Machine learning and a broad range of biochemical and physiological traits were used to develop a new composite metric as a potential proxy for an underlying whole-body aging mechanism.
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“We present machine learning as a promising framework for measuring physiological age from broad-ranging physiological, cognitive, and molecular traits.”
Machine Learning
Machine learning is an important development in computer science that uses artificial intelligence. Algorithms and data (figured and input by human intelligence) are programed to automatically learn and improve through experience and new data. Machine learning approaches allow researchers to build mathematical models onto training data to predict target variables—target variables includinghuman physiological age and rate of aging.
“Here we use a machine learning approach with a broad range of biochemical and physiological traits including blood phenotypes (e.g., high-density lipoprotein), cardiovascular functions (e.g., pulse wave velocity) and psychological traits (e.g., neuroticism) as main groups from the SardiNIA longitudinal study of aging [48, 49] to estimate human physiological age, a metric for phenotypic and functional age progression [7].”
Subjects and Traits
Two very interesting study populations were included in this particular aging model. People living in Sardinia—an island off the coast of Italy and one of the first identified “Blue Zones”—are well-known for their long lives. They are currently contributing to a large longitudinal study on human aging, known as the SardiNIA Project. Data from the SardiNIA Project was used to develop the aging model in the current study.
“Funded by the National Institute on Aging in 2001, the SardiNIA Project (age range 14.0 to 101.3 years, with a mean of 43.7 years; 57% female) is a longitudinal study of human aging on the island of Sardinia, which is notable for its long-lived population[48, 49].”
The second cohort included in the current study was collected from the InCHIANTI study. Participants in this longitudinal population-based study were predominantly older adults living in Tuscany, Italy. After collecting the initial datasets from both cohorts, the researchers reduced the datasets using a “cleaning” strategy they developed. After cleaning, the number of subjects in the study went from 6165 to 4817, and the number of traits included in the algorithms went from 183 to 148. The researchers then configured the selected subjects and traits using computational algorithms and machine learning. Traits were ranked based on importance and weighted accordingly using algorithms the researchers developed. Study methods and materials were detailed thoroughly in the paper and its supplemental materials.
Supplementary Figure 1. Computational workflow for measuring physiological age and physiological aging rates (PAR) using the machine learning framework.
Conclusion
The team developed a promising new composite metric and was able to closely predict chronological age using their machine learning strategy. After they effectively estimated physiological age and validated their results, the researchers then used the ratio of physiological and chronological age to determine physiological aging rate, or PAR. Interestingly, the researchers observed that PAR was highly correlated with the epigenetic aging rate (EAR), which is a DNA methylation-based measure of aging. In addition, the researchers demonstrated that individuals with lower PARs outlived individuals with higher PARs. PAR may be a new proxy for an underlying whole-body aging mechanism.
“The efficacy of treatments aimed at slowing the aging process has traditionally been evaluated using individual biomarkers or limited collections of related biomarkers. Our current study has shown that PAR is a significant predictor for survival and correlated with epigenetic aging rate, providing evidence for a good measurement of ‘aging’.”
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 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 a trending theory article, Dennis Mangan proposes several reasons why iron may be a key driver of aging.
Iron mineral rock
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Iron is a mineral naturally found in the environment on Earth, within food sources and in all living organisms. A number of biochemical systems require this mineral and, in humans, the lack of iron results in anemia and a deficiency in hemoglobin—the protein responsible for supplying the body with oxygen. Anemia can also be caused by iron dysregulation. This occurs when iron damages the protein it should be safely stored in, such as ferritin, and then reacts in a toxic manner with surrounding cellular structures and organs. While iron is essential, the chemical properties of iron can make it a harmful substance if it is not tightly regulated.
“The very property of iron that makes it useful, its ability to accept or donate electrons, also gives it the ability to damage molecules and organelles via the Fenton reaction, in which iron reacts with hydrogen peroxide, leading to the formation of the highly reactive and toxic free radical, hydroxyl.”
