Behind the Study: Second Interventions in Aging Conference

Following the Second Interventions in Aging Conference, meeting organizers Dr. Brian Kennedy and Dr. Linda Partridge discuss their overview of the meeting proceedings that was published by Aging in 2017, entitled, “2nd interventions in aging conference.”

Researchers explain their studies that were published in Aging
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. Visit the Aging YouTube channel for more insights from outstanding authors.

Dr. Brian Kennedy

I’m Brian Kennedy, I’m a professor at the Buck Institute for Research on Aging and a visiting professor at National University of Singapore.

Dr. Linda Partridge

And I’m Linda Partridge and I’m Director at the Max Planck Institute for Biology of Aging in Cologne, Germany. And also Director of the Institute for Healthy Aging at University College London.

So, Brian, how did you get into aging research?

Dr. Brian Kennedy

The funny thing was when I went to graduate school, I’d worked in yeast as an undergraduate, and I decided that I was not going to work in yeast anymore. But the more I realized about how difficult it was to work in mice, the more I wanted to work in yeast. And so there was another graduate student and I that wanted to go to Lenny Guarente‘s lab, and we decided to work in yeast and we wanted to figure out something completely crazy to do.

And we came up with two ideas: One was yeast apoptosis, which was a little weird for a single-celled organism and the other was aging. And we decided that aging was the least-

Dr. Linda Partridge

Mr. Nobel Prize.

Dr. Brian Kennedy

It’s true. We decided that aging was the least implausible of the two. And so we did that, but there’s a whole field on yeast apoptosis now too, so I guess we would have been okay. How about you?

Dr. Linda Partridge

Well, I got into it crabwise, really, because I started out life as an evolutionary biologist. So from the evolution point of view, it’s a completely weird trait because development produces a wonderfully functioning young organism and then it all goes to hell. You’d think it would be a lot easier to maintain it and to produce it in the first place. So I became very interested in how aging evolves and it is indeed really peculiar it’s almost certainly given what we’ve learned recently about the mechanisms of aging, actually bad effects in old age of genes that are good in the young. So I think that’s pretty interesting if you think about it as genes driving the old organism too hard to do the kinds of things that young organisms can do very well. I think it makes quite an easier process to think about, put it that way.

Dr. Brian Kennedy

And what we started the puzzle, both of us have worked on this a lot is, you know we’ve been trying to show that the pathways that are modulating aging are conserved. And it’s always kind of a puzzle that there’s so much conservation if this is a trait that evolution never really cared about that much. So it’s… I’ve never quite got that satisfied in my mind. What do you think about that?

Dr. Linda Partridge

I guess what I think is that the processes that you and other people have come up with, there are ones that do drive good things in young organisms. So the things that make for growth, for reproduction, for strong immune responses, for effective muscles and movement, all the things that young organisms have to do. But they seem to be set at too higher level when you get old, and I think that way it is actually quite easy to understand why it’s evolutionarily conserved because presumably the kinds of genes that control growth and reproduction evolve very early on.

Dr. Brian Kennedy

I agree. I actually argue with people that aging is going to be easier to modify than disease. So I think it’s going to be easier to keep people healthy than it is to wait until they get sick and try to treat them and make them better. I think of it as very simplistically as a state of homeostasis versus disequilibrium, you know, while you’re still relatively healthy, it’s fairly easy to tap into these pathways … relatively easy to tap into these pathways … and try to maintain that. But once you get into a state of disequilibrium, which I would call chronic disease of one sort or another, then you’ve got a problem. You’re kind of fighting entropy at that point and trying to put things back together again is very difficult.

Dr. Linda Partridge

Yes, it’s very interesting talking to colleagues in other areas about that idea because one gets a kind of ‘yuck’ response. So does that mean that humans are going to have to take pills when they’re healthy to prevent disease? You can point out that people do that already around statin and aspirin and things that lower high blood pressure. None of these are dealing with disease states, they’re in anticipation of possible disease states and trying to prevent them. So there’s plenty of taking pills to prevent things already, but for some reason, when you talk about it as a likely outcome of research into aging, there’s quite often a kickback, even from other scientists.

Dr. Brian Kennedy

I think most of the things we take, you know that are really working effectively really are aging drugs as much as they’re disease drugs. So you mentioned aspirin, but not just that I mean, look at statins, look at beta- blockers, look at early diabetes drugs like Metformin. All of them are targeting early risk factors for chronic disease, and I kind of feel like these risk factors are right at the interface between aging and disease itself.

Dr. Linda Partridge

They’re right on the nexus of the way in which aging acts as a risk factor for disease, and I think the other thing about them is that it’s quite clear that they’re turning out to have off-licence effects. Most of these drugs have a much broader therapeutic range than they’re generally used for. Which is exactly what you’d expect if they’re in there in that nexus between aging and disease.

Dr. Brian Kennedy

So what’s exciting to you now in your research? Where are you going in the next five years?

Dr. Linda Partridge

Well, funnily enough, I’m very much into drugs. So we’ve been doing quite a lot of drug work with drosophila and based exactly on this idea that mechanisms of aging are conserved. We’re starting to take a number of these drugs into mice, but also starting to do some big database stuff with humans, looking at particular pathways that have come up in the model organisms and asking whether SNPs associated with those pathways in humans ones that are either likely to increase the activity of the pathways concerned or decrease it or associated with particular types of disease risk.

So one can do this process called Mendelian randomization, which in theory gets rid of a lot of the effects of genetic background and focuses on a particular SNP. Now I think there’s enough data coming in on humans that we can really start to do the population genetics on these pathways, and I’m terribly excited by that.

What about you?

