Ccna2 as a Novel Regulator of Cellular Senescence

Given the present wave of investment into the treatment of aging, in both the business and research communities, and given the significant valuations put on the first companies working on senolytic drugs to clear senescent cells, it should come as no surprise to see a land rush underway in the investigation of the biochemistry of cellular senescence. The state of funding for any specific field of research is to a sizable degree steered by what is going on in the world of startups and venture capital. When finding a new mechanism is a potential ticket to valuable intellectual property, a startup company, and production of clinical therapies, then there will be more funding available for researchers involved in the search for mechanisms, and more researchers joining in.

Senescent cells are clearly significant in all aspects of aging, and removing them is proving, in mice at least, to produce robust reversal of aging and age-related disease. Senescent cells, while small in number even in old individuals, produce a potent mix of signals known as the senescence-associated secretory phenotype, or SASP. This SASP generates chronic inflammation, changes the behavior of normal cells for the worse, destructively remodels the extracellular matrix, and more. In some ways it might be considered an actively maintained aspect of aging. Removing senescent cells removes this signaling, and restores tissue function as a result. Other researchers are interested in modulating or suppressing the SASP, but I have to think that this is a much more challenging proposition, given the complexity of SASP signaling.

The open access paper here is an illustrative example of the sort of detailed investigation of the mechanisms of cellular senescence that is taking place today. Some will give rise to efforts to develop new therapies to destroy, prevent, or alter the behavior of senescent cells. This sort of work is spreading and well funded to a degree that would have been unimaginable prior to the noted 2011 demonstration of the relevance of senescent cells to aging. All of this is driven by success in showing that removal of senescent cells reverses aging and age-related disease, and by the significant investment in clinical development that followed.

The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway

It is demonstrated that the presence and progressive accumulation of senescent cells contribute to overall organism aging; senescent cells aggregate in aging tissues have been considered as a causal factor for aging-related disorders. Senescent cells are characterized as irreversible growth arrest, increased senescence-associated β-galactosidase activity, and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes. Research over last three decades has uncovered a variety of signaling pathways that are involved in the regulation of cellular senescence and determine the lifespan in a manner conserved across species, including insulin growth factor 1 (IGF-1) signaling (IIS), rapamycin (mTOR) signaling, and the sirtuin family. Additionally, p53 activation exerts critical roles in modulating cellular senescence and organismal aging. Senescence-induction stressors including DNA lesions, telomere shortening, oxidative stress, and oncogene activation, initially halt cell cycle progression through p53-mediated induction of p21 and finally trigger cellular senescence.

MicroRNAs (miRNAs) are conserved tiny noncoding RNAs generated from endogenous hairpin-shaped precursors, which have emerged as novel and fundamental actors in gene regulation. These small RNA molecules can direct bind to specific sites presented in target messenger RNA (mRNA). As the recognition of target mRNAs mainly depends on the seed region of the mature miRNA, one single miRNA might regulate hundreds of target mRNAs; meanwhile, distinct miRNAs might co-regulated the same mRNA, thus orchestrating a large variety of physiological and cellular processes. Recently, a growing body of evidence has suggested the potential role of miRNAs in modulating the aging process and cellular senescence. In this work, we evaluated the miRNA and mRNA profile in the physiological aging 20-month-old mouse model by high-throughput analysis.

The data showed that various p53 responsive miRNAs, including miR-124, miR-34a and miR-29a/b/c, were up-regulated in the aging mouse compared to the young mouse. Further investigation unraveled that, similarly to miR-34a and miR-29, miR-124 significantly promoted cellular senescence. As expected, mRNA microarray and gene co-expression network analysis unveiled that the most down-regulated mRNAs were enriched in the regulatory pathways of cell proliferation. Fascinatingly, among these down-regulated mRNAs, Ccna2 stood out as a common target of several p53 responsive miRNAs (miR-124 and miR-29), which functioned as the antagonist of p21 in cell cycle regulation.

Silencing of Ccna2 remarkably triggered the cellular senescence, while Ccna2 overexpression delayed cellular senescence and significantly reversed the senescence-induction effect of miR-124 and miR-29. Moreover, these p53 responsive miRNAs were significantly up-regulated during the senescence process of p21-deficient cells; overexpression of p53 responsive miRNAs or knockdown of Ccna2 evidently accelerated the cellular senescence in the absence of p21. Taken together, our data suggested that the p53/miRNAs/Ccna2 pathway might serve as a novel senescence modulator independent of p53/p21 pathway.

Comments

Very interesting. Now jokingly we can explain why women love on average longer than men. They take better care of their skin... And apparently, our natural aversion to bad skin has more basis...

Posted by: Cuberat at March 16th, 2019 10:12 PM

My idea for targets is instead of trying to directly trigger the senescent cells to kill themselves, if we could upregulate the systems in the body that trigger that process. Its part of my belief that small molecule drugs are still the way forward for anti-aging for the foreseeable future.

Its like stem cells. Trying to reproduce stem cells, inject a bunch of stem cells into a person and hope the stem cells somehow take root seems a long shot. In comparison upregulating whatever hormones there are that tell stem cells to go into action seems a lot easier. And I think this easier path will be able to be done with small molecule drugs.

The systems in the body work on feedback mechanisms to regulate things. So often to upregulate something, you inhibit the aspect of the system that is the feedback brake. You see the way the body regulates things is not always what we want.

Posted by: aa3 at March 17th, 2019 6:56 AM

@Cuberat: Was this "...women love longer than men" intended or a Freudian slip? It reminds me of Madeline Kahn's lyric in the song "Sick and Tired of Love" in Blazing Saddles "I've been with thousands of men, again and again, the promise the moon. They're always coming and going, and going and cumming, and always too soon."

I think you meant "live" not "love" ;)

Posted by: Tom Schaefer at March 18th, 2019 9:10 AM

@Tom Schaefer

Good catch.

Posted by: Cuberat at March 18th, 2019 9:23 AM

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