Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Jan 15;28(2):99-114.
doi: 10.1101/gad.235184.113.

Cellular senescence and its effector programs

Rafik Salama  1 , Mahito Sadaie, Matthew Hoare, Masashi Narita
Affiliations
Review

Cellular senescence and its effector programs

Rafik Salama et al. Genes Dev. .

Abstract

Cellular senescence is a stress response that accompanies stable exit from the cell cycle. Classically, senescence, particularly in human cells, involves the p53 and p16/Rb pathways, and often both of these tumor suppressor pathways need to be abrogated to bypass senescence. In parallel, a number of effector mechanisms of senescence have been identified and characterized. These studies suggest that senescence is a collective phenotype of these multiple effectors, and their intensity and combination can be different depending on triggers and cell types, conferring a complex and diverse nature to senescence. Series of studies on senescence-associated secretory phenotype (SASP) in particular have revealed various layers of functionality of senescent cells in vivo. Here we discuss some key features of senescence effectors and attempt to functionally link them when it is possible.

Keywords: DNA damage; aging; inflammation; metabolism; oncogenes; senescence; tumor suppressors.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Schematic model of senescence and its biological functions. Representative intrinsic effectors of senescence and their relationship are shown on the left. Spatial and functional associations between mTOR (mT) and autophagy (AP) augment each other and facilitate SASP. The SASP provokes ER stress and, as a countermeasure, autophagy. SAHFs might contribute to maintenance of constitutively active gene expression, such as SASP components. SAHFs also restrain DNA damage. Persistent DDR (pDDR) positively regulates many SASP components, whereas p53 negatively regulates or modulates the SASP. Representative impacts of the SASP are shown on the right. The SASP reinforces senescence through autocrine activities. The SASP can be amplified through positive feedback loops between proinflammatory cytokines and the transcription factors (NF-kB and C/EBPβ). Targets of paracrine activities of the SASP include the extracellular matrix (ECM), tumor cells (protumorigenic), normal cells (prosenescent), and immune cells. Senescent cells can be eliminated through the immune cells. It is also conceivable that the SASP causes systemic effects on individual fitness, facilitating aging.
Figure 2.
Figure 2.
Metabolic pathways involved in senescence—a collective view of recent studies. Recent studies suggest that mitochondrial metabolism is highly active during OIS and TIS. In addition to the TCA cycle, TIS was also associated with enhanced glycolysis and fatty acid catabolism (Dörr et al. 2013). It was proposed that enhanced ATP production facilitates energy-consuming effectors, such as SASP and autophagy. Production of the SASP evokes ER stress, which is mitigated by autophagy. We showed that spatial coupling of autolysosomes and mTOR (TASCC) facilitates IL6/8 synthesis in OIS cells. We hypothesize that the rapid protein turnover drives nascent synthesis of secretory proteins, but the precise mechanism for the functional relationship between the TASCC and SASP remains to be elucidated (Narita et al. 2011). ME1 and ME2 have been shown to be p53-repressive targets, and their down-regulation activates p53, triggering and/or reinforcing senescence. MEs are important for the production of NADPH, a reducing agent, which is also necessary for biomass synthesis. Some metabolites derived from the TCA cycle or shift in their balance may also have cellular effects. This is a collective interpretation of data from multiple studies; thus, components do not necessarily link to each other in the same context. For example, the significance of the reciprocal regulation of MEs and p53 is unclear in OIS conditions, and the mechanism for PDH activation appears to be different depending on oncogenes. Note that earlier studies suggest that senescent cells are associated with dysfunctional mitochondria (Moiseeva et al. 2009). In all cases, ROS production appears to be increased.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, et al. 2008. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133: 1006–1018 - PubMed
    1. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang T-W, Lasitschka F, Andrulis M, et al. 2013. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15: 978–990 - PMC - PubMed
    1. Adams PD 2007. Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging. Gene 397: 84–93 - PMC - PubMed
    1. Agger K, Cloos PAC, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K 2009. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev 23: 1171–1176 - PMC - PubMed
    1. Alimonti A, Nardella C, Chen Z, Clohessy JG, Carracedo A, Trotman LC, Cheng K, Varmeh S, Kozma SC, Thomas G, et al. 2010. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest 120: 681–693 - PMC - PubMed

Publication types