Dr. Brian Kennedy

Well, I have two goals right now. One is to try to go back to the simple organisms and really take a systems approach and try to take a yeast cell for example, and be able to describe all the features of aging, not just one gene at a time. And so we’re working a lot in sort of systems biology approaches there, but I think the main goal I have is-

Dr. Linda Partridge

Do you mean you’re looking at gene combinations or how are you doing it?

Dr. Brian Kennedy

Yes. Gene combinations, but also working with collaborators to look at how signaling pathways change with age to start to really understand longitudinal processes in a yeast cell. So the idea is to combine that with the genetic data and try to put the puzzle together.

Dr. Linda Partridge

I think that’s interesting.

Dr. Brian Kennedy

My main goal really is to get human and to start testing interventions in humans because I think we have enough knowledge now that we have things that are likely to work and we have reasonable candidate biomarkers, none of which are completely validated, but I feel good about some of them. And if you put that together, I kind of see it as a lock and key fit. You know we’ve got a bunch of interventions which are potential keys, and we’ve got a bunch of biomarkers which are potential locks, and we have to figure out which keys fit in which locks. So I’m looking at strategies to really test that in humans, either through academic research or through private companies.

Dr. Linda Partridge

So do you think companies are going to be interested in doing the kind of research that would target more than one disease, or do you think the way in is going to be to go for particular disease states? How do you think we should do it, operationally?

Dr. Brian Kennedy

I’d much rather target healthy aging or health span or prevention of multiple diseases. And I think there are companies that are thinking about that now, but they’re still relatively small generally. I think PhRMA kind of walks up to that ledge and looks over and then backs up. But eventually I think that it’s going to happen. I think what we need is some evidence that we can really modulates aging pathways. And that’s where this biomarker strategy or the kinds of things that [inaudible] is doing to get multiple disease parameters simultaneously in clinical trials. Those kinds of things, I think, are you just need a couple of success stories and then people start to get it. So I’m agnostic as to whether it’s done academically or privately, I just want to make it happen and so you know.

Dr. Linda Partridge

So what do you think about… We know so much from the animal studies about rapamycin now we probably know more about that than any other drug in the context of aging. Do you think there are going to be more clinical trials with rapamycin for off-license applications? Do you think it would be a trial for Alzheimer’s for instance?

Dr. Brian Kennedy

You know, there’ve been a lot of talk about trials for Alzheimer’s and I don’t think one has gotten started yet. But I think you’re going to start to see more and more of this. Then of course, there’s a lot of research to try to figure out how to either dose rapamycin or everolimus, which is the first generation of that rapalog in a way that doesn’t have the toxicity or to develop new drugs that have the efficacy without the toxicity. So I think both of those approaches are moving forward.

Novartis just spun off a small company to try to do this, and so I think that there’s renewed interest in trying to inhibit mTOR, but there’s still a lot of open questions about how it’s going to be best to do that. But having said that the number of potential indications, I mean, not to mention aging itself is so large that there’s clearly value into doing this successfully. So I’m pretty excited about where that’s going to go. I think that’s only one of a bunch of pathways though and you’re looking for new drugs and new pathways, and I think we’re going to find that there are a lot of different potential entry points for intervention in aging as we go forward.

Dr. Linda Partridge

I think it’s a time of great excitement. I just hope that some of the human trials get done while I’m still active. I’d love to see some successes with people.

Dr. Brian Kennedy

But you will be active for at least 20 more years, so …

Dr. Linda Partridge

Lots longer if somebody comes up with a pill.

Dr. Brian Kennedy

You know, that’s why I think doing this Fusion Conference has been so fun. You know, we’ve done two of these now in Cancun, and the idea is to bring different groups of people to look at different strategies for interventions in aging. I think that the conferences are relatively small, but we try to recruit a wide range of people. So we get people discussing different kinds of ideas that don’t normally talk. That’s what I think the strength of it is what do you think?

Dr. Linda Partridge

I agree with that. I really like the format of those conferences because they have a low upper limit on the number of delegates deliberately. So that most people can give talks or posters and there’s plenty of time for discussion. And what I noticed at those meetings correspondingly is that the discussion is very intense. Almost everybody talks to everybody else at some point during the meeting. So there’s real interchange of ideas as you say, between people who we deliberately invite from different areas, and I think it’s been a great success and it’s also been very nice to see it going more and more translational. There is more and more interest in mechanisms that are going to give rise to preventative measures rather than just the basic research, which has been fantastic and was necessary to get anywhere. But people really are trying to push it into helping people now. And I find that very exciting. So yes, I think meetings are great.

Dr. Brian Kennedy

Yes, I know, and I think as we go forward with these meetings, we’ll probably continue to try to emphasize these human intervention studies as much as possible.

Dr. Linda Partridge

I think that’s very much a specialty of that meeting.

Dr. Brian Kennedy

Because there are other meetings that really focus on the basic biology of aging, but this is really trying to get at the next step.

Dr. Linda Partridge

Yeah. Yeah. It’s particularly good when we can get basic scientists and clinicians together, I think. And also people from the various companies who might do something about the discoveries. I think it’s a very good mix of people that way.

Dr. Brian Kennedy

I can’t, you know, in my better moments, I think that we’re almost right at a tipping point where we’re going to push over this wall and then all of a sudden everybody’s going to be saying, oh, targeting aging is common sense in 10 years. I still have the bad moments where I feel like the little soldier walking into the wall and never go anywhere too.

Dr. Linda Partridge

Yes. I fluctuate between those two points as well, but I find myself feeling optimistic more and more often seeing what’s happening.

Dr. Brian Kennedy

That’s good. Well, it’ll be exciting to see where the field goes moving forward…

Dr. Linda Partridge

Yeah, indeed. Indeed.

