Behind the Study: COVID-19 and Chronological Aging

Dr. Michael P. Lisanti from The University of Salford describes his 2020 paper published by Aging, entitled, “COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?

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.

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?
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.

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.

Behind the Study: Interview with Dr. Marina P. Antoch

Dr. Marina Antoch of Roswell Park Comprehensive Cancer Center discusses her 2017 study published by Aging entitled, “Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice.”

Researchers explain their studies that were published in Aging
Researchers explain their studies that were published in Aging

My name is Marina Antoch, and I am a member of Department of Pharmacology and Therapeutics for Roswell Park Cancer Institute. And actually working here at Roswell for 10 years now. Recently my group, in collaboration with few other laboratories and the local biotech startup company, Everon Biosciences, summarize the recent research in the paper that was published in the journal, Aging. This paper is related to working out a novel approach that will allow us to assess the overall health in the preclinical animal model organelle.

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.

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.

Complex Drug Screenings Show Anti-Aging Potential in Natural Compounds

In an effort to mimic metformin and rapamycin, researchers used powerful screening methods to analyze over 800 natural compounds to assess their anti-aging potential and safety profile.

Modern Medical Research Laboratory. Scientific Lab, Drug Engineering Center Full of High-Tech Equipment, Computer Screen Showing DNA concept, Technology for Vaccine Development.

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.

Listen to an audio version of this article

By 2030, one in five Americans will age over 65 years old in the United States. As a society, an even larger aging population is fast on our heels. With age comes wisdom, and unfortunately, so does a number of costly and devastating diseases, including cancer, cardiovascular disease, Alzheimer’s disease, and Type II diabetes.

Researchers are currently working to mitigate the upcoming burden for this expanding population by developing anti-aging and anti-cancer drugs, and other geroprotective interventions that could extend healthspan, lower disease rates, and maintain productivity. However, the slow and expensive process of gaining approval for new potential pharmaceutical and nutraceutical interventions is historically arduous and prone to failure—especially when it comes to anti-aging and longevity research.

“Even if successful, to be used preventatively, anti-aging drugs face extraordinarily high safety and efficacy standards for approval [9].”

In 2017, researchers from the United States’ Insilico Medicine, Inc. and Life Extension, the United Kingdom’s Biogerontology Research Foundation, Canada’s Queen’s University, and Russia’s Russian Academy of Sciences, worked together to test a strategy to accelerate the development of safe, wide-scale anti-aging nutraceuticals. Their study was published in Aging’s Volume 9, Issue 11, and entitled, “Towards natural mimetics of metformin and rapamycin.” To date, this top-performing research paper has generated an Altmetric Attention score of 127.

Metformin and Rapamycin

“One strategy to hasten the process has been the repurposing of existing, FDA-approved drugs that show off-label anti-cancer and anti-aging potential [10,11], and at the top of that list are metformin and rapamycin, two drugs that mimic caloric restriction [12].”

Metformin and rapamycin have already been FDA approved for use in renal transplants, Type II diabetes, and metabolic syndrome. These two drugs are both mTOR inhibitors which, through numerous research studies, have shown pleiotropic effects exhibiting multiple anti-aging, anticancer, and anti-cardiovascular disease benefits. However, some adverse side effects pertaining to extended use have made it so these two interventions (used alone) are unable to move forward for wide-scale preventative use.

“Taken together, rapamycin and metformin are promising candidates for life and healthspan extension; however, concerns of adverse side effects have hampered their widescale adoption for this purpose.”

Although there are some adverse side effects, the chemical structures of metformin and rapamycin should not be ignored. These two drugs can be analyzed, and even mimicked, to develop new, safer interventions to prevent and treat age-related diseases. The researchers in this study initiated an effort to identify nutraceuticals as safe, natural alternatives to metformin and rapamycin drugs. 

“Nutraceuticals have received considerable attention in recent years for potential roles in preventing or treating a number of age-related diseases [88].”

The Study

“Our work is done entirely in silico and entails the use of metformin and rapamycin transcriptional and signaling pathway activation signatures to screen for matches amongst natural compounds.” 

Test compounds were selected based on the natural compounds listed in the UNPD and Library of Integrated Network‐based Cellular Signatures (LINCS) datasets. Gene‐ and pathway‐level signatures of metformin and rapamycin were mapped and screened for matches against the over 800 natural compounds chosen. The team used conventional statistical methods, pathway scoring-based methods, and training of deep neural networks for signature recognition. Researchers applied several bioinformatic approaches and deep learning methods, including the Oncofinder, Geroscope, and in silico Pathway Activation Network Decomposition Analysis (iPANDA). The iPANDA extracts robust, biologically relevant pathway activation signatures from the data. 

