The world’s leading Rapamycin researcher, Dr. Mikhail Blagosklonny, has a long background in cancer research and one important discovery he made around 2000 was that Rapamycin slowed down senescent cancer cells in different ways. After that step-by-step, his interest in the longevity field increased and he developed the very interesting hyperfunction theory of aging.
He has made a huge contribution in moving the Rapamycin longevity field forward and his research papers have impacted many people. For example, the Rapamycin physician Alan Green who – thanks to these papers – took the decision in 2017 to start prescribing Rapamycin off label. Today, Alan Green has the biggest clinical experience in the area with more than 1,200 patients. A lot of other physicians have after that also taken these steps and one of those, for example, is physician Peter Attia.
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In a new research perspective, researchers discuss spermidine, rapamycin, caloric restriction, and exercise training to improve cardiac health in aging individuals.
Figure 1. Late-in-life exercise training boosts autophagic flux to an extent that rejuvenates cardiac function.
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Cardiac dysfunction is a major public health concern. While it can occur for various reasons at any age, the prevalence of cardiac dysfunction dramatically increases with advancing age. Unfortunately, the underlying mechanisms of age-related cardiac decline are still largely unknown. Thus, it is essential for researchers to uncover novel strategies to improve cardiac health at advanced ages.
Autophagic Flux
An important physiological process involved in maintaining cardiovascular homeostasis is autophagic flux. Autophagic flux is the process by which cells break down and recycle their own cellular components after they have become damaged or unnecessary. This process is essential for maintaining healthy cardiac function, as it slows age-related oxidative damage, reduces the accumulation of toxic lipid and protein aggregates, and improves energy metabolism. However, the efficiency of autophagic flux decreases with age, resulting in declined cardiac function.
Given its crucial role and fading functioning, the search for strategies to improve autophagic flux may be essential for improving cardiovascular health as humans age. Researchers Jae Min Cho, Rajeshwary Ghosh, Sohom Mookherjee, Sihem Boudina, and J. David Symons from the University of Utah authored a new research perspective about nutraceutical, lifestyle and pharmacological interventions that can reduce age-associated cardiac dysfunction. On December 1, 2022, their research perspective was published in Aging’s Volume 14, Issue 23, entitled, “Reduce, Reuse, Recycle, Run ! : 4 Rs to improve cardiac health in advanced age.”
“In the following sections we review evidence that age-associated cardiac dysfunction can be Reduced by boosting cardiomyocyte autophagy (i.e., the ability to Reuse and Recycle damaged/dysfunctional proteins) via spermidine, rapamycin, and caloric-restriction. In addition, we highlight a new report indicating that a physiological intervention i.e., Running, rejuvenates cardiomyocyte autophagic flux to an extent that lessens age-associated cardiac dysfunction.”
Late-in-Life Interventions
Late-in-life interventions to improve cardiac health are particularly important since many of the world’s elderly populations are reaching advanced age with limited resources. This means that proven, inexpensive and accessible interventions to reduce cardiac dysfunction may have a profound impact on these populations. In this research perspective, the authors discuss four key interventions that reduce age-associated cardiac dysfunction: spermidine, rapamycin, caloric restriction, and exercise training. These interventions can reduce age-associated cardiac dysfunction by improving cardiac autophagy.
In October 2021, Cho et al. published a novel research paper about their study on late-in-life treadmill training in mice and its impact on autophagy, protein aggregates and heart function. The results of this study provided the first evidence that late-in-life exercise training can rejuvenate autophagic flux, clear protein aggregates and attenuate aging-associated cardiac dysfunction. In another murine study, researchers demonstrated that calorie restriction activates AMPK and increases the expression of autophagy-associated genes in the heart muscles.
Spermidine is a polyamine found in certain foods, such as legumes and nuts. A 2016 study linked spermidine to reduced age-associated cardiac dysfunction by attenuating cardiac hypertrophy and preserving diastolic function. Rapamycin is an mTOR inhibitor, immunosuppressant and anti-cancer drug. In a 2013 study, Flynn et al. were the first to report the cardiovascular effects of rapamycin in the context of aging. Rapamycin’s cardiovascular benefits include repressed pro-inflammatory signaling in heart muscles, reduced hypertrophy and preserved systolic function.
Conclusion
As the world’s population continues to age, it is increasingly important to identify interventions that can reduce age-associated cardiac dysfunction while avoiding high costs and potential side effects. In this research perspective, the researchers discussed evidence that spermidine, rapamycin, calorie restriction, and exercise training can improve autophagic flux and reduce age-associated cardiac dysfunction. While the mechanisms responsible for these improvements have yet to be fully elucidated, these strategies are cost-effective, accessible and relatively safe for elderly populations, and could provide a valuable way to improve cardiac health in advanced age.
“Findings from Cho et al. suggest that age-associated cardiac dysfunction can be re-established by Reducing (physical inactivity), Reusing (lysosomal degradation products e.g., amino acids for ATP synthesis), Recycling (damaged intracellular organelles via the lysosome and other protein degradation pathways), and Running (or increasing physical activity via any mode that can be enjoyed regularly and safely by the individual) (Figure 1).”
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 bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.
Researchers analyzed the behavior of hybrid mice and presented a novel method to qualitatively estimate natural lifespan.
