Researchers here argue that cells that become senescent because errors in DNA replication produced entire extra duplicate chromosomes, a state known as polyploidy, are meaningfully different than cells that become senescent due to other forms of damage or stress. The researchers also point out that present studies do not adequately differentiate between polyploid senescent cells and those with normal chromosomes, suggesting that more work is needed here. In general, the research community is motivated to better understand the biochemistry of senescence in order to improve efforts to either selectively destroy senescent cells or alter their behavior to reduce the harmful pro-inflammatory signaling that they produce. Studies in animals suggest that therapies to control the burden of cellular senescence could produce meaningful degrees of rejuvenation in humans, but it is taking longer than expected to translate that research into the clinic.
One understudied form of cellular senescence is polyploidy-induced senescence (PIS) which was initially observed in vitro after drug-induced tetraploidization. We recently reported that polyploid uroepithelial cells in the mouse bladder are senescent over the lifespan, raising new questions about the physiological and pathological significance of polyploid, senescent cells. These senescent uroepithelial barrier cells persisted after treatment of mice with the senolytic combination dasatinib plus quercetin (D+Q). We now hypothesize that some bladder cancers, 90% of which are of urothelial origin, may arise from polyploid umbrella cells that, through loss of senescence enforcers and tumor suppressors such as p16, escaped PIS.
The idea that cancers can arise from cells escaping senescence is well established, but our observations link this specifically to polyploidization. This has important implications in the context of therapy-induced senescence (TIS). Many cancer treatments trigger senescence through replication stress and polyploidization. By contrast, naturally occurring polyploid senescent cells, such as bladder umbrella cells, appear to serve important biological functions - though they too may destabilize under chronic stress.
Not all polyploid cells are senescent, and their relationship is context dependent. Hepatocytes, for example, can be both polyploid and senescent, but polyploid hepatocytes also undergo senescence reversal and ploidy reduction divisions under stress, re-entering the cell cycle and contributing to carcinogenesis. We propose that PIS acts as a developmental timer: replication stress from endoreplication activates the DNA damage response, linking proliferation to differentiation during development, regeneration and repair. In this model, senescence is not merely a stress response but a programmed cellular fate that enforces terminal differentiation, contributes to organ structure, and preserves tissue architecture.
Link: https://doi.org/10.18632/aging.206355
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