There is an undeniable correlation between the accumulation of iron, DNA damage and age-related diseases. Excess iron levels are measurable in age-related illnesses, including cardiovascular disease, diabetes, cancer, and Alzheimer’s disease. In his paper, Mangan explains the important relationship between iron and the mammalian target of rapamycin (mTOR). Iron can act as a growth factor to activate mTOR. Crosswise, mTOR is capable of regulating iron metabolism.
“mTOR activation in diabetes may be responsible for the accumulation of excess iron seen in this illness; alternatively, accumulation of iron might activate mTOR, leading to diabetes.”
Researchers have demonstrated that inhibiting mTOR can extend lifespan and healthspan in animal models. The inhibition of mTOR, by drugs such as rapamycin, inhibits the accumulation of iron through an iron-regulating hormone called hepcidin. Therefore, it would be reasonable to assert that the over-activation of mTOR in diseases such as diabetes may be due to excess iron, or, excess iron may lead to diabetes through the over-activation of mTOR.
Sans Iron
Studies on experimental organisms, such as fruit flies, brewers yeast, roundworms and mice, have shown that the inhibition of iron leads to life extension. Mangan uses a number of natural iron chelators as examples, such as green tea catechins and curcumin. Calorie restriction is a highly effective life-extending intervention, and also a powerful regulator of iron metabolism. He lists iron inhibiting/chelating drugs, such as metformin, enalapril, quercetin, aspirin, tannic acid, ciclopirox, acetaminophen, bacitracin, berberine and baicalein.
“Thus, we can see that a large number of life-extending compounds also interact with iron, either by chelation, inhibition of absorption, or increased iron loss.”
Mangan also refers to a 2020 study which replaced 50% of blood plasma with saline, plus 5% albumin. To summarize their study, the researchers observed “rejuvenating” effects due to the dilution of old factors in the blood plasma. Similarly, elderly blood donors have experienced rejuvenating effects after donating blood. Mangan proposes that the critical old factor thatwas diluted was iron.
“Other components of plasma may be removed or diluted as well, but iron may be the critical element here.”
Conclusion
Mangan wrote a thought-provoking paper—far more detailed than this blog summary. He emphasizes that, since iron is both biologically needed and likely contributes to aging and disease, sufficient iron storage and regulation may be critical for the efficacy of upcoming anti-aging therapies that may be developed to extend lifespan.
“In sum, iron satisfies many of the conditions we might look for in a universally pro-aging substance. It accumulates with age; it is associated with many age-related diseases such as cardiovascular disease, cancer, and Alzheimer’s disease; it catalyzes the formation of cellular junk molecules and helps to prevent their turnover; removal of iron from plasma may be rejuvenating; and people with lower levels of body iron – blood donors – have a lower mortality rate.”
Click here to read the full theory article published by Aging (Aging-US).
Aging (Aging-US) 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.
The mechanisms and pathways involved in the health and aging benefits conveyed by green tea were investigated in C. elegans.
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Boiled or iced with water or milk, blended in smoothies, condensed into shots or even baked into pastries—humans are infatuated with green tea. Today, green tea is one of the most widely consumed beverages in the world. Molecules found in this plant, named catechins, are known to have numerous evidence-based health benefits, including weight loss and age delaying properties. However, the mechanism by which these effects take place have yet to be fully elucidated.
“The popularity of green tea makes it crucial to study its impact on health and aging.”
“We have designed the current study to investigate the impact and to unveil the target of the most abundant green tea catechins, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG).”
The Study
In this study, the researchers focused on testing two of the most common green tea catechins, epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), in isolated mitochondria from murine liver and C. elegans. C. elegans are approximately one millimeter long nematodes, or roundworms, and have been used in a variety of biomedical studies. The reason C. elegans were chosen for this study is likely due to the fact that many genes in C. elegans have functional counterparts in humans. (C. elegans also have the ability to “smell” cancer.)
Over the course of 24 hours or seven days, C. elegans and rodent mitochondria were treated with 2.5 μM of EGCG and/or ECG compounds. To analyze the green tea catechins’ effects on cellular metabolism, reactive oxygen species (ROS) homeostasis, stress resistance, physical exercise capacity, health- and lifespan, and on the underlying signaling pathways, the researchers conducted lifespan analyses, locomotion assay, paraquat stress resistance assay, basal oxygen consumption rate, ROS quantification, glucose oxidation assay, ATP quantification, activity assays for catalase and superoxide dismutase, fat content analysis, quantification of complex I activity in mitochondria, quantification of oxygen consumption rate in mitochondria, and statistical analyses.