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Mice are frequently used as research models in aging studies. In 2019, researchers from the University of Gothenburg, R&D AstraZeneca, Harvard Medical School, and Karolinska Institutet identified logistical and ethical issues with the standard system of handling murine models in aging studies. Historically, researchers have favored using male mouse models instead of females, especially in pharmaceutical drug discovery and testing. However, half of the human population is female, and thus, females are half of the recipients of pharmaceuticals on the market. There is a need to fill this gap in research by emphasizing the assessment of both male and female subjects in research studies. The second logistical problem is the use of inbred mice. Inbred laboratory mice tend to have strain-specific behaviors that can skew study results. Therefore, there is a need to replace inbred mice with hybrid mice, especially in behavioral aging studies.
“In this study, F2 hybrid female and male mice were assessed for behavioral tests with the aim to investigate sex differences and age-related alterations.”
The team used various behavioral tests in order to gain a better understanding of the behavioral effects of aging in female and male F2 hybrid mice. Behavioral tests included an open-field test in an activity box, the shuttle box passive avoidance test, physiological analyses for behavioral phenotyping at seven, 15 and 22 months of age, and a swim test to measure immobility. Immobility in the swim test was an indicator of depressive-like behavior.
In sum, the researchers demonstrated that decreased exploratory behavior is a robust behavioral marker of aging in both male and female hybrid mice. However, altered learning, memory and depressive-like behavior were not significant markers of aging in these models. To this end, the team did not find sex differences in learning or memory using the passive avoidance test. In females, fat mass accounted for 30-46% of the observed increase in depressive-like behavior compared to males.
“This novel finding emphasizes the need to control for body composition in water-based tests.”
Ethical Murine Lifespan Assessment
The ethical method of lifespan assessment the researchers devised involves using estimates of lifespan. In a separate cohort from the behavioral studies, the researchers created this lifespan estimation by separating mice with signs of pain or severe disease from the healthy aging mice. The ill animals were euthanized and then included in two separate data curves. In one curve, the euthanized animals were counted as if their time of death was from natural causes (an underestimation of their lifespan). The researchers then made a second data curve in which they calculated that the euthanized animals as if they had been as healthy as their littermates (an overestimation of their lifespan since the euthanized animals were terminally ill). These curves created an interval that was used as the minimum and maximum lifespan of this cohort.
“We think this is a really good method that we hope people will start using in lifespan analysis,” said Malin Hernebring, from the University of Gothenburg and R&D AstraZeneca, in a recent Behind the Study interview with Aging-US.
Conclusion
The researchers presented a novel method to estimate natural lifespan in survival studies, in which animals in pain or with severe disease are not left to suffer until the end of their natural lifespan. This new method provides a qualitative estimation of natural lifespan, without the expense of animal welfare. The study also showed that F2 hybrid mice are effective in behavioral aging studies, and that fat mass partially accounts for increased immobility in aging female mice.
The researchers hope that their findings will lead to changes in the way aging research is conducted. In particular, they hope that more emphasis will be placed on testing both male and female subjects, that inbred mice will be replaced with hybrid mice and that their ethical method of lifespan assessment in mouse models is adopted at scale.
“In summary, this work is the first behavioral phenotypic aging study to use hybrid mice and include analyses of both sexes.”
Click here to read the full research paper published by Aging (Aging-US).
Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. 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.
Quote: “Blocking iron absorption through drugs or natural products extends lifespan. Many life-extending interventions, such as rapamycin, calorie restriction, and old plasma dilution can be explained by the effects they have on iron absorption, excretion, and metabolism.”
Quote: “This report describes a novel, comprehensive, and personalized therapeutic program that is based on the underlying pathogenesis of Alzheimer’s disease, and which involves multiple modalities designed to achieve metabolic enhancement for neurodegeneration (MEND).”
Quote: “The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends.”
Quote: “Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis.”
Quote: “Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of novel C. sativa cultivars may be used to downregulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis.”
Quote: “Sleep disturbance and deficiency are common among older adults and have been linked with dementia and all-cause mortality. Using nationally representative data, we examine the relationship between sleep disturbance and deficiency and their risk for incident dementia and all-cause mortality among older adults.”
Quote: “Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months.”
Authors: Priscila Chiavellini, Martina Canatelli-Mallat, Marianne Lehmann, Maria D. Gallardo, Claudia B. Herenu, Jose L. Cordeiro, James Clement, and Rodolfo G. Goya
Quote: “The view of aging has evolved in parallel with the advances in biomedical sciences. Long considered as an irreversible process where interventions were only aimed at slowing down its progression, breakthrough discoveries like animal cloning and cell reprogramming have deeply changed our understanding of postnatal development, giving rise to the emerging view that the epigenome is the driver of aging.”
Authors: Kara N. Fitzgerald, Romilly Hodges, Douglas Hanes, Emily Stack, David Cheishvili, Moshe Szyf, Janine Henkel, Melissa W. Twedt, Despina Giannopoulou, Josette Herdell, Sally Logan, and Ryan Bradley
Quote: “Manipulations to slow biological aging and extend healthspan are of interest given the societal and healthcare costs of our aging population. Herein we report on a randomized controlled clinical trial conducted among 43 healthy adult males between the ages of 50-72.”
Quote: “At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence. Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. The aim of the current study was to evaluate whether HBOT affects TL and senescent cell concentrations in a normal, non-pathological, aging adult population.”
Click here to read the latest papers published by Aging.
Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.
Behind the Study is a series of transcribed videos from researchers elaborating on their recent oncology-focused studies published by Aging. A new Behind the Study is released each Monday. Visit the AgingYouTube channel for more insights from outstanding authors.
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.
The Trending with Impact series highlights Aging publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.
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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.
