Researchers from the University of Leeds and the University of Glasgow conducted a 2019 study on the effects of transcutaneous vagal nerve stimulation (tVNS) among participants 55 years of age and older.
Medical illustration of vagus nerve with brain, lungs, heart, stomach and digestive tract.
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.
Among the cranial nerves, the vagus nerve has the largest distribution in the body. Extending from the brain to the abdomen, its name is derived from the Latin word vagari—which means “to wander.” This wandering nerve serves as part of the involuntary, or autonomic, nervous system. The vagus nerve is responsible for a number of important autonomic bodily functions, including lung function, heart rate, inflammation, brain/gut communication, mood, and even the consolidation of memories.
Human aging is accompanied by progressive autonomic changes, including increases in sympathetic nervous activity (“fight or flight” responses) and decreases in parasympathetic nervous activity (“rest and digest” responses). These changes can have considerable effects on heart function, emotion, mood, gut function, and overall quality of life, and can often lead to an increase in medication consumption with age.
TRANSCUTANEOUS VAGAL NERVE STIMULATION (TVNS)
In efforts to boost parasympathetic activity and decrease sympathetic activity, interventions such as vagus nerve stimulation (VNS) and transcutaneous vagal nerve stimulation (tVNS) have been developed. VNS is a highly invasive intervention, which involves surgically implanting an electrode around the cervical vagus nerve and a generator unit in the thoracic wall. Researchers have found that the non-invasive tVNS therapy (an electrical pulse focused on the tragus of the outer ear) is a safer and simpler intervention. Positive effects on autonomic function have been reported in non-patient groups treated with tVNS.
“tVNS is a simple, non-invasive and inexpensive therapy that involves stimulating the auricular branch of the vagus nerve (ABVN) at outer parts of the ear, conferring autonomic benefits in healthy volunteers [10].”
Previous research has shown that tVNS significantly reduces sympathetic nerve activity in healthy participants and boosts measures of parasympathetic activity. However, there are few studies available which detail the effects of tVNS in healthy older participants.
“Despite this evidence, there is little work examining the autonomic implications of administering tVNS in healthy older individuals who are undergoing age-associated shifts towards sympathetic prevalence.”
In the first study, the researchers observed the effects of acute, single-session tVNS on cardiovascular autonomic function compared with the effects of sham (ear lobe/placebo) stimulation among 14 healthy participants 55 years of age and older. They collected baseline values and measured heart rate variability (HVR) and baroreflex sensitivity.
“Since not all participants responded to tVNS, we examined if it was possible to identify potential tVNS responders from baseline parameters.”
In the second study, the researchers explored the effects of acute, single-session tVNS on autonomic function in the same age group and expanded the sample to 51 participants. The third study examined 26 participants in the same age group when administered tVNS once per day, for 15-minutes, over the course of two weeks. The researchers reported the impacts of daily tVNS in measures of autonomic function, health-related quality of life (QoL), mood, and sleep.
“Transcutaneous vagal nerve stimulation (tVNS) acutely administered to the tragus in healthy volunteers aged ≥ 55 years was associated with improvements in spontaneous cardiac baroreflex sensitivity and HRV.”
CONCLUSION
“For the first time, we have shown that age-related autonomic, QoL, mood and sleep changes may be improved with tVNS administered every day for two weeks.”
Although the researchers note that there are opportunities for improvement in this study design and further research is needed, participants reported improved sleep, depression, tension, vigor, and mood disturbance after two weeks of daily tVNS.
“These findings therefore suggest that daily tVNS may be an effective means of improving aspects of everyday life in this age group.”
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 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.
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.
We became interested in epigenetics because we practice functional medicine. So we’re concerned with genetic expression. Particularly, I would say that my first big wake-up call came from the research in cancer, epigenetics where the tumor micro environment hijacks epigenetic expression kind of takes over hypermethylating tumor suppressor genes, turning on oncogenes, et cetera. Our question became if we are pushing methylation forward with high dose methyl donors such as full later B12, could we be influencing cancer, epigenetics at all? That and a few other reasons prompted us to develop the diet and lifestyle intervention and try a very nutrition forward approach to changing epigenetic expression.