“We conclude that applying the green tea catechins EGCG and ECG at a low dose extends the lifespan of C. elegans via inducing a mitohormetic response.”
They found that the catechins hindered mitochondrial respiration in C. elegans after 6–12 hours, the activity of complex I in isolated rodent mitochondria and temporarily increased ROS levels. Then, after 24 hours and through adaptive responses, catechins reduced fat content, enhanced ROS defense and, in the long term, improved healthspan in C. elegans.
Conclusion
Mechanisms and pathways observed to be involved in this process of C. elegans fitness and lifespan extension by green tea were further described in the paper. The researchers note that additional studies will be required to determine the best timing and dosage for administering catechins. They also acknowledge that the low bioavailability of green tea catechins may limit the lifespan extending effects of green tea in humans, despite the promising effects demonstrated in C. elegans.
“Despite the promising results obtained in animal experiments, the low bioavailability of EGCG [7] still raises the question of whether green tea catechins can reliably provoke beneficial effects in humans. Consequently, additional efforts might be needed to identify complex I inhibitors with increased bioavailability.”
Click here to read the full priority research paper published by Aging (Aging-US).
Aging (Aging-US) 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 adopted 103 retired sled dogs for a longitudinal study on canine aging that may one day be used to increase human healthspan and longevity.
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Whether they are sprinters or distance runners, sled dogs are known for their competitive nature and athletic prowess. With age, however, these athletes eventually run out of steam—just as humans inevitably do. Canines of all breeds are affected by aging, including a loss of resilience, accumulation of molecular damage and age-related diseases. These relatively short-lived, large mammals are one of the few to share environments with humans, and even have access to advanced medical care. Many believe the canine aging process resembles human aging the closest compared to any other animal.
The researchers chose to adopt retiredsleddogs for this study in particular for a variety of reasons: 1) Based on the type of events they partake in, sled dogs usually have a record of health and performance that can be used for reference as they age. 2) Sled dogs are selected for performance, but are not limited to a particular breed and can be crossbred. This provides a somewhat homogeneous population to study while being less prone to breed-specific biases. 3) Sled dogs are used to working with many handlers, therefore, the transition into the kennel/research facility may be easier for them to adjust to. 4) Over their career, these dogs have been exposed to environmental pathogens in frequent group interactions. This provides the researchers a sufficient immune system model to study. 5) Sled dogs are used to living in packs, but forming short-term bonds—making them adaptable to living with a variety of handlers in a population of 103 other dogs.
“Thus, it is essential to establish a reference set of ‘healthy aging’ parameters specifically for each dog model, and we see this as one of the main goals of our sled dog study.”
The optics of caring for 103 retired sled dogs between the ages of eight and 11 (when the study began) may initially sound problematic, but all indications suggest that these dogs are living better than many humans. Their 8,254-square foot kennel is located on the Baker Institute campus of the College of Veterinary Medicine at Cornell University. The researchers designed the study so that the dogs are thoroughly examined, observed, fed, socialized, exercised, vaccinated and anything else they may need. The dogs’ personalities and special needs are taken into consideration when cohabitating with other dogs, in their separate rooms and during playtime outside. They have in-house veterinarians and researchers to monitor their health. Importantly, the researchers are monitoring not only the dogs’ health but also parameters of their individual aging experience.
“Our goal is not just to assess the state of health of a given dog but rather to dissect the aging process into its two key components: (i) declining resilience and (ii) acquisition of aging-related diseases.”
In order to observe declining resilience and aging-related diseases, the dogs participate in regular physical fitness (treadmill and pull tests) and cognitive tests (handler questionnaires, β-amyloid plaques, brain atrophy, neuron loss, and etc.). Their performance and scores are measured and compared to their previous scores. The researchers also regularly collect blood samples to assess the dogs for somatic cell genome modifications (accumulation of DNA damage) and immune system status (immunosenescence).
