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The phenomenon in which cells are still metabolically active but can no longer proliferate is known as cellular senescence. Cellular senescence is a normal mechanism in development and tissue homeostasis—and a hallmark of aging.
“Most of my lab works on a process called cellular senescence, which is a cellular response to stresses and damage, many of which increase with age,” Dr. Judy Campisi, Professor at the Buck Institute for Research on Aging and Senior Scientist at the Lawrence Berkeley National Lab, said in a recent Aging interview.
An international team of researchers from Dr. Campisi’s lab are in search of new biological markers of cellular senescence and aging. Understanding mechanisms of aging such as senescence is key for developing new, safe interventions that may extend human life—with compounding socioeconomic and cultural impacts. Researchers from this lab come from institutions including the Buck Institute, the University of California, Berkeley’s Lawrence Berkeley National Lab, Universidad de Córdoba, Universidad Mayor, Geroscience Center for Brain Health and Metabolism, and Unity Biotechnology. The team published a trending 2021 paper in Aging‘s Volume 13, Issue 10, entitled, “Cdkn1a transcript variant 2 is a marker of aging and cellular senescence.”
“Our results are, to our knowledge, the first to study Ckdn1a transcript variants in the context of aging.”
The Study
There are a number of mechanisms that seem to drive cellular senescence. Previously, mRNA and protein coding gene Cdkn1a transcript variant 1 (p21var1) has been better-studied compared to Cdkn1a transcript variant 2 (p21var2). The authors of this paper explain that this is likely because the encoded protein is identical to that encoded by variant 1, and both variants are regulated by p53. However, neither variants have ever before been studied in the context of aging. In this study, the researchers explored the expression levels of both Cdkn1a transcript variants 1 and 2 in the context of cellular senescence using several tissues from aged mice and a cell culture model of mouse cells.
“The stringent cell growth arrest associated with cellular senescence is determined, among other mechanisms, by activities of cyclin-dependent kinase inhibitor proteins p16Ink4a and p21Cip1/Waf1, encoded by the Cdkn2a and Cdkn1a loci, respectively [1].”
Results
Study results demonstrated that during cellular senescence, both variants are induced. They showed that p21var1 and p21var2 are equally sensitive to transcriptional upregulation via p53 stabilization. The in vitro models found that p21var2, not p21var1, is preferentially induced with age.
“In sum, p21var2 expression is consistently elevated with age, in contrast with an absence of age-related change in p21var1 levels.”
The researchers conducted further tests in vivo to examine the expression pattern of these variants and their results suggested that the circadian regulation of p21Cip1/Waf1 is driven solely by expression of p21var1. The team also induced cellular senescence in vivo with doxorubicin and ABT-263 (navitoclax) and evaluated the expression of both variants. These results confirmed their in vitro findings that p21var2 is more prone to cellular senescence than p21var1, thus making it a better marker for assessing the presence of senescent cells in vivo.
Conclusion
In conclusion, the team’s study showed that p21var2 (not p21var1) is a better candidate marker of aging and senescence in mice. The authors note that tissue-specific exceptions may arise.
“We looked at these two mRNAs separately and found that one of them, which is called the variant 2, is a better marker of senescence and aging than the other mRNA,” Dr. Judy Campisi said.
Click here to read the full research paper, published by Aging.
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