However, we can’t get an Illumina EPIC array in clinical practice. And so once we designed the program and started to use it in clinical practice, the next question was: Are we making a difference at all, in epigenetic expression? We were given an unrestricted grant by Metagenics. Metagenics is a professional supplement company out of California so they were not involved in study design. They had no control over the study and/or findings or investment in products that we used.
We didn’t include women, because at that age range … so, we wanted to look at middle-age when we know DNA methylation starts to go awry, global hypomethylation with those regions of aberrant hypermethylation … so that was the time we wanted to look at, but we didn’t have enough money to have a larger population. So if we included women in that age range, we would have premenopausal perimenopause and post-menopausal subjects, and it would be difficult for us to tease out that influence on the findings. So we decided in our pilot to just go with men and we did our eight-week diet and lifestyle intervention. The diet is again, designed specifically to influence methylation. It’s very methyl, donor dense. There are a lot of greens. There are other nutrients that can influence the methylation cycle, such as beets, choline from eggs.
Figure 1.CONSORT 2010 flow diagram.
We encouraged people to have liver a few times a week, which is high again in folate and B12. We also included a lot of the polyphenols that have preclinical data on them for influencing DNMT and Tet enzymes. In fact, a lot of really interesting research, again, going back to cancer, epigenetics, and these polyphenols actually influencing the re-expression of hypermethylated and inhibited tumor suppressor genes. So we were interested in that particularly because a lot of those polyphenols actually have very long traditional use history. So for instance, curcumin or EGCG or resveratrol, luteolin, lutein, ellagic acid, quercetin. When you look into traditional medicine, we see of course millennia long use for green tea and curcumin by way of example, but they’re all pleiotropic in their effect: Anti-inflammatory, antioxidant, anti-tumor agenetic, et cetera. And at least some of those mechanisms I suspect are driven by epigenetic changes.
So diet heavy methyl donors, but also these methylation augmenting polyphenols. We included an exercise prescription, which was at least five days for 30 minutes at a perceived exertion of 60 to 80%. So not necessarily intense. We tracked sleep and encouraged them to get at least seven hours per night and gave them some basic sleep hygiene tips as they requested. There was a meditation intervention as well. So everything that we did has some evidence in the literature, either in clinical studies or preclinical of influencing favorably DNA methylation. We use two supplements, a prebiotic lactobacillus plantarum. We did that specifically because there’s some evidence that lactobacillus plantarium may increase that endogenous microbial production of folate, of natural folates. And we also included a greens powder. So again, the polyphenols that I just mentioned, those in a concentrated powder and our participants took each of those supplements twice a day.
Outcome, we looked at the EPIC Illumina array. We looked at a host of blood biomarkers, subjective questionnaires. Our chief finding, our most exciting finding, was using Horvath … we collected saliva and then using Horvath’s 2013 DNA methylation biological clock we showed a significant reversal of biological age in our subjects by 3.23 years as compared to the control group and that was a P value of 0.018. The within group change in our study participants was 1.96 years, so almost 2 years with a trend towards significance. The P value there is 0.066, so super excited about that finding. We’ve got more to unpack on the Illumina array. Triglycerides dropped in our study participants and LDL dropped in the study participants. Now I should state, I didn’t mention at the beginning, but these were healthy men, not on medication. We had a pretty strict criteria for enrollment.
It actually took us a while. We started this study in 2017. It took us quite a while to enroll because the program was rigorous and the selection process was relatively involved. Circulating folate, circulating methylfolate increased also in our study participants. I think that covers most of it.
We worked with nutritionists. This is another good point. Again, the program is rigorous and we had nutritionists support the study participants. They didn’t do any coaching. They actually just had an IRB approved script where they asked them if they had questions on the diet and then questions on exercise, et cetera, et cetera. So they were required to have some contact with the nutritionists. We had high adherence findings, and I look forward to publishing those and just exploring it. Nutrition interventions are notoriously poor, and I think we actually did well. I suspect it’s because we had these nutrition contact points with the subjects. To my knowledge, it’s the first of its kind study, randomized control study.
It was a double blind obviously, but it was a randomized control study where we had 20 in the control group and 18 in the study group, what else? It was eight weeks in duration. The other diet intervention, as we wrote about in the paper is the new age study and that was a Mediterranean diet over the course of the year. And they had some interesting epigenetic DNA methylation changes and a subgroup of that population did have lowering of biological age.
