Tag: Cellular Senescence

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Trending With Impact: A New Marker of Aging and Cellular Senescence

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Researchers from the Campisi Lab discovered new insights while investigating Cdkn1a transcript variants 1 and 2.

Embryonic stem cell colony

The Trending with Impact series highlights Aging publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.

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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 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].”

Study results showed that both variants are induced during cellular senescence. They showed that p21var1 and p21var2 are equally sensitive to transcriptional upregulation after p53 stabilization. The in vitro models also found that p21var2 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 p21var2 and their results suggested that the circadian regulation of p21Cip1/Waf1 is driven solely by expression of Cdkn1a transcript variant 1. The team also induced cellular senescence in vivo with doxorubicin and ABT-263 (navitoclax) and evaluated the variants’ expression. 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

“We show that, although tissue-specific exceptions may arise, p21var2 but not p21var1 is a better candidate marker of aging and senescence in mice.”

Click here to read the full research paper, published by Aging.

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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2021 Ride for Roswell
2021 Ride for Roswell
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Behind the Study: Cdkn1a Transcript and Aging

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Dr. Judith Campisi discusses her priority research paper published in 2021 by Aging, entitled, “Cdkn1a transcript variant 2 is a marker of aging and cellular senescence.”

Researchers explain their studies that were published in Aging

Behind the Study is a series of transcribed videos from researchers elaborating on their recent oncology-focused studies published by Aging. A new Behind the Study is released each Monday. Visit the Aging YouTube channel for more insights from outstanding authors.

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Hello, my name is Judy Campisi. I am a Professor at the Buck Institute for Research on Aging and also a Senior Scientist at the Lawrence Berkeley National Lab. And my laboratory, which is a pretty international laboratory with people from Asia and Europe, published a paper in aging, “Cdkn1a transcript variant 2 is a marker of aging and cellular senescence.”

So why do we care about this?

Well, 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. And it’s now clear from mouse models that if you eliminate senescent cells, which increase with age, you can increase the health span of a mouse – not necessarily the lifespan, but the health span. So it becomes kind of important to have ways of identifying senescent cells in detail, and we have not been able to do that so far with absolute certainty because there frankly are no senescent-specific markers. So there are markers that are commonly expressed by senescent cells, but none of them are absolutely specific.

Figure 1. The Cdkn1a variant 2 transcript is preferentially induced during aging.
Figure 1. The Cdkn1a variant 2 transcript is preferentially induced during aging.

And so what we have done is we have looked at one of those markers, which is a gene called Cdkn1a and it codes for approaching, called P21. So everyone knows that P21 is one of those common biomarkers of aging, but it also is not necessarily strictly limited to aging. And what we’ve found is that there are two mRNAs that are made from that gene, that had been known before. 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. And that gives us a little bit of a edge in trying to unambiguously identify senescent cells in vivo and even in culture.

So the importance of this work is that it helps refine our ways of identifying these cells. We now know that these cells are important in aging, certainly in mice, probably in humans as well. So with this group of mine, many of which come from Spain or France or Russia, many of them contributed to refining this marker and allowing us to be able to have a better way of having some confidence that a senescent cell is indeed senescence.

And I can stop here.

Click here to read the full study published by Aging.

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.

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Pressurized Oxygen Therapy Can Reverse Mechanisms of Aging

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For the first time, researchers demonstrate that hyperbaric oxygen therapy can reverse the mechanisms that mark the aging process.

Oxygen molecules and erythrocytes floating in a vessel in the blood stream.
Oxygen molecules and erythrocytes floating in a vessel in the blood stream.
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Aging is the progressive loss of physiological integrity, which results in impaired functionality and increased susceptibility to diseases, and ultimately death. For the first time, researchers collaborated in an in vivo study to observe the effects of hyperbaric oxygen therapy on cellular mechanisms to reverse aging.

Researchers based out of Israel from Shamir Medical Center, Tel-Aviv University, and Bar Ilan University published a groundbreaking new paper titled, “Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial,” in the open access journal, Aging. The importance of this study hinges on understanding the mechanisms of aging that were evaluated by the researchers.

