In Search of More Ways to Destroy Senescent Cells by Unleashing p53

Based on animal data, the growing burden of senescent cells with age appears to provide a significant contribution to age-related degeneration. Cells become senescent in response to tissue injury, significant cellular damage, signaling from other senescent cells, or reaching the Hayflick limit on replication. In youth, senescent cells are efficiently cleared, either destroying themselves via programmed cell death, or being destroyed by the immune system. In later life, clearance slows, and as a result there are ever more lingering senescent cells delivering signals that disrupt tissue structure and function and provoking chronic inflammation. Removing these cells via senolytic therapies has been shown to produce rapid reversal of many age-related pathologies in mice, and thus the research community is actively engaged in finding more ways to selectively provoke programmed cell death in senescent cells, to add to those already discovered.

Super-enhancers regulate genes with important functions in processes that are cell type-specific or define cell identity. Mouse embryonic fibroblasts establish 40 senescence-associated super-enhancers regardless of how they become senescent, with 50 activated genes located in the vicinity of these enhancers. Here we show, through gene knockdown and analysis of three core biological properties of senescent cells that a relatively large number of senescence-associated super-enhancer-regulated genes promote survival of senescent mouse embryonic fibroblasts.

Of these, Mdm2, Rnase4, and Ang act by suppressing p53-mediated apoptosis through various mechanisms that are also engaged in response to DNA damage. MDM2 and RNASE4 transcription is also elevated in human senescent fibroblasts to restrain p53 and promote survival. These findings further support the idea that senescent cells actively combat apoptosis on multiple fronts and therefore have numerous therapeutically exploitable vulnerabilities for elimination of detrimental senescent cells implicated in aging and aging-related diseases. These insights provide molecular entry points for the development of targeted therapeutics that eliminate senescent cells at sites of pathology.



Now that AdG is out of SRF he should write an updated version of Ending Aging that includes all updates within 7 various fields.

Posted by: ciclo at July 7th, 2022 6:05 AM
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