So a big team, thank you to Dr. Steve Horvath and Dr. Josh Mitteldorf. Josh worked on Horvath, the DNA methylation clock analysis with some guidance from Steve Horvath. And so we’re deeply appreciative that work for us.
That’s our study. Our future is what we want to continue to look at this. I mean, this was our pilot study and we’d like to do a longer study, a larger study with men and women. So stay tuned, thank you.
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 surveyed available literature related to exercise and its association with longevity and aging. This extensive review expands on exercise as a lifestyle intervention and its ability to counteract cellular and tissue aging.
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Regular physical exercise provides benefits for both the body and mind, but how exactly does this healthy habit benefit our cells, signaling pathways, organs, and even bones? Furthermore, how can we employ regular exercise as part of an anti-aging strategy to extend our healthspan and lifespan?
Two researchers from the Beta Cell Aging Lab at Harvard Medical School authored a recent review paper which breaks down the currently available research on this very topic, with a special focus on pancreatic beta-cells and Type 2 diabetes. The authors detailed the recorded effects of exercise at systemic and cellular levels, its effects on each of the hallmarks of aging, and a potential molecular regulatory node that may integrate those effects. This review was published in May of 2021 by Aging, and entitled: “Effects of exercise on cellular and tissue aging.”
THE NINE HALLMARKS OF AGING
With age, cellular functions and systems in the human body progressively decline and destabilize, which eventually leads to disease and all-cause mortality. There are nine hallmarks of aging, which are classified as either primary, secondary, or integrative: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
“Exercise is a promising lifestyle intervention that has shown antiaging effects by extending lifespan and healthspan through decreasing the nine hallmarks of aging and age-associated inflammation.”
The researchers in this review explain that exercise is capable of counteracting each of these hallmarks of aging at systematic and cellular levels. They used publicly available research to cite and discuss the effects of exercise in each hallmark of aging in clear and thorough detail. The purpose of this article is to summarize this review, though readers are highly encouraged to read the full paper for deeper insights.
“The literature was surveyed on MEDLINE through freely accessible PubMed as a search engine for the terms: ‘exercise’, ‘longevity’ and ‘aging’; the most relevant studies were included as they related to the 9 hallmarks of aging.”
AMPK AS A CENTRAL REGULATOR
“In summary, exercise attenuates all hallmarks of aging through different molecular pathways and effectors that seem independent and disconnected.”
Given that exercise regulates each of these hallmarks individually, the researchers hypothesize that there must exist some kind of molecular regulatory node(s) capable of coordinating these responses. They propose that the 5’ adenosine monophosphate-activated protein kinase (AMPK) enzyme/protein could play this role.
“In summary, AMPK activation through exercise can impact all the hallmarks of aging through different signaling pathways as summarized in Figure 2 and can act as a signaling node capable of orchestrating many of the effects of exercise on the health span of different tissues and organs.”
EXERCISE AND TYPE 2 DIABETES
The researchers also discuss the effects of exercise on Type 2 diabetes mellitus (T2D).
“In summary, exercise activates molecular signals that can bypass defects in insulin signaling in skeletal muscle and increase skeletal muscle mitochondria, which are associated with improved insulin sensitivity in skeletal muscle and therefore improve aging-associated effects of T2D.”
Figure 1.Effects of exercise upon the aging process of different organs and systems. Created in BioRender.
CONCLUSION
“We propose that future studies should address the effects of exercise on tissues which are not considered its direct targets but do show accelerated aging in T2D, such as pancreatic β-cells. In these, the role of AMPK and its physiological control will become especially significant as exercise is considered a cellular antiaging strategy.”
Click here to read the full review, 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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Researchers discuss the role that the epigenetic clock may play in the aging process and in rejuvenation as an approach to set back epigenetic age.
Figure 3.Morphological changes induced by long-term OSKM gene action in human umbilical cord perivascular cells (HUCPVC).
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.
A centenarian is a human that has lived as long or longer than one hundred years. These individuals are marvels to aging researchers and have been studied at length in hopes of uncovering clues about the mechanisms that drive aging. Many researchers have crafted views and theories about the roots of gerontology; these curiosities have preceded the development of modern science.