“In an application of these methods, we focused on mimicry of metformin and rapamycin, seeking nutraceuticals that could preserve their anti-aging and disease-preventive potential while being better suited for wide-scale prophylactic use.”

Results and Conclusion

“The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin.”  

Their initial list of over 800 natural compounds was condensed to a shortlist of candidate nutraceuticals that showed similarity to metformin and rapamycin and had low adverse effects. 

“This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.”

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.

Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21

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

Behind the Study: Dr. Alex Zhavoronkov

Aging Editorial Board member Dr. Alex Zhavoronkov discusses his 2020 research paper published by Aging, entitled, “Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections.”

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 in Aging. A new Behind the Study is released each Monday. Visit the Aging YouTube channel for more insights from outstanding authors.

Hello, my name is Alex Zhavoronkov and I’m the Founder and CEO of a company called Insilico Medicine. We are focused on the latest applications of artificial intelligence to drug discovery, biomarker development, and aging research. And I’m also a Chief Scientist at the Biogerontology Research Foundation. It’s a UK-based charity, 12 years old now founded in 2008. It’s called the Biogerontology Research Foundation because it’s focused primarily on biological and biomedical gerontology with support research worldwide. And we also conduct policy outreach, policy documents, and promote aging research worldwide.

We got into the coronavirus theme in mid-January as a company and also as an extended group of collaborators. At Insilico, we decided to go directly after viral proteins. So we have the ability at Insilico to identify new targets, but also to generate normal compounds very quickly using generative cell networks and reinforcement learning. So it’s kind of imaginative and strategy oriented AI to create molecules that specifically bind to the proteins of interest.

So we originally published and put out the paper and the molecules for the 3C-like main protease of the SARS-CoV-2. And we’re working with multiple collaborators worldwide to provide the molecules for their proteins of interest, and also we are generating a bunch of others. However, for the purposes of this paper we are not using AI in any way. It’s human intelligence and it is quite obvious that SARS-CoV-2 is more harmful to the elderly, the people over 50. So it’s infecting more people over 50, it is a much more severe and much more lethal in that age group.

So that is why it’s actually pretty unique compared to other viruses. So if you look at influenza and the other common viruses we do not see another virus, we do not see such effects in the elderly, so it’s a little bit more equal opportunity infections. For SARS-CoV-2 it infects mostly the elderly and there is actually no term to describe it right now. So in the paper that I put forward in Aging, I propose a new term so it’s gerophilic and gerolavic infection from Greek géros, old man and epivlavís, harmful. So it’s more harmful to the elderly, more severe in elderly. And gerophilic it’s géros again old man and philia is love, so it loves old people.

And if we’ll look at the data from Wuhan in China, you will see that 90% of the population, 89.7% of the population, who got the virus were over 30. And 99.2% of the population that died of it were over 30. So it’s really uneven distribution for both severe cases and lethal cases in the population. And one of the really important case studies that has been studied quite extensively is the Diamond Princess cruise ship. So the world’s most watched lab that came into attention because a few thousand people got stuck, very diverse population group was stuck on one cruise boat. And out of those few thousand, around 700 contracted the virus and most of them were over 65 and there were originally seven deaths, and a few more people died.

Figure 1. COVID-19 as a gerophilic and gerolavic infection.

And we see that people who had the infection, even with mild symptoms, they have dark spots in their lungs on CT. So it looks like they have some lesions and there is some fibrosis. Even if the disease has mild symptoms, in the elderly more so, it leaves the fibrotic trace. And in the paper, I’m hypothesizing that the disease is associated with immunosenescence. So both the involution of the thymus and many other processes that lead to immunosenescence. Immunosenescence leads to infection, so here you have of course chances of death. Infection leads to more damage and loss of homeostasis and that leads to accelerated aging. And also acceleration of age-related pathology also increase the chances of death that lead to more immunosenescence. So it’s kind of the vicious circle of immunosenescence and infection.

And there have been many studies in the past showing that some of the geroprotectors like sirolimus, rapamycin, are maybe effective in potentiating response to vaccines and also preventing infection in the elderly. So it’s paradoxical observation that immunosuppressant, like rapamycin, might have immunostimulatory effects. And there was anecdotal evidence showing that it protects the elderly from influenza and other virus not infections. It’s pretty obvious to try something like rapamycin that is reasonably safe in low doses. So in high doses it has substantial side effects, but in low doses it’s very well tolerated.

So there are others what is called rapalogs, very famous one is called everolimus. It’s so very close structural analog to sirolimus, developed by Novartis which has claimed to be selective to specific coattails and outdoor complex that make it more beneficial for aging and for other diseases. However, I would really like to see more evidence of that because those are very close structural analogs and there are other inhibitors that serve the same purpose. So 2013, Novartis conducted few experiments with everolimus, the drug is called RAD001 and demonstrated that in healthy elderly patients a low dose treatment with RAD001. Results in even potentiation and less infection with influenza and also potentiation of vaccines. So that was promising news.