Click here to read the full meeting report, 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.

Press Release: Aging’s Latest Impact Factor

In June 2021, Web of Science (Clarivate Analytics) released their 2020 JCR Impact Factor. Aging‘s 2020 impact factor is 5.682.

In June 2021, Web of Science (Clarivate Analytics) released their 2020 JCR Impact Factor. Aging is pleased to report that our 2020 impact factor is 5.682.
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BUFFALO, NY-August 20, 2021 – Aging is indexed by Web of Science: Science Citation Index Expanded (abbreviated as Aging‑US). In June 2021, Web of Science (Clarivate Analytics) released their 2020 JCR Impact Factor. Aging is pleased to report that our 2020 impact factor is 5.682. This number has increased from last year’s 4.831. Without self-citation, Aging’s 2020 impact factor is 5.279.

Aging is listed in the Web of Science: Science Citation Index Expanded in two categories: Cell Biology and Geriatrics & Gerontology. According to the Journal Citation Indicator (JCI), Aging is ranked in the Q1 quartile in both categories. 

Since 2009, Aging has published research papers in all fields of aging research including, but not limited to, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan.

This journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, and prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

To learn more about Aging, publication standards, and past or current issues, visit www.aging-us.com.

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About Impact Journals:

Impact Journals is an open-access publisher of research journals in biomedical sciences. Our publications focus on topics surrounding cancer research and all fields of aging research. Our mission is to provide scientists with the opportunity to share their exceptional discoveries, offer services that enable rapid dissemination of results, and to present vital findings from the many fields of biomedical science.

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Protocol Reverses Symptoms of Alzheimer’s Disease in Small Cohort

The MEND (Bredesen) protocol to treat neurodegeneration associated with Alzheimer’s disease was tested in a small cohort. In 2016, researchers followed up with objective results.

Blue synapse and neuron on a blue background. 3D rendering
Blue synapse and neuron. 3D rendering

The Top-Performer series highlights papers published by Aging that have generated a high Altmetric Attention score. Altmetric scores, located at the top-left of trending Aging papers, provide an at-a-glance indication of the volume and type of online attention the research has received.

Read Aging’s Top 100 Altmetric papers.

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Precursors to the onset of early Alzheimer’s disease (AD) include mild cognitive impairment (MCI) and subjective cognitive impairment (SCI). Many have viewed this looming neurodegeneration as an unavoidable fate that accompanies aging. However, in a 2014 study, a novel precision medicine treatment approach, termed the metabolic enhancement for neurodegeneration (MEND) protocol, yielded unprecedented results. Nine out of 10 participants with memory loss associated with AD, amnestic MCI, and SCI, were treated using the MEND protocol. Participants displayed subjective improvement in cognition within 3-6 months of this protocol. The study claims their only failure was one patient with very late stage AD.

In 2016, researchers—from the University of CaliforniaBuck Institute for Research on AgingPacific Medical Center, and Brainreader—followed up on the anecdotal results from the 10 patients in this study. They provided objective results from quantitative magnetic resonance imaging (MRI) and neuropsychological testing. The researchers authored another paper on results of the MEND protocol, which was published by Aging and entitled, “Reversal of cognitive decline in Alzheimer’s disease.” To date, this paper has generated an Altmetric Attention score of 263. The original 2014 paper on the MEND study has also generated an impressive Altmetric Attention score of 470.

“In each of these cases, obvious subjective improvement, noted by the patient, his/her significant other, and his/her co-workers, was accompanied by clear, quantitated, objective improvement.”

THE MEND PROTOCOL

The MEND protocol, also known as the Bredesen Protocol (named after the creator of the protocol, Dr. Dale Bredesen), consists of a multifaceted, tailored approach to treating each AD patient for their individual symptoms of cognitive decline—and not only a few symptoms. This strategy uses a combination of diet, lifestyle, and therapeutic interventions. Treatment is based on the hypothesis that AD occurs due to an imbalance in an extensive plasticity network in the brain. The authors note that the MEND protocol is an iterative process and designed to improve with continued patient visits. 

“The therapeutic system described in this report derives from basic studies of the role of APP signaling and proteolysis in plasticity, and the imbalance in this receptor proteolysis that reproducibly occurs in Alzheimer’s disease.”

Upon clinical assessment and lab testing, the patients’ physical and cognitive health were evaluated. Based on this assessment, patients were prescribed a lengthy personalized therapeutic system. Among other objectives, the MEND protocol recommends treating diabetes; improving sleep and digestive health; reducing stress, inflammation, and blood sugar; increasing physical exercise, intellectual stimulation, antioxidants, and vitamins; and optimizing hormone balance, synthesis of acetylcholine, nerve growth factors and mitochondrial function.

ANECDOTAL AND OBJECTIVE RESULTS

“The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective.”

Before participating in the MEND protocol, most of the 10 participants reported a family history of AD, confusion, difficulty with word finding, following instructions, remembering, reading, concentrating, driving, completing work related tasks, and other cognitive struggles. Over the course of between five and 24 months on the MEND, nine of 10 patients and their families or caregivers reported improved cognitive function. Some patients were able to go back to work, play games, and even babysit their grandchildren. One spouse of a patient mentioned that her husband had stopped following the protocol for a period of time, which resulted in him leaving the car in the driveway idling with the keys in the ignition. After he resumed the protocol, no such instances were reported.

Bearing in mind that this study used an extremely small cohort to test this very expensive protocol, the objective results observed by the researchers were still considerably significant. Quantitative neuropsychological testing showed improvements of up to three standard deviations. One patient showed an increase in hippocampal volume from 17th percentile to 75th percentile. These results must be verified in a larger sample size to validate efficacy.

