The world’s leading Rapamycin researcher, Dr. Mikhail Blagosklonny, has a long background in cancer research and one important discovery he made around 2000 was that Rapamycin slowed down senescent cancer cells in different ways. After that step-by-step, his interest in the longevity field increased and he developed the very interesting hyperfunction theory of aging.
He has made a huge contribution in moving the Rapamycin longevity field forward and his research papers have impacted many people. For example, the Rapamycin physician Alan Green who – thanks to these papers – took the decision in 2017 to start prescribing Rapamycin off label. Today, Alan Green has the biggest clinical experience in the area with more than 1,200 patients. A lot of other physicians have after that also taken these steps and one of those, for example, is physician Peter Attia.
The podcast is for general information and educational purposes only and is not medical advice for you or others. The use of information and materials linked to the podcast is at the users own risk. Always consult your physician with anything you do regarding your health or medical condition.
Researchers explain their studies that were published in AgingListen to an audio version of this post
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.
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.
Behind the Study is a series of transcribed videos from researchers elaborating on their recent oncology-focused studies published by Aging. Visit the AgingYouTube channel for more insights from outstanding authors.
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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.
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 3in 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.
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.
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.
Researchers from the Campisi Lab discovered new insights while investigating Cdkn1a transcript variants 1 and 2.
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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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.
“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.
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.
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 AgingYouTube channel for more insights from outstanding authors.
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.
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.
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.
Researchers from Harvard University and the Broad Institute wrote a theory article, published by Aging in 2021, and entitled, “Shifting epigenetic contexts influence regulatory variation and disease risk.”
Figure 1. Cross-tissue accessibility.
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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Listen to an audio version of this article
From birth to advanced age, chemical changes occur which affect the genetic material in human cells comprising chromosomes—known as chromatin. These nongenetic changes, otherwise referred to as epigenetic aging, accumulate with age and impact transcriptional programs. From growth and development to adulthood, these changes can denote shifting epigenetic contexts.
“Shifting epigenetic contexts influence regulatory variation and disease risk”
There is a considerable amount of evidence that suggests a causal relationship between changes in epigenetic state and cell aging. Curiously, researchers have repeatedly observed similar epigenetic changes occurring across different cell and tissue types, throughout different stages of life. These potentially synchronized changes may implicate mechanisms of the aging process.
“Together, these findings suggest that a central trajectory for epigenetic state that reflects innate aging processes may exist [20], upon which extrinsic and cell-type effects are layered.”
The researchers point out that in order to better understand the contribution of epigenetic changes to disease and aging, it is important to understand the developmental changes that occur between fetal and adult tissues, and their interaction with epigenetic aging.
“Furthermore, these fetal to adult epigenetic shifts can be compounded by additional modifications through aging-associated epigenetic changes.”
Characterizing these epigenetic trends and examining their potential interaction with later-in-life epigenetic aging were main goals of this study. In order to do this, the researchers defined genomic regions where, over the course of development and aging, chromatin accessibility consistently shifts. Chromatin can be broadly classified in either of two epigenetic states: activating or repressing modifications. These states refer to chromatin accessibility and the increased or decreased ability of DNA to access gene-regulatory machinery, such as transcription factors. The authors note that they used an accessibility-based definition of epigenetic context, and that there are other marks of epigenetic changes (e.g. methylation, and etc.) that are not captured by this definition.
“Epigenetic marks established during development can persist into adulthood [9], but they do so in the context of shifts in epigenetic states (see below) as tissues transition into their adult forms and functions.”
CONCLUSION
The researchers utilized genome-wide association study (GWAS) datasets to find that gene variants in adult tissues gaining nearby accessibility have stronger associations across a number of aging-related diseases, including neoplasms, arthritis, and atherosclerosis.
“In other words, it is the change in epigenetic context that modifies the regulatory potential of these variants, and this has direct impacts on individual associations with multiple diseases.”
Among their many findings, the researchers explain that the regulatory sequences which are most active during development are subject to strong negative selection later in life.
“We utilize our findings to propose a model for how evolutionary forces may have acted at these loci in humans, and how these forces in turn influence the distribution of mutations conferring heritable disease risk across a number of age-associated pathologies.”
Click here to read the full theory article, published by Aging.
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.
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 AgingYouTube channel for more insights from outstanding authors.
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Hi, I’m professor Michael Lisanti and I’m the Chair of Translational Medicine at the University of Salford, and today I want to talk about our new prospective article, which links COVID-19 and chronological aging, and is focused on potential treatments and prevention strategies. I got interested in this topic because there seems to be an association between COVID-19 fatalities and aging, especially in patients with advanced chronological age. Patients over 65, and their 70s and 80s, are more likely to have increased morbidity and mortality. And so, I thought there may be a link there, between aging and senescence and the viral replication, as well as the potential therapy.