“The hypothesis proposing the epigenome as the driver of aging was significantly strengthened by the converging discovery that DNA methylation at specific CpG sites could be used as a highly accurate biomarker of age defined by the Horvath clock [5].”
THE EPIGENETIC CLOCK
Throughout our lifetime, the rate of change in DNA methylation at age-dependent CpG sites has been found to consistently correlate with our rate of epigenetic aging and organismal aging. In 2013, researcher Stephen Horvath devised a mathematical algorithm using DNA methylation at specific CpG sites that is a highly accurate biomarker of age.
“In humans, the epigenetic age calculated by the clock algorithm shows a correlation of 0.96 to chronological age and an error margin of 3.6 years, an unprecedented accuracy for a biomarker of age [5, 24].”
In human babies, from birth to one year old, researchers explain that the ticking rate of the epigenetic clock is very high, as is our rate of aging at this point in the lifecycle. Then, from one to 20 years of age, the rate progressively decelerates. After age 20, the ticking rate is much slower. Among individuals with conditions such as cancer, HIV, obesity, Alzheimer’s disease, and even alcohol abuse, the ticking of the epigenetic clock and aging rate is, unsurprisingly, much higher. In another example, the rate of epigenetic aging is slower in supercentenarians and their children compared with non-centenarians.
“There is compelling evidence that the ticking rate of the clock is significantly correlated with the rate of biological aging in health and disease.”
THE EPIGENETIC CLOCK & AGE REJUVENATION
Even while they continue to proliferate, embryonic cells (ES) may remain indefinitely young—in a type of “suspended animation.” The epigenetic clock does not tick in embryonic cells, until they differentiate.
“In ES cells, the epigenetic clock does not tick [5] nor does the circadian clock oscillate [26]. Only when ES cells differentiate, both clocks become active and cells begin to age.”
Over the years, there have been clues indicating that it is possible to rejuvenate non-reproductive (somatic) cells back to induced pluripotent stem (iPS) cells, or embryonic-like cells. When somatic cells are reprogrammed to iPS cells, their epigenetic clocks stop ticking, their circadian clocks cease to oscillate, and ultimately, their epigenetic clock is set back to zero (or close to zero). These clues came from the development of animal cloning in the early 60s and, more recently, cell reprogramming.
The authors of this research perspective explain rejuvenation strategies including cell reprogramming, cyclic partial cell reprogramming, and other non-reprogramming strategies.
Two cell rejuvenation studies were described by the authors of this paper which suggest that, even at advanced stages of age, the epigenome continues to be responsive to command signals, including the OSKM genes, also known as the Yamanaka factors. This finding is compatible with the hypothesis that aging is not associated with DNA damage. The researchers explain two additional possible theories: 1.) Aging is preprogrammed in our DNA and due to progressive epigenome disorganization and loss of epigenetic information. 2.) Aging is not a programmed process, but a continuation of developmental growth driven by genetic pathways, such as mTOR.
“What seems to be clear is that epigenetic rejuvenation by cyclic partial reprogramming or alternative non-reprogramming strategies holds the key to both, understanding the mechanism by which the epigenome drives the aging process and arresting or even reversing organismal aging.”
CONCLUSIONS
In summary, the researchers explain that what the few initial study results seem to suggest is that when the epigenetic clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. However, the researchers emphasize that no firm conclusions should be drawn from the very few experimental results currently documented.
“Since we now have molecular tools, like the Yamanaka factors, that allow us to make the clock tick backwards, the time is ripe for opening a new dimension in gerontology, moving from aging research to epigenetic rejuvenation research.”
Click here to read the full research perspective, 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.
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 AgingYouTube channel for more insights from outstanding authors.
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Greetings. My name is Andrei Gudkov. I am working in Roswell Park Cancer Institute, designated cancer center located in Buffalo, New York. I am Senior Vice President for Basic Science and chair of Department of Cell Stress Biology. My research is focused on understanding of the mechanisms of deregulation of a variety of stress response pathways in cancer cells as well as in normal cells in relation to cancer origin, progression, or engraftment and trying to use the information which we are generating during this research to come up with new types of treatment of cancer or cancer prevention.