CONCLUSION

“The initial results for these patients show greater improvements than have been reported for other patients treated for Alzheimer’s disease. The results provide further support for the suggestion that such a comprehensive approach [3] to treat early Alzheimer’s disease and its precursors, MCI and SCI, is effective. The results also support the need for a large-scale, personalized clinical trial using this protocol.”

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.

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

Aging Testimonial: Dr. Kara Fitzgerald

Below is a transcript of the testimonial by Dr. Kara Fitzgerald, from the Institute for Functional Medicine in Federal Way, Washington, about her experience publishing the paper, “Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial,” with Aging.

Researchers explain their studies that were published in Aging
Researchers explain their studies that were published in Aging
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Dr. Kara Fitzgerald:

I am thrilled with our study being accepted into the journal Aging. I think it’s the perfect home for it.

The process of submitting and our peer review journey was actually, it was actually a lot of fun! I found our peer reviewers, they really move our study forward and help us to articulate our findings and inquisitive, appreciative of what we’ve done. And so that whole piece of it was good.

Dr. David Sinclair actually suggested that Aging would be the right home for us and I couldn’t agree more.

What else? It’s open access. I think open access is essential. Having our study behind a paywall and inaccessible to other scientists and just the community who might be interested in the longevity research that’s happening, particularly this, which is a diet and lifestyle program so, it’s something that people could actually do if they wanted to. We want that available. So I’m all for open access.

I enjoyed working with Aging. I thought that they were good across the board. And I just appreciate David’s recommendation that we go here.

Click here to read the full study published by Aging.

Click the links below for more information on corresponding author, Dr. Kara Fitzgerald:
Biological Aging Summary | Instagram | Facebook | Twitter | General Site | Younger You Program

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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.

Trending With Impact: New Drug Combinations Inhibit Stress Proteins

Researchers tested antiviral, anticancer, and immunosuppressive drug combinations that may aid in treating neurodegenerative disorders, including Alzheimer’s disease.

Figure 5. Neratinib and AR12 combine to reduce the expression of HSP90, HSP70, GRP78 and HSP27 via autophagy.
Figure 5. Neratinib and AR12 combine to reduce the expression of HSP90, HSP70, GRP78 and HSP27 via autophagy.

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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Heat shock proteins (HSPs), also known today as stress proteins, were first observed in fruit flies in the 1960s. After Dr. Ferruccio Ritossa inadvertently subjected a preparation of fruit fly salivary glands to a non-lethal increase in temperature, he discovered a new pattern of chromosomal “puffing.” In 1974, researchers identified the proteins that were encoded by the “puffs” recorded by Dr. Ritossa, and named them heat shock proteins. 

These newfound proteins appeared to only become detectable when the cells were heated. Researchers later learned that HSPs can also be induced by oxidants, toxins, heavy metals, free radicals, viruses, and other stressors. Since its discovery, variations of this genetic system have been found in all bacteria, plants, and animals—including humans. HSPs have been well-studied since this revelation, and researchers now believe these molecular chaperones play important roles in protein refolding, aging-related diseases, and overall longevity. 

“Toxic misfolded proteins are key drivers of AD [Alzheimer’s disease], ALS [Amyotrophic lateral sclerosis], HC [Huntington’s Chorea] and other neurodegenerative diseases.”

Researchers from Virginia Commonwealth UniversityTranslational Genomics Research Institute, and the Banner Alzheimer’s Institute took part in a research study experimenting with combinations of therapeutic agents that may improve neurodegenerative diseases. In 2021, their paper was published in Aging’s Volume 13, Issue 13, and entitled, “Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43.”

“In this paper we examined using isogenic colon cancer cells [with] several existing drugs that function by increasing autophagy and degrading misfolded proteins.”

THE STUDY

“Aberrant expression of chaperone proteins is found in many human pathologies including cancer, in virology and in AD, ALS and HC.”

In this study, researchers tested drugs that have been used preclinically and clinically in several anticancer studies. The drugs used were: AR12, an antiviral chaperone ATPase inhibitor; Neratinib, a tyrosine kinase inhibitor; a combination of AR12 and Neratinib; Fingolimod, an immunosuppressive sphingosine l-phosphate receptor modulator; MMF, monomethyl fumarate; and a combination of Fingolimod and MMF.

The cells they tested these drug combinations on in vitro included Vero cells (African Green Monkey kidney cells), isogenic HCT116 colon cancer cells (genetically manipulated colon cancer cells), and GB6 cells (glioblastoma cancer stem cells). They also used plasmids, antibodies, and siRNAs. Researchers acknowledged that the use of non-neuronal cells may be a limitation of this study.

“Our present studies were performed in non-neuronal cells and as a caveat, it is possible that our data in HCT116 and Vero cells will not be reflective of the same processes in neuronal cells.”

Despite this caveat, results from their research were promising. Some combinations of these drugs were capable of knocking down many disease specific proteins that form toxic aggregates inside cells and in extracellular environments via autophagy. 

CONCLUSION

“As the mechanism of drug-action became clearer it was apparent that these agents should also be tested in neurodegenerative diseases. The entire neurodegenerative field needs rapid translational methods that target the underlying cause of disease, toxic misfolded protein. The findings from this work warrant further testing with a focus on clinical utility.”

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

WATCH: MORE AGING VIDEOS ON LABTUBE

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.

Salt Water-Infused Blood Reverses Aging

From the University of California Berkeley and Apheresis Care Group, researchers ​​discovered a method of “refreshing” blood that reverses some of the effects of aging.

Infusion drips with bottles of yellow albumin fluid.
Infusion drips with bottles of yellow albumin fluid.