“In general, the canine immune system undergoes similar age-related changes to that of humans [85]. However, since completed canine studies are generally less comprehensive and predominantly cross-sectional, the reliability and relative significance of various immune parameters in aging have yet to be characterized.”
CONCLUSION
This research is still ongoing, and the researchers believe the infrastructure they established in this sled dog study is an important advancement in aging research. In the future, this animal model may be used to test anti-aging therapies and translate into advancing human healthspan and lifespan.
“We expect that these analyses will allow us to (i) characterize the mechanism(s) and regulation of canine aging, (ii) identify parameters and biomarkers suitable for assessment of biological age, and (iii) define factors that may act as aging accelerators or decelerators.”
Click hereto read the full research perspective, published by Aging (Aging-US).
Aging (Aging-US) is an open-access journal that publishes research papers twice a month—in all fields of aging research and other biomedical 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 2020, researchers conducted an analysis of multimodal data on Alzheimer’s disease (AD). Their research concluded that AD may not begin with amyloid-β.
Figure 2. The network of genetic polymorphisms associated with Alzheimer’s disease.
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The root cause of Alzheimer’s disease (AD) is still unknown. For the past decades, the dominant paradigm many scientists have based their AD therapeutic solutions on has been the amyloid cascade hypothesis. The amyloid cascade hypothesis proposes that AD begins with the overproduction and accumulation of amyloid-β, followed by a number of other cascading symptoms. However, over 200 drug candidates based on this model have failed to prove clinical benefits in trial phases.
“The unsettlingly consistent failure of clinical trials led to questioning of the amyloid cascade hypothesis, stimulating a search for alternative AD paradigms [10–13].”
“In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer’s disease.”
THE STUDY
The researchers attempted to conduct an unbiased analysis of clinical profiles of early-stage Alzheimer’s disease patients and accumulated research data. Their search algorithms were hypothesis-independent and they used “expert assistance” to synthesize multimodal data. A list of AD plasma biomarkers were compared with classical acute-phase response reactants. A network of genetic polymorphisms associated with AD were aggregated in addition to a quick reference guide for select AD susceptibility factors. In totality, their expansive research and organization of accumulated data has led them to conclude that Alzheimer’s disease may be a system-level network disorder.
“Reconciling multimodal clinical profiles of early-stage AD patients and research knowledge accumulated in diverse expert domains suggests that sporadic Alzheimer’s disease may not be a homogenous CNS disease, but a heterogeneous, system-level, network disorder, which is driven by chronic network stress and dyshomeostasis.”
CONCLUSION
Key structures and circuits of the central nervous system may be preferential targets of AD symptoms, including chronic systemic stress, toxicity and inflammation. The researchers believe this is mainly due to the central nervous system’s centric positions and functions. In AD, symptoms are initially highly heterogeneous until the disease reaches its “endpoint,” which is recognized as Alzheimer’s disease. This may be the reason that treating AD with monotherapies has not yet yielded effective results.
Given this new model of viewing Alzheimer’s disease as a system-level network disorder, the researchers propose that patients should be treated using precision medicine tactics. Dr. Bredesen has developed a novel therapeutic approach designed to treat each individual patient for their unique symptoms of cognitive decline and Alzheimer’s disease. Using the Bredeson Protocol, many patients have reported years of improved, and even reversed, cognitive decline. Dr. Bredesen also notes in a recent Aging Interview that it is important to treat early signs of AD, just as it is important to detect other diseases in early stages.
“The promising results of an integrative, systemic, precision medicine approach to treating Alzheimer’s disease suggests that evaluating and addressing the individual organism as a whole rather than focusing exclusively on an apparently failing part may represent a promising strategy to approach other complex chronic multifactorial disorders, which warrants further exploration and development.”
Click hereto 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.
Following theSecond Interventions in Aging Conference, meeting organizers Dr. Brian Kennedy and Dr. Linda Partridge discuss their overview of the meeting proceedings that was published by Aging in 2017, entitled, “2nd interventions in aging conference.”
Researchers explain their studies that were published in Aging
Behind the Study is a series of transcribed videos from researchers elaborating on their recent oncology-focused studies published by Aging. Visit the AgingYouTube channel for more insights from outstanding authors.