What I’d like to highlight about this particular article is that it proposes potential treatment strategies as well as prevention strategies. The reason is because it appears that this disease, the virus itself, may target senescent cells and senescent cells have been rewired to increase protein synthesis and also to increase the secretion of inflammatory mediators, which is known as the SASP, the senescence-associated secretory phenotype.
And so, one idea would be to use drugs that are senolytics. Senolytics are drugs that target and lyse senescent cells, but also to use protein synthesis inhibitors. The reason is because proteins synthesis inhibitors and senolytic drugs would prevent viral replication, which would reduce viral transmission. And so this could be used as a preventative strategy. I’ll just give you a couple of examples. If you have a drug which is an FDA-approved protein synthesis inhibitor, it should inhibit the secretion of inflammatory mediators, like IL-6. It should inhibit the fibrosis by preventing the secretion and production of collagen. And most importantly, the virus is also made of protein, so if you have a protein synthesis inhibitor, it will also inhibit viral replication.
Figure 1.What is the relationship between COVID-19 and advanced chronological age?
There are three drugs I’d like to mention in particular. One is azithromycin, which is a senolytic. The others are also protein synthesis inhibitors, like doxycycline and rapamycin. All three have been shown to reduce IL-6 production because of their inhibition of protein synthesis activity. And also, all three of them have been shown to inhibit viral replication, not specifically of COVID 19, but since this effect on protein synthesis is a generalized effect, it should work for any virus. For example, azithromycin has been shown to inhibit the replication of Zika virus and Ebola virus, doxycycline has been shown to inhibit the replication of dengue virus, and rapamycin, which is another protein synthesis inhibitor with anti-aging properties, has been shown to inhibit replication of the HIV virus.
So, it seems to me that it’s a no-brainer that we should be repurposing FDA-approved drugs that are protein synthesis inhibitors, both for prevention, to prevent the inflammation fibrosis that’s occurring that’s killing people with COVID-19, and also to prevent the contagion by inhibiting viral replication. So I think this could provide a very inexpensive way forward because drugs like doxycyclin are only less than 10 cents a day, and could be used, as I said, for both prophylaxis and treatment. But, I think we need to use it early in the disease to prevent the fibrosis and inflammation, which makes them long, very inflexible and unable to expand and contract, and leads them to a fibrotic lung disease, which prevents patient recovery and could explain lethality of the disease.
I would like to directly engage with people to pick this up, to bring this forward as potential clinical trials. These clinical trials could be done directly in healthcare workers because they are the most vulnerable. In addition, they could be done in patients with advanced chronological age, or even with patients that are asymptomatic, that have been identified as the virus-positive. And it would be like a window trial where you would do viral titers first, and then you would give the drug and then you could also look at the viral titers after administering the drugs. So this would be a very easy, straightforward trial.
All the diagnostic tools for COVID-19 have already been identified and perfected, so all we need to do is interject FDA-approved drugs, which are protein synthesis inhibitors, to look at the eradication, the virus. So this would also be a very inexpensive clinical trial. But I would like to engage with infectious disease experts and virologists to help facilitate. Thank you.
Of course, I would like to thank two foundations which have supported our work: The Fox Point Foundation in Canada and The Healthy Life Foundation in the UK for providing the equipment and infrastructure at the University of Salford.
Click here to read the full paper, published by Aging.
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.
Hyperbaric oxygen therapy (HBOT) provides significant benefits for patients who have suffered brain damage. In this 2020 study, researchers assessed the effects of HBOT among healthy aging participants.
Figure 4. Brain regions with significant post hyperbaric oxygen therapy changes in cerebral blood flow.
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.
Cognitive decline among elderly populations 60 years of age and older is common. At least 50% of all community-dwelling individuals in this demographic express concern about declining cognitive abilities. Interventions such as exercise, healthy diets, and cognitive training (if maintained habitually) have shown positive effects on cognitive function. Another intervention with potential cognitive benefits—dating as far back as 1662 (before the discovery of oxygen)—in short, is the ingestion of pure pressurized oxygen, or hyperbaric oxygen therapy (HBOT).
Hyperoxic exposures increase the amount of oxygen dissolved in the body’s tissues and induce hypoxia-like physiological effects, including stem cell proliferation and angiogenesis. Previous studies have shown that repeated intermittent HBOT to improve cognitive functions in post-stroke, traumatic brain injury, and anoxic brain damaged patients, even years after an incident. While a number of studies have demonstrated that this therapy induces neurotherapeutic effects in injured patients, the effects of HBOT in normal aging populations had previously not been evaluated.
“The aim of the current study was to evaluate whether HBOT affects cognitive function and brain perfusion in normal, non-pathological, aging adults.”
