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.
Cellular senescence is a process in which cells cease dividing and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes, and tumour-suppressor activation1–6. Hayflick and Moorhead first introduced the term senescence to describe the phenomenon of irreversible growth arrest of human diploid cell strains after extensive serial passaging in culture7. Later, this particular type of senescence (replicative senescence) was causally linked to telomere attrition, a process that leads to chromosomal instability and promotes tumorigenesis, supporting the original hypothesis that senescence guards against unrestricted growth of damaged cells7,8. Subsequent studies have reinforced the importance of cellular senescence as a safeguard against cancer9. Emerging evidence indicates that the physiological relevance of cellular senescence extends beyond tumour suppression into biological processes such as embryonic development10–12, wound healing13, tissue repair14 and organismal ageing15,16. In fact, Hayflick and Moorhead initially postulated a role for replicative senescence in ageing, but until recently this theory remained untested7. The multifunctional nature of cellular senescence raises the question as to whether fundamentally different senescence mechanisms underlie these diverse biological roles. This Review focuses on this and other key emerging concepts in the senescence field, including ‘assisted’ cell cycling, multi-step senescence (or senescence progression), acute versus chronic senescence and senescence of post-mitotic cells. How these concepts relate to the role of senescent cells in ageing and age-related diseases and how the rapidly accruing new information could be exploited to clear detrimental senescent cell populations selectively to improve healthy lifespan are also discussed.
Research on the causes (or stresses), signalling networks and mechanisms underlying the various types of cellular senescence is still in its infancy and current insights are largely based on cell culture experiments. In addition to telomere erosion, several other tumour-associated stresses have been shown to induce a senescent growth arrest in vitro, including certain DNA lesions and reactive oxygen species (ROS)17–19. What both these stresses have in common with telomere damage is that they activate the DNA damage response (DDR), a signalling pathway in which ATM or ATR kinases block cell-cycle progression through stabilization of p53 and transcriptional activation of the cyclin-dependent kinase (Cdk) inhibitor p21. Activated oncogenes are also prominent inducers of senescence. Oncogenic Ras acts through overexpression of Cdc6 and suppression of nucleotide metabolism, causing aberrant DNA replication, formation of double stranded DNA breaks (DSBs) and activation of the DDR pathway20,21. However, senescence caused by E2F3 activation or c-Myc inhibition is DDR-independent and involves p19Arf and p16Ink4a (refs 17, 22). BRAF(V600E) is also DDR-independent and induces senescence through a metabolic mechanism involving upregulation of mitochondrial pyruvate dehydrogenase (PDH; )23. Several other studies underscored that senescence is closely linked to profound metabolic changes24,25. Furthermore, various tumour suppressors trigger a senescent growth arrest when inactivated, including RB, PTEN, NF1 and VHL17,26. Of these, RB inactivation engages the DDR26, whereas the others are DDR-independent and act through p19Arf and p16Ink4a. A notable species-specific difference is that senescence pathways of murine cells are more dependent on p19Arf than senescence in human cells27.