The Top-Performer series highlights papers published by Aging that have generated a high Altmetric attention score. Altmetric scores, located at the top-left of trending Aging papers, provide an at-a-glance indication of the volume and type of online attention the research has received.

Read Aging’s Top 100 Altmetric papers.

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Is it possible for old blood to be “refreshed” in order to rejuvenate youth and combat the effects of aging? Aging researchers have a long history of analyzing the blood in search of the keys to healthy aging. In 2020, researchers from the University of California Berkeley and Apheresis Care Group uncovered groundbreaking new insights about the rejuvenation of aging blood with the potential to slow, and potentially to reverse, aging. Their well-read priority research paper was published by Aging and entitled, “Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin.” To date, this top-performing paper has generated an impressive Altmetric Attention score of 147.

Blood Plasma

Approximately 55% of the body’s total blood volume is composed of a pale yellow liquid—plasma. Plasma largely consists of water (about 92%), with traces of mineral salts, sugars, fats, hormones, and vitamins. This watery substance also contains important proteins, such as immunoglobulin (antibodies), clotting/coagulation factors, and albumin.

“In people, albumin levels correlate with disease, nutrition, and socio-economic status rather than chronological age; and even when health, etc. status are not considered, albumin diminishes only marginally, by 2-4% at 75 years of age from its 26 years of age levels [2124].”

Plasmapheresis is a general term used to describe procedures that remove, treat, and return or exchange blood plasma to the blood. Patients with autoimmune diseases, sickle cell disease, certain forms of neuropathy, and even severe cases of malaria have benefitted from plasmapheresis. 

Heterochronic Parabiosis

Heterochronic parabiosis, a plasmapheresis-like procedure, is the surgical joining of two organisms in an effort to study the physiological changes that result from shared blood flow. Researchers have used this model of joining young and old animals together to observe the effects of old blood in young mice, and vice versa. In a 2005 study, University of California Berkeley and Apheresis Care Group researchers found that, through the process of heterochronic parabiosis, old mice sharing blood with young mice produced rejuvenating effects in old mice. 

“The general conclusion of these studies was that the old partners had better health and/or repair of cartilage, muscle, liver, brain, spinal cord, kidneys, bone, skin, etc., and often the young animals experienced premature aging of their respective tissues [13468].”

However, the same researchers suspected that the rejuvenating effects demonstrated by heterochronic parabiosis were not direct results of youthful factors in the young murine blood itself. They also suspected that the premature aging experienced by the young mice were not due to old factors in the aged blood either. The team proposed that simply diluting the young and old factors in the blood may be the cause of these effects. In 2020, the researchers conducted a new study, this time using saline and albumin, to test their hypothesis.

“Historically, the phenomena of heterochronic parabiosis and blood exchange remained unconfirmed with respect to the key assumption as to whether the addition of young factors is needed for rejuvenation, and if premature aging of young mice stemmed from the introduction of old blood factors or a simple dilution of young factors.”

The Study

In this study, the researchers began by conducting a plasmapheresis procedure in mice called a neutral blood exchange (NBE). Half of the platelet-rich-plasma (PRP) was removed from the blood in young and old mice and was replaced with a simple saline and 5% purified albumin.

“Through a half-hour long series of small volume exchanges, 50% of the PRP of old and young mice was replaced with saline plus 5% mouse albumin while the circulating red and white blood cells were returned isochronically to the animal.”

Their results showed that a single session of NBE improved regeneration, reduced fibrosis, enhanced myogenesis, and other factors in the old mice. In the young mice, they found that this procedure did not have adverse effects or worsen the aforementioned factors. To verify their findings, the team studied human blood samples from four older individuals (between the ages 65 and 70) and conducted an FDA approved procedure, Therapeutic Plasma Exchange (TPE), using the same saline/albumin formula.

“To confirm these findings and to explore their evolutionary conservation, we took advantage of the fact that there is a procedure for human patients analogous to NBE, where most of the plasma is replaced by physiologic solution supplemented with commercial human albumin, called Therapeutic Plasma Exchange, TPE, which is FDA approved and routinely used in the clinic [1618].”

Conclusion

In summary, their research found that simply diluting old blood factors with a neutral substance such as saline and albumin contributes to improving muscle repair, attenuating fibrosis, enhancing myogenic proliferation, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis. In some areas, they found that these effects were even stronger in TPE than results after heterochronic parabiosis or blood exchange.

“The theoretical significance of this study is in a better understanding of how blood heterochronicity acts to quickly and profoundly rejuvenate old mammals, and the clinical significance of this work is in developing TPE as a new modality to broadly improve organ health and repair in older individuals preventing illnesses that develop or become more severe in later decades of life.”

Click here to read the full priority 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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Trending With Impact: Circulating Mitochondria and Inflamm-Aging

Authors from the National Institute on Aging wrote a trending editorial paper on mitochondria extracellular vesicles and aging.

Figure 1. Mitochondrial DNA in extracellular vesicles and association with human aging.
Figure 1. Mitochondrial DNA in extracellular vesicles and association with human aging.
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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.

Some structures inside cells play elusive, yet important roles in human aging. Researchers believe structures classified as extracellular vesicles (EVs), released outside of cell walls, may also play key components in the aging process—specifically related to chronic inflammation.

“EVs are lipid-bound nano-sized vesicles that are secreted outside of cells into the circulation (Figure 1A).”

Two researchers from the National Institutes of Health‘s National Institute on Aging wrote a trending editorial paper, published by Aging in 2021, and entitled, “Mitochondria as extracellular vesicle cargo in aging.” 

Inflammation and Aging

The term “inflamm-aging” has been coined to describe the common state of chronic low-grade inflammation associated with aging. Researchers believe that inflammation contributes to many age-related diseases, including cardiovascular disease, diabetes, cancer, and even dementia.

