Physiological impact of cell senescence in vivo: Limiting Tissue Damage

In addition to their tumor suppression function, senescent cells also play a beneficial role in non-cancer pathology by limiting tissue fibrosis.   For instance, tissue damage within the liver stimulates the activation of hepatic stellate cells (HSCs), which hyper- proliferate and secrete extracellular matrix components to form a fibrotic scar.  Hyper- proliferation of HSCs induces cell senescence leading to a reduction in the secretion of ECM proteins and enhanced secretion of ECM degrading proteins, thereby limiting fibrosis.  Senescent HSCs are then eliminated in a timely manner by immune cells such as natural killer (NK) cells.  When the mechanisms leading to NK cell mediated elimination are disabled, fibrosis is increased.  In mice lacking molecular components required for induction of cell senescence, HSCs continue to proliferate, depositing ECM components and elevating the fibrotic response.  Therefore, induction of senescence in HSCs prevents short-term tissue damage by limiting fibrosis.  In addition to the liver, a similar process occurs during tissue repair within the pancreas by senescent pancreatic stellate cells.   In this instance, it was suggested that lymphocytes at the sites of wounds might play a duel-specific role in pancreatic fibrogenesis by triggering both the initiation of wound healing by activating stellate cells and its completion by clearance of senescent stellate cells.

Cell senescence also limits tissue damage at sites of cutaneous wound healing, where secretion of CCN1 induces fibroblast senescence associated with an elevation in the DNA damage response and the activation of p53 and RAC1-NOX1 complex.  The expression of anti-fibrotic genes by CCN1-induced senescent cells prevented excess fibrosis, whereas mice that express a senescence-defective Ccn1 mutant resulted in elevated fibrosis.    CCN1 also appears to play a role in the regression of liver fibrosis through induction of cell senescence in HSCs.  Therefore, cell senescence is a mechanism that limits tissue damage in multiple tissues and serves not only to restrain the damage, but also to initiate the repair and return the tissue to the pre-damaged state.

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The main focus of ageing research is to prevent/combat age-related disease and disability, allowing everyone to live healthier lives for longer.