“At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence.”

Telomere Length

Telomeres (TLs) function to protect chromosomes from DNA damage and are located at the end of the chromosome. In each instance of cell division, the telomeres shorten due to an inherent inability to fully replicate the DNA strand. Given that cells can only replicate a finite number of times before they can no longer engage in mitosis, the shortening of telomeres has been shown in adults to lead to increased rates of mortality.

Researchers in this study also provide examples of studies that are finding a number of pharmacological agents capable of reducing the shortening rate of telomeres.

“Shortened TLs can be a direct inherited trait, but several environmental factors have also been associated with shortening TL, including stress, lack of physical endurance activity, excess body mass index, smoking, chronic inflammation, vitamins deficiency, and oxidative stress [2, 8, 9].”

Cellular Senescence

The other hallmark mechanism of the aging process is cellular senescence. Previously, senescent cells have been viewed as mechanisms that protect the body against cancer through cell-cycle arrest, however, recent discoveries have found that they also have a role in processes such as development, tissue repair, aging, and age-related disorders. The phase of senescence can be triggered by telomere shortening and other non-telomeric DNA damage.

“The primary purpose of senescence is to prevent propagation of damaged cells by triggering their elimination via the immune system. The accumulation of senescent cells with aging reflects either an increase in the generation of these cells and/or a decrease in their clearance, which in turn aggravates the damage and contributes to aging [1].”

Oxidative Stress

In this well-written paper, the researchers introduce the topic by citing numerous interventional studies measuring the association between telomere length and lifestyle modifications. Studies include the measuring of diet, supplements, physical activity, stress management, and social support. However, the team found that the most common mechanism associated with telomere shortening is oxidative stress.

“Oxidative stress can occur from imbalances between the production of reactive oxygen species (ROS) and cellular scavengers.”

Previous studies indicate that telomeres are highly sensitive to oxidative DNA damage which occurs due to an excess of reactive oxygen species (ROS), or molecular oxygen by-products. The excess formation of these ROS occurs through the sequential reduction of oxygen via the addition of electrons and a lack of scavenger cells to digest excess microorganisms. This leads to the shortening of telomeres.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) has been observed to stimulate brain function and increase cognitive ability in previous studies. HBOT involves patients breathing in 100% oxygen in a pressurized chamber on a repeated basis. Being in this type of environment increases the amount of oxygen that is dissolved in the blood and tissue. Increasing oxygen levels in the body using pure oxygen on a daily basis can induce the hormesis phenomenon. This eustress type of therapy has been shown to have beneficial and positive effects on the body and mind.

“Single exposures [to HBOT] increase ROS generation acutely, triggering the antioxidant response, and with repeated exposures, the response becomes protective [13, 18].”

The Study

This study was designed to evaluate the effects of HBOT on the telomeres and concentrations of senescent cells in aging/healthy adults. Thirty-five participants living independently at 64+ years of age received HBOT exposures daily, over the course of 60 days.

Researchers collected whole blood samples prior to intervention (baseline), at the 30th and 60th session, and 1-2 weeks after the last HBOT session. They assessed the telomere lengths and senescence of peripheral blood mononuclear cells (PBMCs) in each participant’s blood sample.

Figure 3. Senescent cell changes with HBOT.
Figure 3. Senescent cell changes with HBOT.

“In this study, for the first time in humans, it was found that repeated daily HBOT sessions can increase PBMC telomere length by more than 20% in an aging population, with B cells having the most striking change. In addition, HBOT decreased the number of senescent cells by 10-37%, with T helper senescent cells being the most affected.”

Conclusion

Following HBOT, telomere lengths increased by over 20% in T helper, T cytotoxic, natural killer, and B cells. There was also a significant decrease in the number of senescent T cytotoxic and T helper cells observed in the participant blood samples, allowing for new healthy cells to regenerate.

“In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.”

Click here to read the full scientific paper, published in Aging.

Learn more about Hyperbaric Oxygen Therapy (HBOT)

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Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues and other researchers, far and wide.

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