“In fact, inflammation-related diseases account for more than 50% of worldwide deaths, stressing the importance of inflammation in driving age-related disease and mortality [1,2].”

In the elderly, cellular damage and stress (among other causes) may contribute to chronic inflammation, which can initiate a release of mitochondrial damage-associated molecular patterns. This process can initiate cells to release mitochondrial DNA (mtDNA) into the space outside of the cell as circulating cell-free mitochondria DNA (ccf-mtDNA).

“Due to the similarities between mtDNA and bacterial DNA, this release can in turn elicit a sterile inflammatory response through activation of the innate immune system.”

Circulating Cell-Free Mitochondria DNA

Authors of this editorial believe that ccf-mtDNA may contribute to systemic chronic inflammation. In a previous study, researchers found, in general, that higher plasma/serum levels of ccf-mtDNA were reported in patients with inflammatory-related diseases and after acute injury or infection. However, ccf-mtDNA’s role in aging is complex, as one study showed that ccf-mtDNA levels initially decline into middle-age, and then gradually increase after age 50. 

The molecular details of how ccf-mtDNA exists within blood circulation has yet to be elucidated. Questions still linger surrounding whether or not components in the blood bind to ccf-mtDNA. If components do bind to ccf-mtDNA, are they capable of protecting ccf-mtDNA from destruction in circulation?

Extracellular Vesicles and mtDNA

“Given these gaps in the field, we recently explored whether plasma mtDNA can be encapsulated in extracellular vesicles (EVs) [5].”

The researchers evaluated multiple studies to find that mtDNA can be encapsulated in EVs isolated from plasma—both in cells that have been grown in vitro and in plasma EVs from patients with breast cancer. The next question the researchers addressed was: How do levels of mtDNA in plasma EVs fair in normal conditions and with age?

“To address this need, we isolated plasma EVs and analyzed mtDNA levels with human age. Individuals in this aging cohort had donated plasma at two different time points approximately 5 years apart, which enabled us to examine both crosssectional and longitudinal changes.”

Conclusion

“In both our cross-sectional and longitudinal analyses, EV mtDNA levels decreased with advancing age [5] (Figure 1B).”

The researchers concluded by reporting EV mtDNA levels decreased over a span of five years in the longitudinal cohort. Mitochondrial components, including mtDNA, may be important EV cargo. They emphasized that further research is needed and that it is important for researchers to consider age when using EVs as diagnostic or prognostic markers of disease. 

Click here to read the full editorial 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.

2021 Ride for Roswell

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

Behind the Study: COVID-19 Affect on Elderly

Dr. David Sinclair from Harvard Medical School and member of the Aging Editorial Board details his review published by Aging on May 29, 2020, entitled, “Why does COVID-19 disproportionately affect older people?

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. Visit the Aging YouTube channel for more insights from outstanding authors.

It’s David Sinclair here. I’m talking to you from my home in Boston during this pandemic stayed home time, but also wanted to talk to you about a new paper that we have coming out, or just came out in our journal, Aging, and its title is, “Why Does COVID-19 Disproportionately Affect the Elderly?”—which has become one of the biggest questions I think in this whole pandemic. And, if we could understand why the elderly were more susceptible, first of all, we could help them survive and have less severe cases, but also we could learn perhaps why younger people are also more susceptible. One thing that I often hear when I pose that question is oh, it’s just that old people are sicker and they die. Well, that’s not a good enough explanation because the elderly, even if they are healthy, have a much greater chance of dying than someone whose say, less than 65.

In fact, of all the main causes of death or risk factors in COVID-19, age is by far the most important one, independent of all those other risk factors. So a study just came out in the UK that looked at 17 million people that had COVID-19 and they could tell us based on that, what the ranking of the what’s called the hazard ratio of which symptoms and which lifestyle and cobalt morbidities track with COVID-19 more fatality risk.

And actually, in order starting with number five, it was diabetes/obesity. Number three was being male, that’s fairly risky. Having cancer of the blood was bad, which makes sense because you’ve disrupted your immune system. But by far the riskiest thing is age, independent of all these other things. In fact, compared to these other risks, age is basically the major determinate. If you’re 80, numbers where you’re about tenfold higher to someone who’s in their late 50s. So that led us to try to figure out what is going on with the age that makes them more susceptible. And again, it’s not just that those people start out sicker. And so we’ve written this perspective and gathered a lot of data from around the world, papers that have come out, papers that have been in publication. So in this perspective, we’ve gathered a lot of data from around the world, new papers, old papers, and really put together a list of things that we think are the most likely explanations for the elderly succumbing to COVID-19, independent of their actual underlying diseases and frailty.

Figure 1. Ineffective clearance of SARS-CoV-2 infection in the aged respiratory system.
Figure 1. Ineffective clearance of SARS-CoV-2 infection in the aged respiratory system.

So let’s first go through one of the figures—you’ll see figure one is a beautiful illustration drawn by my wonderful coauthors, Amber Mueller and Maeve McNamara. And it’s a picture of what goes wrong in the elderly compared to someone who can clear the infection. And what you’ll see is that there’s a cut through the lung. And what happens in the elderly is that the virus goes down into the lung, causes hyper immune response. And in the late stages of the disease in the elderly particularly, it’s a hyper immune response, which we call the cytokine storm. And what we’ve recently discovered, the planet that is not just my lab, is that the virus can attack the endothelial cells of the agent. And that’s not just in the lung, which of course is a problem for getting blood flow and oxygen across, but what’s also important is that these endothelial cells that line the blood vessels, particularly the micro capillaries, line at the heart, the brain, even the extremities.

