Cellular senescence is a stable form of cell cycle arrest that limits the proliferative potential of cells. Senescence is triggered in many cell types in response to diverse forms of cellular stress. Activation of senescence in premalignant lesions acts as a potent barrier to tumourigenesis. In addition, senescence has been shown to contribute to the cytotoxicity of anti-cancer agents and to support tissue repair by limiting excessive proliferation of cells.
While short-term induction of cellular senescence can be beneficial in various settings, long-term retention of senescent cells appears to be deleterious to the organism. These cells commonly secrete pro-inflammatory factors that can facilitate their removal by the immune system in some settings.
However, if senescent cells are retained in tissues, these factors can promote local inflammation, tissue aging, tissue destruction and, potentially, tumourigenesis and metastasis in a cell non-autonomous manner. The elimination of senescent cells in a mouse model of premature aging was shown to reduce tissue aging.
Understanding how senescent cell viability is regulated at the molecular level could therefore point to pharmacological targets allowing specific elimination of senescent cells in vivo. Such elimination would allow the assessment of the functional importance of cellular senescence in different pathological conditions, and, potentially, lead to development of therapies.
Senescent cells have been reported to be resistant to extrinsic and intrinsic pro-apoptotic stimuli. While the mechanisms driving senescence are well studied, understanding of the mechanisms endowing these cells with increased survival capacity is limited.
The BCL-2 protein family plays a central role in cell death regulation by diverse mechanisms, including apoptosis and autophagy. This family includes the anti-apoptotic proteins BCL-2, BCL-W, BCL-XL, MCL-1 and A1, and is intensively studied as a target for pharmacological intervention in cancer.
Authors set out to evaluate the individual contributions of each of these BCL-2 family members and their combinations to the viability of senescent cells. They found that the increased presence of BCL-W and BCL-XL underlies senescent cell resistance to apoptosis, and that their combined inhibition by siRNAs or the small-molecule ABT-737 specifically leads to senescent cell death.
We show that a small-molecule inhibitor targeting the BCL-2, BCL-W and BCL-XL proteins (ABT-737) causes preferential apoptosis of senescent cells, both in vitro andin vivo, and eliminates these cells from tissues, opening the door for targeted elimination of senescent cells.
The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies.
Getting rid of senescent cells to prevent ageing
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