce a SASP with defined paracrine functions. Acute senescence is induced through cell-extrinsic stimuli that target a specific population of cells in the tissue. Acute senescent cells self-organize their elimination through SASP components that attract various types of immune cells. Induction of chronic senescence occurs after periods of progressive cellular stress or macromolecular damage when tarry cycling transitions into a stable cell-cycle arrest. Chronic senescence is not programmed and does not seem to target specific cell types. Conceivably, owing to age-related immunodeficiency or production of less proinflammatory SASPs, immune cells may inefficiently eliminate chronic senescent cells, allowing continuation of multi-step senescence. Senescence induced during cancer therapy may initially be acute and later chronic in nature.

Figure 4. Mechanisms of tissue and organ deterioration by cellular senescence

Cellular senescence is thought to contribute to age-related tissue and organ dysfunction and various chronic age-related diseases through various mechanisms. In a cell-autonomous manner, senescence acts to deplete the various pools of cycling cells in an organism, including stem and progenitor cells. In this way, senescence interferes with tissue homeostasis and regeneration, and lays the groundwork for its cell-non-autonomous detrimental actions involving the SASP. There are at least five distinct paracrine mechanisms by which senescent cells could promote tissue dysfunction, including perturbation of the stem cell niche (causing stem cell dysfunction), disruption of extracellular matrix, induction of aberrant cell differentiation (both creating abnormal tissue architecture), stimulation of sterile tissue inflammation, and induction of senescence in neighbouring cells (paracrine senescence). An emerging yet untested concept is that post-mitotic, terminally differentiated cells that develop key properties of senescent cells might contribute to ageing and age-related disease through the same set of paracrine mechanisms.