And so what we’re seeing in elderly patients particularly that undergo this cytokine storm is what’s called a coagulopathy, which means that lining of the blood vessels is getting inflamed and causing clots to form. And you get a rise in this marker called the D-dimer, which is a breakdown product of clotting. And what we’re seeing is even in young people, there’s propensity for stroke, myocardial infarction, heart attack, and even things like numbing of the toes and the fingers. And you can see that there are what are called chilblains in some people, you get these dark areas on the body. So that’s particularly fatal if it’s not controlled and it’s very difficult to control that. So what’s behind all of this susceptibility to the agent?

Well, there are two things going on, mainly one is the inability to clear the virus initially. So if you’re young, you can have a spike in viral numbers. It starts to get in your throat, drift down into the lungs. But young people tend to not have this overreaction, they tend to form antibodies fairly rapidly and clear the viral. If you clear the virus very quickly, you’ll actually have very little risk of going into hospital or the ICU. As an aside, if you don’t have a very strong case of COVID-19, looks like you don’t mount a very strong immune response, but that’s another topic for a future discussion. What’s more important is to focus on: What is it about the aging immune system that’s defective that leads to their inability to clear the virus? And then the second part that’s important for the agent is: What happens once they start to clear the virus and why is that so detrimental?

And what we are seeing is that the virus particles, particularly the viral RNA, lasts a long time, sometimes for weeks in the body. And those remnants actually are what we think are stimulating this hyper-immune reaction cytokine storm, which is driven largely by a particular protein complex called the inflammasome, which is already hyperactive, chronically in the agent. And we’ll talk about that later on, but just to give a shout-out to my co-authors, their drawings were beautiful. So we’ll get back to the disease course in a moment. One of the things I want to bring up is one of the great things in this article that Amber and Maeve did was that they drew a table of respiratory viral infections and what are the risk factors? And so I have the table in front of me so I’ll just read off some of them, which you can see in the paper.

Mers in the original SARS, they actually had high risk. One of the risks was one in Type 2 diabetes, obesity, cardiovascular diseases, hypertension, old age, this is for Mers. For SARS one, it was again diabetes, renal disease, neurological diseases, metabolic, and interestingly dermatological diseases, which is probably an immune thing. But why is that important? What that tells us is that these particular type of corona viruses attack the agent, and in particular, the agent with underlying co-morbidities, these underlying diseases. But what I would like to us to consider and what I’d like to argue is that it’s not just about having obesity, having diabetes, having heart disease that is the problem. Those are symptoms of a more insidious problem, which is that those people are most likely older than their chronological age, or they’re actually very old biologically because they’ve lived a long time, but we know that biological age will be accelerated by being obese, by not exercising and just living the lifestyle that we know from epidemiology is not the perfect one.

At least half of America is overweight or obese. If you include certain cutoffs, some people estimate that it’s over 75% and this drives the aging process. And one of the side effects of course is obesity but obesity may not be the main driver actually, that’s a symptom of the problem that I want to talk to you about. So there are lots of things that go wrong in the aged body. And by age, I’m not just talking about birthday candles, I’m talking about actual biological age. Now biological age can be measured in a variety of ways. Let’s just talk about that for a minute. We can measure the DNA methylation status of ourselves, the so-called Horvath DNA methylation clock, we can measure that pretty easily in a blood test or a swab from the cheek these days get a very accurate estimation of how old someone is biologically.

But there are other things that change in a predictable way. And unlike 10 years ago where we thought we’d never have biomarkers, now we have quite a few. You can look at changes in immune cell diversity, such as T-cells, you can build a very good immune clock. You can look at the levels of NAD in the body, which decline with time. One of the things that we, Gordan Lauc and I, professor Gordan Lauc and I, wrote about is a paper actually also in the journal, Aging, is that the immune system changes in part because sugars change that are attached to proteins. This is the process of glycation and Gordan’s lab has done an amazing job, they’ve found that there’s a glycan clock and what he calls it is the glycogen age of a person.

And why is that important? Because as we get older, the type of sugars that are attached to proteins in the body, whether it’s antibodies or actually the coronavirus spike protein, and even the H2 so-called receptor on the surface of endothelial cells, these are all changed as we get older in terms of their glycation. And if you look at figure 3 in the paper, you can see a beautiful rendition of these changes. And we also have epigenetic changes that control how cells behave. And we know that during aging, epigenetic changes occur, and we think that cells lose their identity. And that’s true for immune cells, it’s true for the lining of the blood vessels, the endothelial cells, and that may be why the virus has a greater chance of attacking an older person’s body as well.

And then finally, there’s the process of immunosenescence. Now that there’s two types of immunosenescence and I don’t want to get people confused here. Immunosenescence typically refers to just the aging of the overall immune system. That means that there’s less variety of T-cells. There’s less ability to mount an immune response and clear viruses, but there’s also cellular immunosenescence or what you call immuno. But there’s also cellular senescence which is a different story, which is about cells checking out of the cell cycle and becoming more like zombie cells. And you can stay in those for galactosidase or p16, and this is another type of cellular senescence.

There’s some overlap between the immunosenescence and cellular senescence, but it’s important to realize they’re not the same thing. And so that’s the lead-up to the whole paper, which goes into detail about these various causes susceptibility to viruses in general, but also to COVID-19. Now, one of the areas that we work on of course are the sirtuins. These are enzymes that our bodies make. There are seven of them in most of our cells, and they’re very important for fighting against diseases, both chronic diabetes, heart disease, Alzheimer’s, we believe based on a lot of mouse and human genetic studies. But also we’re finding are important for viral defenses. And we put forward a hypothesis in this paper that the sirtuin defenses are lost during COVID-19 infections. And one of the reasons for that is the following.