Recently, our interests have significantly switched towards studying of the mechanisms of aging in its relations to cancer, since, as we all know, both conditions are closely connected. During the last, probably 20 years, one of the central theories of aging in mammals has been evolving towards connection between chronic sterile inflammation, which is accumulating in tissues with age of a mammal, including humans, with systemic decline in regeneration capabilities, in function of organs and tissues, and increasing risk of major diseases, altogether known as aging-related diseases. And the source of this inflammation, its origin, has been the central focus of studies of many.
During last couple of years, the dominating opinion in the field is about the central role of senescent cells, cells which chose to stay irreversibly growth-arrested in response to DNA damage, which they acquire during their life. And, through that, change their phenotype in more significant way than just growth arrest, acquiring the ability to secrete a spectrum of pro-inflammatory factors.
These senescent cells, which initially were defined as such in tissue culture experiments, eventually were proclaimed to be the main suspects in their putative role of inflammation creators in aging organism. This idea has become really popular, especially following a series of brilliant works coming from number of laboratories, in which senescent cells were detected in vivo in mice and mouse models. And when these mice were treated with agents which eradicated these senescent cells, numerous signs of rejuvenation were observed.
I’m talking about the first paper of that kind appeared in 2011, Mayo Clinic, and the group led by Jim Kirkland and Jan van Deursen and a series of follow-up papers with similar results. In general, the idea of putting senescent cells in the position of the key sources of sterile chronic inflammation associated with aging came from Judy Campisi, who has provided the most important discoveries in that field.
Well, this theory is extremely appealing for many reasons. First, it is very well supported by evidence. Indeed, senescent cells, when they turn into senescents in culture, switch their phenotype into, so-called, SASPs, and that’s an associated secretory phenotype, the state in which cells continuously secrete pro-inflammatory factors. Second, these cells appear in culture as a result of serial passaging resembling aging. And, therefore, this link became kind of natural between aging and senescent cells. The presumption was that certain cells in the body who used up the number of divisions they can go through before they reach this state may be increasing with age and, therefore, these cells accumulate.
Each of them may become the source of sterile inflammation. Each single one provides a very weak signal, but, when they accumulate altogether, the impact may become significant and translated into pathological conditions. So recently, there were very few – and, even now, it is like that – very few biomarkers of senescent cells, none of which is very reliable because every single biomarker is kind of promiscuous and is not universally selective for senescent cells.
Among these biomarkers, two have been most popular. One is high level of expression of, so-called, senescent-associated senescent-associated beta-galactosidase, which can be detected chemically in fixed cells and tissues which undergo staining, including X-gal, which turn beta-galactosidase reaction into the blue dye under conditions which is not optimal for endogenous beta-galactosidases mammalian cells at low pH. And, under these conditions, the background beta-gal activity of normal cells is practically not seen and senescent cells become brightly visible. So this reaction, which unfortunately requires a cell… It can not be done on paraffin-embedded sections and require preservation of the enzymatic activity and, therefore, is available, mostly, on the frozen sections or in cells in culture… has been used very, very frequently. And in many papers, it has been just the only assay which was used for detection of so-called senescent cells.
Figure 1.Induction of p16Ink4a and SAβG in macrophages does not require p53.
The other biomarker, which resulted from a detailed analysis of promoters which are active selectively in senescent cells is the gene encoding cyclin-dependent kinase inhibitor p16. And the genes name is INK4a. In fact, this promoter of this gene is frequently upregulated in senescent cells, and it has relatively low background in other cells of the organism.
Again, p16 activation is not limited to senescent cells and, moreover, not every senescent cells has elevated p16, but that’s the best we have as of today. That is why, whenever the investigators want to create a mouse model in which they could have the desirable gene expressed exclusively in senescent cells, they use p16 promoter. And there are several mouse models; I’m aware of three in which reported constructs were put under p16 promoter. And the claim was that, when these reporters become obviously expressed in mouse tissues, that was interpreted as accumulation of senescent cells. Also, one can put under this promoter the gene which enables selective eradication of cells with this expression, and, therefore, there is an opportunity to selectively kill such cells. Again, this can be interpreted as a selective eradication of senescent cells.
