Thursday 1 March 2018

Hallmarks of Cellular Senescence

https://www.sciencedirect.com/science/article/pii/S0962892418300205

Alejandra Hernandez-Segura, Jamil Nehme, Marco Demaria

A senescent cell is one which permanently stops dividing. In vitro, this can be caused by various stimuli, although it is unclear which amongst these cause senescence in vivo. The accumulation of senescent cells is observed through ageing, and a growing body of evidence is pointing towards the removal of senescent cells as a strategy to combat ageing.

Types of senescence currently known:

- DNA damage-induced senescence. This can be induced in vitro through radiation or drugs
- Oncogene-induced senescence. Activation of oncogenes (e.g. Ras or BRAF) or inactivation of tumour suppressors (e.g. PTEN) can induce senescence
- Chemotherapy-induced senescence. Drugs such as bleomycin or doxorubicin induce DNA damage. Drugs such as abemaciclib and palbociclib can inhibit cyclin-dependent kinases which regulate the cell cycle
- Mitochondrial dysfunction-associated senescence. The so-called "senescence associated secretory phenotype" (SASP) appears to be characteristic of this kind of senescence
- Epigenetically induced senescence. Inhibitors of DNA methylases or histone deacetylases can cause senescence
- Paracrine senescence. Senescence can be induced via the SASP produced by primary senescent cells

The senescence phenotype is often characterised by:

- Activation of a chronic DNA damage response
- Engagement of various cyclin-dependent kinase inhibitors
- SASP (which comprises, in part, various proinflamatory and tissue-remodelling factors)
- Induction of anti-apoptotic genes
- Altered metabolic rates
- Endoplasmic reticulum stress
- Consequent to the above, senescent cells are: enlarged and more flattened; have altered plasma membrane composition; accumulate lysosomes and mitochondria.

Current methods which are used to detect senescent cells include:

- DNA damage response: Immunostaining for γ-H2AX, p53
- Cell cycle arrest: Measurement of colony-formation potential or DNA synthesis rate via BrdU/EdU-incorporation. Expression level of the cyclin-dependent kinase inhibitors p16 and p21.
- Secretory phenotype: Cytokines (IL-1a, IL-6 and IL-8) , chemokines (CCL2) and metalloproteinases (MMP-1, MMP-3). However, the SASP is heterogeneous.
- Apoptosis resistance: Upregulation of BCL-proteins, BCL-2, Bcl-w or Bcl-xL.
- Cell size: Enlarged cell body and irregular shape using bright-field microscopy. Immunofluorescence targetting vimentin, actin or other cytoplasmic proteins have been used.
- Increased lysosomal content: e.g. SA-βgal, SSB, GL13, LysoTrackers, orange acridine
- Accumulation of mitochondria: MitoTrackers

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