So sirtuins need NAD and unfortunately, as we get older, we think that a lot of our cells lose the ability to make an NAD effectively and they also destroy it for reasons that we don’t fully understand yet. But what we’ve also discovered in my lab and in others, Charlie Brenner put out a nice paper about this a few weeks ago, is that a virus, coronavirus and other types of viruses, deplete NAD in cells. And we think this is part of their defense, the viral attack and the inability of cells to survive the attack. Now they do this through activation of the PARPs. PARPs are poly ADP road to cell trans… polimeracion. So they do this by activating the PARPs, such as PARP1, PARP12, PARP14. And PARPs are enzymes that polymerize NAD and depleted from the cell. And we think that by either blocking the PARP activity or replacing, replenishing the NAD levels in infected cells and in the body of patients, we can give them a better chance of survival.

Now, why would we worry about NAD and sirtuins? Well sirtuins, particularly sirtuin 6, sirtuin 1, sirtuin 2, they control inflammation and they dampen it when it’s overactive. I mentioned the inflammasome. Well, one of the key components of the inflammasome is called NLRP3, and the acetylation chemical to that protein is what causes it to be active. Actually, if we deescalate of enzymes like CERT1, CERT2 deacetylate NLRP3, it brings that activity down. And so what we’re thinking is that when cells are infected, the NAD levels go down. So sirtuins are unable to dampen the inflammatory response and you get this cytokine storm. So in other words, if we were to raise NAD levels in patients, we may be able to prevent their bodies from going into this state of shock and aseptic like response.

Figure 2. Factors that increase the fatality risk of COVID-19.
Figure 2. Factors that increase the fatality risk of COVID-19.

Now I will admit, at first I didn’t think this was something that I should rush into. Of course, I would look like somebody with a hammer looking for a nail because you’d think that everything that I do looks like an NAD problem, but studies like the Brown paper that came out as well as studies over the last five years in my lab that have looked at NAD changes during macrophage activation and the PARP response have really pushed me into the belief that, as I write in this article with my coauthors, that NAD is part of this story. Now it’s not the whole story. In fact, the NAD story in this paper is only a small part of it, about 5%, but I want to talk about it because a lot of people are asking me, “David, what about NAD?” And interestingly, I’ve been working with a team in Boston on making an NAD precursor a drug.

And so for the last two years, with the help of a great team at Brigham and Women’s Hospital, they’ve been testing the safety and efficacy of an NAD precursor called MIB626, which is a proprietary version of NAD booster. So far, the molecule is extremely safe in the people that have been tested. It’s able to greatly raise NAD levels. Now there’s some debate out there in the Twitter-verse that the molecules that we work on in my lab and in these clinical trials don’t raise NAD and are not effective. Well, I can tell you that you probably shouldn’t get your scientific information from Twitter because it’s completely wrong. And now what’s interesting and exciting is that in the next few weeks, very extensive, double blind placebo controlled study is about to begin with this molecule. And we’ll see, pretty quickly I think, whether patients are helped by raising an NAD. Particularly the more severe ones.

Now, there are anecdotal case studies already. Some of them are online that you can look up if you’re interested, of patients recovering quite rapidly, supposedly, with treatment with NAD boosters like NMN, which is one of the ones that we work on. But those individual case studies don’t prove anything as we now know from having studied other molecules in other people’s study molecules in the world for COVID-19. So that’s why we’ve decided to do this very rigorous placebo controlled study and not just go for compassionate use. And we’ll see over the next few weeks, perhaps few months, realistically, whether this molecule that we’re working on is going to dampen the inflammatory response in patients that really need it. Drugs are very hard to make, most of them don’t work, so I’m not promising anything, I’m not expecting too much, but I think that we need to give this a shot.

And the other reason for believing in this work is that aging, as I started out in this review, in this talk mentioning, we think aging is the major driver of COVID-19 susceptibility. Aging of all of the different parts of the body in particular, the immune and circulatory systems. Now, if we can delay aging or reverse it, perhaps in some way with NAD boosting or with other drugs that are out there such as Metformin, which [inaudible] is arguing could be used to bring down blood sugar to improve the body’s survival. These kinds of longevity molecules could be used to bring not just the virus down, but boost the survival and the resilience and the defenses of the host up in the same way that you don’t just have weapons of war, you have the defenses as well.

And so on the defensive side, I think bringing up the defenses of the age is just as valid, if not more important than attacking the virus itself. So why would I say, “It’s just as important or more important?” Well consider that this is not the only virus that’s going to attack humanity going forward and vaccines while they’re great and we hold out full on. It probably won’t work against the next outbreak, whether it’s bird flu, regular flu, or another coronavirus, or even a mutated version of this one that’s out in the population. So we need to work also on the body’s ability to fight infections, in general.

So with that, I think I should let you all go. I’ve talked long enough about this paper. I hope you enjoy it. We really enjoyed writing it. It was challenging I’ll admit because it was written in real time as data was coming in and do a lot of things to update. And I’m grateful to Aging, the journal, for making papers available and published within rapid time. And I can tell you that the review process, the peer review process, was extensive. We’ve got pages and pages of comments from reviewers that really helped, particularly in this case. So, enjoy the paper and I’ll keep you updated through my other social media, but also through papers that we hope to publish in the next few months.

Thanks, take care.

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.

Aging - 2021 Ride for Roswell
Aging – 2021 Ride for Roswell

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

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.

Listen to an audio version of this article

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 CórdobaUniversidad MayorGeroscience 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.

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

2021 Ride for Roswell
2021 Ride for Roswell

Behind the Study: Cdkn1a Transcript and Aging

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.

Listen to an audio version of this post

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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