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Dr. Brian Kennedy
I’m Brian Kennedy, I’m a professor at the Buck Institute for Research on Aging and a visiting professor at National University of Singapore.
Dr. Linda Partridge
And I’m Linda Partridge and I’m Director at the Max Planck Institute for Biology of Aging in Cologne, Germany. And also Director of the Institute for Healthy Aging at University College London.
So, Brian, how did you get into aging research?
Dr. Brian Kennedy
The funny thing was when I went to graduate school, I’d worked in yeast as an undergraduate, and I decided that I was not going to work in yeast anymore. But the more I realized about how difficult it was to work in mice, the more I wanted to work in yeast. And so there was another graduate student and I that wanted to go to Lenny Guarente‘s lab, and we decided to work in yeast and we wanted to figure out something completely crazy to do.
And we came up with two ideas: One was yeast apoptosis, which was a little weird for a single-celled organism and the other was aging. And we decided that aging was the least-
Dr. Linda Partridge
Mr. Nobel Prize.
Dr. Brian Kennedy
It’s true. We decided that aging was the least implausible of the two. And so we did that, but there’s a whole field on yeast apoptosis now too, so I guess we would have been okay. How about you?
Dr. Linda Partridge
Well, I got into it crabwise, really, because I started out life as an evolutionary biologist. So from the evolution point of view, it’s a completely weird trait because development produces a wonderfully functioning young organism and then it all goes to hell. You’d think it would be a lot easier to maintain it and to produce it in the first place. So I became very interested in how aging evolves and it is indeed really peculiar it’s almost certainly given what we’ve learned recently about the mechanisms of aging, actually bad effects in old age of genes that are good in the young. So I think that’s pretty interesting if you think about it as genes driving the old organism too hard to do the kinds of things that young organisms can do very well. I think it makes quite an easier process to think about, put it that way.
Dr. Brian Kennedy
And what we started the puzzle, both of us have worked on this a lot is, you know we’ve been trying to show that the pathways that are modulating aging are conserved. And it’s always kind of a puzzle that there’s so much conservation if this is a trait that evolution never really cared about that much. So it’s… I’ve never quite got that satisfied in my mind. What do you think about that?
Dr. Linda Partridge
I guess what I think is that the processes that you and other people have come up with, there are ones that do drive good things in young organisms. So the things that make for growth, for reproduction, for strong immune responses, for effective muscles and movement, all the things that young organisms have to do. But they seem to be set at too higher level when you get old, and I think that way it is actually quite easy to understand why it’s evolutionarily conserved because presumably the kinds of genes that control growth and reproduction evolve very early on.
Dr. Brian Kennedy
I agree. I actually argue with people that aging is going to be easier to modify than disease. So I think it’s going to be easier to keep people healthy than it is to wait until they get sick and try to treat them and make them better. I think of it as very simplistically as a state of homeostasis versus disequilibrium, you know, while you’re still relatively healthy, it’s fairly easy to tap into these pathways … relatively easy to tap into these pathways … and try to maintain that. But once you get into a state of disequilibrium, which I would call chronic disease of one sort or another, then you’ve got a problem. You’re kind of fighting entropy at that point and trying to put things back together again is very difficult.
Dr. Linda Partridge
Yes, it’s very interesting talking to colleagues in other areas about that idea because one gets a kind of ‘yuck’ response. So does that mean that humans are going to have to take pills when they’re healthy to prevent disease? You can point out that people do that already around statin and aspirin and things that lower high blood pressure. None of these are dealing with disease states, they’re in anticipation of possible disease states and trying to prevent them. So there’s plenty of taking pills to prevent things already, but for some reason, when you talk about it as a likely outcome of research into aging, there’s quite often a kickback, even from other scientists.
Dr. Brian Kennedy
I think most of the things we take, you know that are really working effectively really are aging drugs as much as they’re disease drugs. So you mentioned aspirin, but not just that I mean, look at statins, look at beta- blockers, look at early diabetes drugs like Metformin. All of them are targeting early risk factors for chronic disease, and I kind of feel like these risk factors are right at the interface between aging and disease itself.