Using these models, two groups of investigators claim that eradication of senescent cells in aged mice led to substantial demonstration of signs of rejuvenation and, in one case, with increased lifespan. Well, obviously, these data not only provided a very powerful support for the theory about the role of senescent cells in aging but also provided the proof of concept for development of pharmacological approaches to anti-aging treatment and treatment of conditions which lead to the high risk of development of age-related diseases, including cancer.
We obtained such mice in our laboratory, and we have been working with them during last couple of years. The mice we are using are coming from the laboratory of Norman Sharpless from North Carolina. And they have a luciferase reporter gene, which is substituting one of the alleles of p16 and, thereby, being expressed from the p16 promoter. We were pleased to see that these mice accumulate p16-driven luciferase-positive cells detected by in vivo imaging during their lives, which, actually, very well fit the senescent cell theory in their accumulation during life.
However, we were very surprised not seeing accumulation of these cells following total-body radiation or treatment with other genotoxic conditions, which, supposedly, should create lots of senescent cells. We also were puzzled that we were unable to see activation of p16-driven luciferase when we take tissues from these mice and isolated mesenchymal cells from these tissues in vitro and then turn them into senescents, and we failed to see activation of luciferase.
Again, all this together stimulated us to look at the nature of p16-positive cells in these mice and determined their nature, their origin, and their fate in vivo. We started from following the consequences of injection of cells, which would turn into senescents in vitro following injection in vivo into mice. And we labeled cells. We made cell senescents in culture by gum radiation. Then, we injected them intraperitoneal, subcutaneously, into mice. And we looked for their presence by monitoring the label which they were marked with.
Well, it appears that these labeled cells – their traces are disappearing quite quickly, and, within a few days, there are none left in the mice. However, if you put normal cells of similar origin, they actually last much longer. That was the first indication that there may be a mechanism of selective eradication of senescent cells in the body. To check this mechanism and one of our hypotheses was that this mechanism is associated with physical attack of some cells of immunity against senescent cells, and there’s supposed to be innate immunity because it’s happening immediately without any education over the organism.
Figure 5.Poly(I:C) abrogates elevated p16Ink4a expression in two independent in vivo models.
We use a trick in which we embedded senescent cells created in vitro into algenate beads, small spheres consisting of a polymer, which enables to keep cells alive inside them, does not interfere with acquisition of nutrients and oxygen by the cells, but prevents any attack against the cells from any immunocytes. When we took these beads filled with senescent cells and put them in peritoneal cavity of mice, we were pleased to see that they are lasting four weeks without significant death, indicating that senescent cells, who disappear if they are injected without protective beads, are indeed killed by some, so far, unknown mechanism.
In order to identify the executors of senescent cells, we put these beads filled with senescent cells as bait inside, very peritoneal cavity of normal mice, and two weeks later, we pulled them out and analyzed who was accumulating in terms of how cells around these beads in lavage liquid, as well as in the capsule, which was formed around every bead.
Our results brought us to a very important and quite striking observational. The major part of the cells, which was so in these beads as well as in the lavage, appeared to be cells with macrophageal markers on them, which appeared to be bright fluorescence, meaning that they have activated p16, and also positive for beta-gal staining conducted under conditions we are using to reveal senescent cells. So we had to conclude that senescent cells put in the beads attract, probably, by the products of their secretion special subtypes of immune cells, significant proportion of which become reprogrammed to start expressing two biomarkers which people have been using to distinguish senescent cells.
We studied these macrophages in detail, and, after we published our first paper in which we describe this phenomenon, we published a second one, also in Aging, where their properties were described in further details. And we confident that these are bonafide macrophages, not only because they have have biomarkers, they have surface antigen specific for macrophages, but also they are capable of phagocytosis and, moreover, they can be selectively killed by liposome-embedded clodronate, a poison which only kills cells capable of phagocytosis. This killing could be done both in vitro and in vivo when you inject liposomal clodronate inside mice.
So, as far as the presence of these cells in the body of those mice which are not embedded with algenate beads with senescent cells, today, we are confident that these macrophages are accumulating in subcutaneous fat of aged mice in large numbers. And, again, they express biomarkers of macrophages that can be selectively eradicated by clodronate.
