Trends in Cell Biology
ReviewHallmarks of Cellular Senescence
Section snippets
The Complexity of the Senescence Phenotype
The functional decline of an organism throughout its life affects multiple organs and is accompanied by the appearance of several diseases. This general decline of functional capabilities is known as aging (see Glossary) and is fairly conserved among species [1].
A main feature of aged organisms is the accumulation of cellular senescence [1], a state of permanent cell cycle arrest in response to different damaging stimuli [2] (Box 1). Excessive and aberrant accumulation of senescent cells in
DNA Damage Response
In the presence of DNA damage, cells activate a robust response, the DDR. Double-strand DNA breaks (DSBs) are powerful activators of DDR, and can lead to cellular senescence when unresolved. DSBs promote the recruitment and binding of ATM kinase to the DNA damage site 8, 9. This recruitment drives phosphorylation of the histone H2AX, which facilitates the assembly of specific DNA repair complexes (Figure 1) [10]. Histone methylation can also contribute to the assembly of damage response
Cell Size and Shape
A key feature of in vitro senescence is the enlarged and irregularly shaped cell body. Activation of the mTOR pathway is necessary for the enlargement of the cell body of senescent endothelial cells [68]. mTORC1 is known to integrate various stress signals and to modulate cell growth accordingly [112], and mTORC1 activation occurs in response to senescence-inducing stimuli [113]. In normal aging, the decline in growth factors, such as GDF11, might also contribute to the activation of mTORC1 and
Implications for Senescence Interventions
Among the various biological functions in which cellular senescence is involved, its role in diseases such as cancer and aging has made it an attractive therapeutic target. Strategies to interfere with senescent cells are mostly based on the markers listed above (Figure 3). Two main approaches are currently under development: (i) specific elimination of senescent cells; and (ii) inhibition of the SASP.
The first approach focuses on identifying compounds that can specifically induce senescent
Concluding Remarks
Since the discovery of senescent cells by Hayflick and Moorhead in 1961 [160], the scientific community has struggled to identify universal and unequivocal markers characterizing the senescence state. The difficulty in identifying such markers reflects the complexity of the senescence phenotype and the existence of highly heterogeneous senescence programs (see Outstanding Questions). Currently, the only possibility resides in combining the measurement of multiple hallmarks in the same sample [3]
Glossary
- Aging
- functional decline or an organism throughout life [1].
- Alternative splicing
- process that allows a gene to encode different mRNA products by differentially using exons and excluding introns in a primary transcript to give rise to different processed mRNAs.
- Apoptosis
- normal physiological form of cell death [82].
- Autophagy
- intracellular degradation system. It can degrade nonspecific (general autophagy) or specific (selective autophagy) targets [149].
- Caveolae
- cholesterol-enriched microdomains of the
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