So they published in 2014 in Science Translational Medicine and it was very promising study. Then in 2018, they showed that a combination of everolimus and another ToR inhibitor also results in immune potentiation and prevention of several infections, primarily influenza. So for influenza, they published in Science Translational Medicine, and a spinoff out of Novartis took those molecules into clinic, into Phase 3. And in Phase 3, they decided to instead of using everolimus, they used the molecule called BEZ235 rebranded as RTB101 which had high concentrations. It’s also a PI-3K inhibitor, so it’s not a very selective inhibitor or ToR, and they failed in Phase 3.

But they haven’t used RAD001 or sirolimus in combination or as control. I believe that it’s likely to be because of the molecule and also patient selection, so it should be biomarker used for that. But those promising early experiments clinical studies with RAD001 and also substantial evidence from the clinic met-studies showing that rapamycin is potentiating a vaccine response and immune status in the elderly. That gives us very promising data to try sirolimus in Phase 3 in low doses maybe once a week, maybe in combination with other geroprotectors like metformin, like NAD boosters, like senolytic to potentiate the immune system of the elderly before they get sick.

So in this paper, I also want to highlight that it’s not a medical advice, it’s not a recommendation, it’s a call for a clinical trials of an alternative view on how to address COVID-19 also SARS-CoV-2 and prevent infection and increase survival in the elderly, and also make it less severe for the elderly. So in this paper, I’m calling for clinical trials of rapamycin, a very well known geroprotector. It was actually implicated in Aging by Professor Mikhail Blagosklonny at Roswell Park in early 2000s. So 2004, 2005, 2006 with seminal papers showing that cancer agent is very likely to be also an anti-aging compound, and I now believe that this compound should be tried in multiple age associated pathologies and also for immmunosenescence, versing immunosenescence.

But other geroprotectors, promising geroprotectors, like metformin, can be very well combined with rapamycin, NAD boosters like nicotinamide riboside, nicotinamide mononucleotide may be tried in clinical trials. Senolytic, these could be tried also after COVID because of the fibrotic build-up, fibrosis in the lungs and also as rehabilitation after COVID. I think that some other promising geroprotectors including [inaudible] B3 activation. Again, that’s much less explored, could lead to gene clocks. So since 2013 there has been a revolution in gene clocks starting from our Panam and Horvath work showing that methylation data is very predictive of chronological age.

There are very highly accurate markers of aging but there are many others, so like lab tests, very simple clinical blood tests can be used to predict chronological age and my group published the first ones using deep learning. And there are many others including microbiomics aging clock, including imaging aging clocks, including transcriptomic aging clocks, and proteomics aging clocks, and whatever data there is longitudinal data that could be used to construct clocks should be collected during the clinical trials. And we should look at whether some of the molecules are making you younger or older compared to the chronological age from the various data types and look at the effects.

So that’s the current proposal on the paper, so I’m calling to try geroprotectors to protect the elderly, to potentiate their immune response to COVID, and also to try the aging clocks for both clinical trials enrollment and for monitoring to see what molecules are making you younger or older on pretty much every level. I’m also calling for those clinical trials because after COVID-19, after the epidemic is over, we’re going to have major economic consequences. There’s a lot of people who have been out of work, there’s been substantial capital influx from pretty much every government into the economy, so quantitative easing that might lead to inflation. We don’t know what’s going to happen to the economies of developed countries.

Previously, I published several papers and a book on economics of aging showing that increases in productive longevity would lead to substantial economic growth. If we manage to reduce the amount of money being spent on healthcare in the elderly by preventing disease and by rejuvenating the elderly, making them more resilient to disease, just that leads to unprecedented economic growth. And of course, if we make them more productive and contributing to the labor force longer, we will see unprecedented economic growth even further.

So we’re talking about double digit growth in developed countries. So here we can kill many birds with one stone, so to speak, even though I don’t like the word “kill.” And if we can try geroprotectors to prevent disease, but at the same time we can boost the economy after the epidemic is over if some of those geroprotectors show efficacy and people start believing more that aging is plastic and we can push the envelope in that area and really rejuvenate the elderly.

So that’s the paper and thank you very much for watching this. Stay healthy.

Click here to read the full study published in 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.

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

Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21
Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21

Rapamycin Rules out DNA Damage Theory of Aging

Dr. Mikhail Blagosklonny gleans an important new discovery in aging research—deduced from recent studies on short-lived mice and rapamycin.