Dr. Linda Partridge
They’re right on the nexus of the way in which aging acts as a risk factor for disease, and I think the other thing about them is that it’s quite clear that they’re turning out to have off-licence effects. Most of these drugs have a much broader therapeutic range than they’re generally used for. Which is exactly what you’d expect if they’re in there in that nexus between aging and disease.
Dr. Brian Kennedy
So what’s exciting to you now in your research? Where are you going in the next five years?
Dr. Linda Partridge
Well, funnily enough, I’m very much into drugs. So we’ve been doing quite a lot of drug work with drosophila and based exactly on this idea that mechanisms of aging are conserved. We’re starting to take a number of these drugs into mice, but also starting to do some big database stuff with humans, looking at particular pathways that have come up in the model organisms and asking whether SNPs associated with those pathways in humans ones that are either likely to increase the activity of the pathways concerned or decrease it or associated with particular types of disease risk.
So one can do this process called Mendelian randomization, which in theory gets rid of a lot of the effects of genetic background and focuses on a particular SNP. Now I think there’s enough data coming in on humans that we can really start to do the population genetics on these pathways, and I’m terribly excited by that.
What about you?
Dr. Brian Kennedy
Well, I have two goals right now. One is to try to go back to the simple organisms and really take a systems approach and try to take a yeast cell for example, and be able to describe all the features of aging, not just one gene at a time. And so we’re working a lot in sort of systems biology approaches there, but I think the main goal I have is-
Dr. Linda Partridge
Do you mean you’re looking at gene combinations or how are you doing it?
Dr. Brian Kennedy
Yes. Gene combinations, but also working with collaborators to look at how signaling pathways change with age to start to really understand longitudinal processes in a yeast cell. So the idea is to combine that with the genetic data and try to put the puzzle together.
Dr. Linda Partridge
I think that’s interesting.
Dr. Brian Kennedy
My main goal really is to get human and to start testing interventions in humans because I think we have enough knowledge now that we have things that are likely to work and we have reasonable candidate biomarkers, none of which are completely validated, but I feel good about some of them. And if you put that together, I kind of see it as a lock and key fit. You know we’ve got a bunch of interventions which are potential keys, and we’ve got a bunch of biomarkers which are potential locks, and we have to figure out which keys fit in which locks. So I’m looking at strategies to really test that in humans, either through academic research or through private companies.
Dr. Linda Partridge
So do you think companies are going to be interested in doing the kind of research that would target more than one disease, or do you think the way in is going to be to go for particular disease states? How do you think we should do it, operationally?
Dr. Brian Kennedy
I’d much rather target healthy aging or health span or prevention of multiple diseases. And I think there are companies that are thinking about that now, but they’re still relatively small generally. I think PhRMA kind of walks up to that ledge and looks over and then backs up. But eventually I think that it’s going to happen. I think what we need is some evidence that we can really modulates aging pathways. And that’s where this biomarker strategy or the kinds of things that [inaudible] is doing to get multiple disease parameters simultaneously in clinical trials. Those kinds of things, I think, are you just need a couple of success stories and then people start to get it. So I’m agnostic as to whether it’s done academically or privately, I just want to make it happen and so you know.
Dr. Linda Partridge
So what do you think about… We know so much from the animal studies about rapamycin now we probably know more about that than any other drug in the context of aging. Do you think there are going to be more clinical trials with rapamycin for off-license applications? Do you think it would be a trial for Alzheimer’s for instance?
Dr. Brian Kennedy
You know, there’ve been a lot of talk about trials for Alzheimer’s and I don’t think one has gotten started yet. But I think you’re going to start to see more and more of this. Then of course, there’s a lot of research to try to figure out how to either dose rapamycin or everolimus, which is the first generation of that rapalog in a way that doesn’t have the toxicity or to develop new drugs that have the efficacy without the toxicity. So I think both of those approaches are moving forward.