A total of 63 patients were admitted into this study. The participants’ age, gender, right/left hand dominance, education, employment, medical conditions, medications, and other characteristics were collected at the start of the study. The median age was approximately 69 years old. Cognitive function of each participant was evaluated at baseline in terms of memory, attention, information processing speed, motor skills, and a number of other measures of neurocognitive function.
The participants were then assigned either the HBOT arm or the control arm of the study. Both groups had similar characteristics and cognitive function at baseline. Half of the participants received 60 daily sessions of HBOT over the course of three months. All post-intervention measurements were taken at least one week after the last hyperbaric session. The assessors were blind to the assignment each participant was given when reevaluating for cognitive function after HBOT intervention.
“Our protocol included 60 sessions of 100% oxygen at 2 ATA including 3 air breaks during each session in order to utilize the hyperoxic hypoxic paradox and minimize the risk for oxygen toxicity.”
RESULTS & CONCLUSION
“In summary, the study indicates that HBOT can induce cognitive enhancement in healthy aging populations.”
While the researchers are forthcoming about limitations of this study, results show that 60 sessions of hyperbaric oxygen therapy improved attention, information processing speed, executive function, and global cognitive functions. Importantly, HBOT also significantly improved cerebral blood flow in certain cortical regions of the brain.
“Moreover, the HBOT group had a significantly enhanced brain perfusion in the superior and middle frontal gyri, supplementary motor area and superior parietal lobule.”
Click here to read the full research paper, published by Aging.
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Aging is an open-access journal that publishes high-quality research papers bi-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 communities from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.
So the paper that I’m talking about is, “The complex genetic of gait speed: genome-wide meta analysis approach.” And what we did here is to combine 21 studies around the world and try to figure out what is the genetic predisposition for gait speed. The idea was that if we are going by number, then we will find something because the size is a matter of the resolution that you can pinpoint the genetic variant that might have an effect on the phenotype that, in our case, is gait speed. So when you’re talking about challenges, think of do you have 21 people or 21 groups that you need to combine together and figure out how you harmonize the data that they provide you with and try to figure out what’s going on there. This is a challenge because it lasted for almost four years until we had the paper done and published.
But eventually what we found was great. Although what we expected to find once we started this endeavor, we thought we’d have variants that have genomic significance. Meaning, if you have this variant either you have a lower gait speed or you have higher gait speed or normal gait speed. And we’re talking about elderly people. That’s what we tried to figure out. We found out that we didn’t find such a variant, but we find other alternatives.
We try to use protein analysis, group analysis, pathway analysis on all kinds of stuff. And every time that we put the finger on such a different analysis, we found something, some other interesting views. As I said, for genetic variant we didn’t find any, meaning the closest that we have was 10 to the -7 when the threshold was 10 to the -8.
Figure 1.Manhattan plot of meta-analysis of genome wide association studies of gait speed for ~2.5 million genotype and imputed SNPs
But when you look at these genes, we found that there are a couple of them that have higher prevalence among the top hit. Again, they didn’t reach a significance, but the minute you have such a number in the top hits, you think it might be relevant. We have a HLA-DPB1, we have the POM121-L2, and so forth and so forth. And you can see in the paper to look at those variants.
The interesting idea I’m seeing of the observation was that there was a couple of hits that we saw only once, but they are hits such as the [inaudible 00:03:36] 12I02 with a peak, meaning there is aggregation of a couple of hits around this gene or inside this gene. Again, it tells us that this gene might be relevant to what we are looking for. When we did the pathway analysis we found a couple of them that are associated with diabetes, which if you think about it, that really can cause people to either have slow gait speed or higher gait speed. It depends on the disease that you have. We have a couple of hits in the pathway, and a lot of this link us to cancer. And again, the same thing. If you think about it, the minute you have a disease, your performance, in this case it’s gait speed, is either declined or increased.
So we can see in both cases, though we didn’t find the right hit, still what we found has some biological explanation. It also does expression analysis or expression QTL. QTL means that those genes that are associated with the expression of the genes didn’t code in the phenotype, we found a couple of them that were higher significance. Again, another example of what is the predisposition of those genes to the phenotype that we had.
So, all in all, we concluded that we found some relevant genetic predisposition for this phenotype. And although we didn’t find the exact variant that can say “if you have it, you have low speed, and if you don’t have it, you have a higher speed,” we think that if we’re looking at the story that we crafted, we think that we’ve found some ideas, some biological explanation which is what is inside this paper.
