A Less Well Explored Cdkn1a Transcript is a Marker of Aging and Cellular Senescence

The gene Cdkn1a (or P21) generates two different RNA transcripts that both lead to the production of the same protein. Researchers here provide evidence to suggest that the less well explored second transcript is a good marker of aging and cellular senescence, at least in mice. The biochemistry of senescence seems to be well conserved across species, so with luck the same data will be replicated in humans in the near future. Better and less invasive approaches to robustly assess senescent cell burden, improvements on the the current standard of tissue samples and immunohistochemistry, are very much needed. A well-validated blood test, for example, would be a step forward in terms of speeding up the development of senolytic therapies to clear senescent cells.

Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16Ink4a and p21Cip1/Waf1. In mice, the p21Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues.

Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.

Link: https://doi.org/10.18632/aging.203110

Comments

"A well-validated blood test, for example, would be a step forward in terms of speeding up the development of senolytic therapies to clear senescent cells. "

It would be great if you could write an update on where these therapies are in research and development - a state-of-the-union kind of post like that one was. You've been referencing the 2017 post a few times, but it's now 4 years later. Any real progress to tout? I've begun to follow this space, and it seems like progress is remarkably slow. Maybe it is expected because study results take years just by their nature, but it can be frustrating to follow.

Posted by: Bob at June 9th, 2021 7:17 AM

I hope OISIN is taking notes as a potential target here

Posted by: Cuberat at June 9th, 2021 6:09 PM

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