3D illustration of a mutated or damaged DNA strand

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.

Listen to an audio version of this article

The exact mechanisms at play in the human aging process are still up for debate. A number of great minds in science have proposed plausible aging mechanisms and theories, such as DNA damage, telomere shortening, and DNA damage theories of aging. DNA damage theories suggest that aging is functional decline, caused by the accumulation of molecular damage. However, some scientists counterclaim that neither DNA damage nor telomere shortening limit lifespan or cause aging.

Dr. Mikhail Blagosklonny—an adjunct faculty member at the Roswell Park Comprehensive Cancer Center and Editor-in-Chief at Aging, Oncotarget, Oncoscience, and Cell Cycle—gleaned an important new perspective from recent aging studies, which could have been overlooked. He expanded on this discovery in a recent research perspective that was published in February 2021 in an issue of Aging, entitled: “DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.” To date, this research paper has generated an Altmetric Attention score of 43.

Rapamycin is a macrolide antibiotic that has immunosuppressive properties, regulates a key cellular growth pathway (mTOR), and has been at the center of numerous studies of aging since its discovery in 1964. Dr. Blagosklonny explains that, based on findings from recent mouse-model studies of rapamycin’s effects on short-lived mice, normal aging is not caused by the accumulation of molecular damage or telomere shortening.

“Here I discussed new evidence that normal aging is not caused by accumulation of molecular damage or telomere shortening: while extending normal lifespan in mice, rapamycin failed to do so in mice dying from molecular damage (Figure 1).”

Evidence From Rapamycin

In the study which Dr. Blagosklonny refers to, researchers genetically modified mice to artificially shorten telomeres, administered rapamycin to normal mice and the telomerase-deficient short-lived mice, and observed the effects. In normal mice, results were congruent with a number of other studies that found lifespan was significantly extended. In the telomerase-deficient mice, lifespan was shortened as a result of rapamycin. 

“While shortening lifespan by 18% in unnatural telomerase-deficient mice, in the same study in natural mice, rapamycin increased lifespan by 39% and healthspan by 58% (measured as tumor-free survival) [3].”

Given that rapamycin prolongs life in normal mice, Dr. Blagosklonny asserts that this study proves that normal lifespan is not constrained by telomere length. Telomeres only become life-limiting when they are artificially shortened to the point where rapamycin can no longer extend lifespan. Furthermore, Dr. Blagosklonny explains that although molecular damage and telomere shortening could be life-limiting, they ultimately do not limit life because quasi-programmed aging occurs at a faster rate.

“Although molecular damage accumulates, this accumulation is not life-limiting because quasi-programmed aging terminates life first (Figure 1A). Quasi-programmed (hyperfunctional) aging is life-limiting, because it is favored by natural selection.”

Quasi-Programmed (Hyperfunctional) Aging

In 2012, Dr. Blagosklonny wrote another widely-read research perspective that explains in great detail what his proposed hyperfunction theory of aging is, entitled, “Answering the ultimate question “What is the Proximal Cause of Aging?

“According to hyperfunction theory, aging is quasi-programmed, a continuation of developmental growth programs, driven in part by hyper-functional signaling pathways including the mTOR pathway [9].”

He explains that hyperfunction is an excessive, yet normal function that occurs later in life. Hyperfunction in this context does not necessarily mean an increase in function and, in some cases, it even means a decrease in function. The same pathways and functions that drive growth and development earlier in life, also drive age-related diseases later in life. Dr. Blagosklonny proposes that quasi-programmed (hyperfunctional) aging is favored by natural selection and is what limits life.

“It is hyperfunctional signaling pathways such as mTOR (one of many) that drive both growth and aging, causing age-related diseases that in turn damage organs, leading to secondary loss of function.”

Many signaling pathways interact with mTOR to drive aging, forming a network, including MEK/MAPK, NF-kB, p63, HIF-1, and many others. Dr. Blagosklonny suggests that, in theory, there could be a number of mTOR-independent factors of quasi-programmed aging that are life-limiting, as well. He goes on to exemplify several lines of evidence concluding that it is not molecular damage that causes normal aging or limits life—it is normal, quasi-programmed (hyperfunctional) aging.

Conclusion

Dr. Blagosklonny mentions a forthcoming review that will be entitled: “When longevity drugs do not increase longevity: Unifying development-driven and damage-induced theories of aging.”

“Once again, damage accumulates and must cause death eventually, but quasi-programmed (hyperfunctional) aging terminates life first. Molecular damage can become life-limiting, when artificially accelerated or, potentially, when quasi-programmed aging is decelerated.” 

Click here to read the full research perspective, published in 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.

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

Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21
Aging is a proud participant in the AACR Annual Meeting 2021 #AACR21
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