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.