So, altogether, it means that the cells which become p16-positive vivo, not necessarily our senescent cells – our operations does not disprove that the signal which we and other investigators are seeing in these mice and increasing with age is not associated with senescent cells. So, potentially, certain proportion of cells we see are, indeed, senescent. However, we are confident that significant part of the signal goes from macrophages, which can be induced into the phenotype associated with expression of both senescent markers when they’re exposed to senescent cells. What is also interesting that this phenotype is reversible. And, in our second paper, we provide a number of physiological stimuli which can either stimulate or suppressed acquisition of this phenotype by macrophages.
All this, together, provides a very interesting step forward in evolution of the theory of aging associated with accumulation of certain specific cell types, contributing to the sterile inflammation occurring in tissues. Today, we can say that those cells which we claim to be the main source of that are not necessarily senescent, but also can be immunocytes who share with senescent cells some of their properties but are not senescent by nature and simply reprogrammed macrophages.
What is the relative impact of these macrophages versus senescent cells towards the process of aging is a very important question, not only from a theoretical standpoint, but also from practical standpoint because, from the time when senescent cells were claimed to be the key players of aging, there have been a substantial effort in the field in generating and testing senolytic compounds, drugs, emerging drugs, which potentially can have anti-aging effect due to eradication of senescent cells from the body.
Whether senolytic compounds would, indeed, solve the issue because, presumably, they will eliminate only a part of the p16-positive cells. To what extent, we need to redirect our attention to the senescent cell-associated macrophages as potential alternative source of secreted factors is an open question. And these are the questions which we are trying to address in our ongoing work, which stems from these observations. Thank you.
Click here to read the full study published in 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.
Researchers used a bioinformatics approach (ESHRD) that leverages gene expression data from brain tissue to derive cell-type specific alterations in Alzheimer’s disease.
Neurons cells from the brain under the microscope.
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Cell-to-cell variability in the human brain is significantly heterogeneous. An abundance of differential brain cell types makes it laborious and expensive for researchers to generate single-cell gene expression data. While some studies use laser capture microdissection (LCM) and single-cell RNA sequencing (scRNA-Seq) to directly address the cellular heterogeneity in brain tissue, due to labor and cost, these studies generally have a small sample size and face power concerns. Most gene expression profiling studies of patients with Alzheimer’s disease (AD) are conducted post-mortem using brain tissue homogenates.
“Ultimately, the overall goal of gene expression profiling in AD is to understand the transcriptome changes in all major cell types of the brain in a well-powered approach that would facilitate the exploration of all the variables mentioned above.”
“We applied our approach to different gene expression datasets derived from brain homogenate profiling from AD patients and Non-Demented controls (ND) from 7 different brain regions.”
Researchers conducted brain region cell-specific pathway analysis and Gene Set Enrichment Analysis (GSEA). The team mapped and measured five different cell types in seven different brain regions. The cell types included: microglia, neuron, endothelial, astrocyte, and oligodendrocyte. Endothelial and oligodendrocyte are two cell types that are not easily examined in the brain and only very little gene expression data previously existed for Alzheimer’s disease.
“We conducted RNA expression profiling from both brain homogenates and oligodendrocytes obtained by LCM from the same donor brains and then calculated differential expression.”
The researchers used a dataset of Multiple System Atrophy (MSA) patients (n = 4) and controls (n = 5) to validate their ESHRD method. Homogenate, LCM, and scRNA-Seq results were compared using the ESHRD method. They also compared their findings to other research studies.
Results
“The ESHRD approach replicates previously published findings in neurons from AD patient brain specimens, and we extended our work to characterize novel AD-related changes in relatively unexplored cell types in AD, oligodendrocytes and endothelial cells.”
Neuronal, endothelial cells, and microglia were found to be the most represented “cell-specific” gene classes in patient brains with Alzheimer’s disease. Neuronal-specific genes were downregulated and enriched for synaptic processes. Endothelial genes were found to be upregulated in AD and enriched for angiogenesis and vascular functional processes.
“Differentially Expressed Genes (DEGs) we labeled as “mixed” represent the most prevalent class (73.4%), followed by DEGs labeled as microglia (6.6%), neuron (5.9%) and endothelial (5.7%). Astrocyte and oligodendrocyte labeled DEGs have a frequency of 3.6% and 3.1%, respectively.”