Speaker
Aging was launched in 2009 and is currently a traditional peer reviewed journal with free access which publishes in monthly issues. Topics include high impact research papers of general interest and biological significance in all fields of aging research, as well as topics beyond traditional gerontology. You can click on the link in the description below to order a reprint or read the manuscript that was discussed in this interview on aging-us.com. Please feel free to subscribe to our YouTube channel and connect with us on Facebook, Twitter, or LinkedIn. Thank you.
Click here to read the full paper, published by Aging.
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.
Working with the company that’s really interested in developing some therapeutics that could combat aging, slow down the aging, we really need to get some quantitative tools that we can use to assess the efficacy of those molecules of those potential drugs that they identify in their preclinical studies. There were few works that would suggest some approaches how we can do that, but none of these really satisfy the goals that we have.
So we have to think of some other approaches that we may use, and there were several requirements that we really need for developing the successful protocols. First of all, we wanted this protocol to be absolutely non-invasive for our preclinical animal models, so it could be repeated on the same subject for several times. We can actually look through the lifespan of the subject, how these parameters and overall health is changed with age. They have to be really quantitative. So we didn’t really want to rely on some observational things like the hair grain, for example, that’s been considered the hallmark of aging for many years. Many of these observations, they really require coring by several individual observers and then they are compared, and they’re very subjective. (We) really wanted to get something more objective that we could put in numbers.
This manuscript that was published actually summarized almost three-year work that was dedicated to this problem. We tried many different approaches and finally came up with a protocol that we called determining physiological frailty index. And this frailty index is just the cumulative estimate of many, many physiological parameters that are related to the health of the animal. And they’re very relevant to human studies since these such parameters as body weight or physical strength that we could measure, usually using special equipment or blood pressure that we can measure in animal models-very similar to how we do it in humans, blood cell parameters, and a few others that can really give us the quantitative assessment of each parameter. Then we compare how much it is in older animals – or in animals that don’t feel well. How much of these parameters differ from when compared to the younger animals, and that gave us a certain quantitative estimate. So why is that important? It’s important for the reason of testing, as I mentioned already, various potential biologicals that would be developed as anti-aging drugs.
Figure 1.Assessment of individual biological age of NIH Swiss mice.
This protocol will now allow us to assess, quantitatively, the health status of animals then treat them with potential therapeutics, and then down the road, repeat this measurement to see if this frailty index, brought any improvement or not, and that would be indicative of the efficacy of the therapy. So this is one of the major goals of our research and why we developed this protocol. But for all future studies, we have actually another thought in mind, how we may use this particular approach. We’re now related to cancer research as you may know, due to the really successful development of many anti-cancer drugs, and many anti-cancer therapies. There are more and more cancer survivors. Actually in 2016, the American Cancer Society published statistics saying that there’s about 15 million people that went through the very harsh chemotherapeutic and radiation therapies. They are cancer-free. They never had relapsed cancer, but these therapies definitely affect a lot of other aspects of their health. And one of those aspects, besides any specific diseases, that they may develop is the accelerated aging.
With the development of more and more therapeutics, the expectation is that in 2026, there’ll be more than 20 million of cancer survivors. We’ll really need to be thinking about developing novel cancer therapeutics. We really should think not to make them more efficient and less toxic, but also to be able to diminish their damaging effect down the road at the latest stages of the life of basically to improve the quality of life of cancer survivors by adjusting the treatments at the time that we treat cancer. So we have less problems later on. To do that first, we have to test this in our preclinical models and for success of those tests, we really needed some quantitative assay that we can apply.
We think that our protocol of physiological frailty index would serve this purpose very well. So, basically, testing the efficacy and the therapeutic efficacy of different chemotherapeutic drugs. We may also look on a long-term effects to see how that affects animals health and adjust treatments based on the preclinical evaluation. This is why we think it’s really an important tool that could be very useful in many aspects of preclinical studies, and maybe sometimes applied then as many of preclinical studies translated into the clinical applications.
I’m also thinking that it may be very relevant for treatment of childhood cancers. Childhood cancers are very specific type of cancers. First of all, the regiments are actually the same as are worked out for adult people. Although young people and adult people are very different physiologically. They’re just adjusted by the weight, the age a little bit. But in principle, they are about the same.
The rate of cure for some types of childhood cancers nowadays is also pretty sufficient. So there is a large population of kids that went through chemotherapy and radiation that was applied to a very critical moment in their development. So they are effective. It’s really very significant. Actually the longevity of those childhood cancer survivors is statistically lower and they will premature age and develop a lot of different complications. So I think that that could be particularly important for treating various types of childhood cancers, and that can really affect the way we are treating childhood malignancies.
If we are able to reach our goal and adjust the treatment so we’re focusing not only on immediate therapeutic effect, but take into account these long-term complications that would inevitably arise after the treatment, we can significantly improve the quality of life of cancer survivors. That would be a very significant impact on the overall health of the population, I would say.
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.