Microglia showed different patterns of expression across the brain in multiple regions. They found that astrocyte genes were enriched in SLC transport and immune processes and oligodendrocytes were enriched for the Glycoprotein metabolism in Alzheimer’s disease.
Conclusion
“We demonstrate the ability of this approach to highlight known neuronal-specific changes in the AD brain and utilize it to identify novel changes in endothelial cells and oligodendrocytes, two cell types not easily examined in the brain and for which only minimal gene expression knowledge exists in AD.”
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.
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.
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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].”
“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 silicoPathway 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.
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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 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
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 AgingYouTube channel for more insights from outstanding authors.
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Hello, my name is Alex Zhavoronkovand 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.
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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.
Researchers conducted an eight-week study on diet and lifestyle among a small cohort of 43 male participants between the ages of 50 and 72.
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In addition to the well-known personal and social costs of aging, the economic costs of aging are also considerably high. Research finds that investing in delaying aging is much more cost-effective than disease-specific spending. A study found that if Americans as a whole delayed their aging by 2.2 years (while extending healthspan), economic savings over 50 years could amount to a cumulative $7 trillion.
“The growing health-related economic and social challenges of our rapidly aging population are well recognized and affect individuals, their families, health systems and economies.”
The researchers organized a cohort of 43 healthy adult males between the ages of 50 and 72. Half of the participants (n=21) completed an eight-week treatment program, and the other half (control group=22) received no intervention. Interventions within the treatment program included regimented diet, sleep, exercise, relaxation guidance, and supplemental probiotics and phytonutrients. Prior to the treatment program, participants were enrolled in a preliminary education week to become acquainted with the researchers’ prescribed dietary and lifestyle interventions.
“To our knowledge, this is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge (2013) epigenetic aging in healthy adult males.”
Diet Prescription
Researchers prescribed the participants with mostly (not entirely) plant-based diet instructions to consume measured portions of liver, eggs, dark leafy greens, cruciferous vegetables, colorful vegetables (excluding white potatoes and sweetcorn), beets, pumpkin seeds (or pumpkin seed butter), sunflower seeds (or sunflower seed butter), methylation adaptogens, berries, rosemary, turmeric, garlic, green tea, oolong tea, animal protein, and low glycemic fruit. They were prescribed two daily doses of PhytoGanix®, which is a combination of organic vegetables, fruits, seeds, herbs, plant enzymes, prebiotics, and probiotics. A daily two-capsule dose of UltraFlora® Intensive Care, containing Lactobacillus plantarum, was also prescribed.
General guidance included that participants should choose organic food products over conventional, and to consume “healthy” oils and balanced types of fat, including coconut, olive, flaxseed, and pumpkin seed oil. Participants were told to avoid consuming added sugar, candy, dairy, grains, legumes/beans, and to minimize using plastic food containers. In addition, the prescription instructed participants to stay hydrated and not to eat between 7pm and 7am.
Lifestyle Prescription
The participant exercise prescription was a minimum of 30 minutes per day for at least five days per week, at 60-80% intensity. They completed two 20 minute breathing exercises daily, using the Steps to Elicit the Relaxation Response process developed by Herbert Benson, MD. Participants were prescribed to sleep a minimum of seven hours per night.
Measuring Epigenetic Age
“Currently, the best biochemical markers of an individual’s age are all based on patterns of methylation [5].”
To extract DNA from the participants, researchers collected saliva samples and evaluated their RNA and DNA. They used methylation kits, assays, and the Horvath DNAmAge clock to conduct genome-wide DNA methylation analysis and calculate epigenetic age (DNAmAge) at the beginning of the study, and at the end.
“Horvath’s DNAmAge clock predicts all-cause mortality and multiple morbidities better than chronological age. Methylation clocks (including DNAmAge) are based on systematic methylation changes with age.”
Conclusion
According to the Horvath DNAmAge clock, participants in the treatment group scored an average 3.23 years younger at the end of the eight-week program when compared to participants in the control group. While these findings are meaningful, additional studies with a larger cohort size, longer duration, and other human populations will be needed in order to confirm these results.
“Notably, the shorter timeframe of this study and the scale of potential reduction, while modest in magnitude, may correlate with meaningful socioeconomic benefits, and appears to have the potential to be broadly achievable.”
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.