Novartis just spun off a small company to try to do this, and so I think that there’s renewed interest in trying to inhibit mTOR, but there’s still a lot of open questions about how it’s going to be best to do that. But having said that the number of potential indications, I mean, not to mention aging itself is so large that there’s clearly value into doing this successfully. So I’m pretty excited about where that’s going to go. I think that’s only one of a bunch of pathways though and you’re looking for new drugs and new pathways, and I think we’re going to find that there are a lot of different potential entry points for intervention in aging as we go forward.
Dr. Linda Partridge
I think it’s a time of great excitement. I just hope that some of the human trials get done while I’m still active. I’d love to see some successes with people.
Dr. Brian Kennedy
But you will be active for at least 20 more years, so …
Dr. Linda Partridge
Lots longer if somebody comes up with a pill.
Dr. Brian Kennedy
You know, that’s why I think doing this Fusion Conference has been so fun. You know, we’ve done two of these now in Cancun, and the idea is to bring different groups of people to look at different strategies for interventions in aging. I think that the conferences are relatively small, but we try to recruit a wide range of people. So we get people discussing different kinds of ideas that don’t normally talk. That’s what I think the strength of it is what do you think?
Dr. Linda Partridge
I agree with that. I really like the format of those conferences because they have a low upper limit on the number of delegates deliberately. So that most people can give talks or posters and there’s plenty of time for discussion. And what I noticed at those meetings correspondingly is that the discussion is very intense. Almost everybody talks to everybody else at some point during the meeting. So there’s real interchange of ideas as you say, between people who we deliberately invite from different areas, and I think it’s been a great success and it’s also been very nice to see it going more and more translational. There is more and more interest in mechanisms that are going to give rise to preventative measures rather than just the basic research, which has been fantastic and was necessary to get anywhere. But people really are trying to push it into helping people now. And I find that very exciting. So yes, I think meetings are great.
Dr. Brian Kennedy
Yes, I know, and I think as we go forward with these meetings, we’ll probably continue to try to emphasize these human intervention studies as much as possible.
Dr. Linda Partridge
I think that’s very much a specialty of that meeting.
Dr. Brian Kennedy
Because there are other meetings that really focus on the basic biology of aging, but this is really trying to get at the next step.
Dr. Linda Partridge
Yeah. Yeah. It’s particularly good when we can get basic scientists and clinicians together, I think. And also people from the various companies who might do something about the discoveries. I think it’s a very good mix of people that way.
Dr. Brian Kennedy
I can’t, you know, in my better moments, I think that we’re almost right at a tipping point where we’re going to push over this wall and then all of a sudden everybody’s going to be saying, oh, targeting aging is common sense in 10 years. I still have the bad moments where I feel like the little soldier walking into the wall and never go anywhere too.
Dr. Linda Partridge
Yes. I fluctuate between those two points as well, but I find myself feeling optimistic more and more often seeing what’s happening.
Dr. Brian Kennedy
That’s good. Well, it’ll be exciting to see where the field goes moving forward…
Dr. Linda Partridge
Yeah, indeed. Indeed.
Click here to read the full meeting report, published by Aging.
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 June 2021, Web of Science (Clarivate Analytics) released their 2020 JCR Impact Factor. Aging‘s 2020 impact factor is 5.682.
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BUFFALO, NY-August 20, 2021 – Agingis indexed by Web of Science: Science Citation Index Expanded (abbreviated as Aging‑US). In June 2021, Web of Science (Clarivate Analytics) released their 2020 JCR Impact Factor. Aging is pleased to report that our 2020 impact factor is 5.682. This number has increased from last year’s 4.831. Without self-citation, Aging’s 2020 impact factor is 5.279.
Aging is listed in the Web of Science: Science Citation Index Expanded in two categories: Cell Biology and Geriatrics & Gerontology. According to the Journal Citation Indicator (JCI), Aging is ranked in the Q1 quartile in both categories.
Since 2009, Aginghaspublished research papers in all fields of aging research including, but not limited to, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan.
This journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, and prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.
To learn more about Aging, publication standards, and past or current issues, visit www.aging-us.com.
Impact Journals is an open-access publisher of research journals in biomedical sciences. Our publications focus on topics surrounding cancer research and all fields of aging research. Our mission is to provide scientists with the opportunity to share their exceptional discoveries, offer services that enable rapid dissemination of results, and to present vital findings from the many fields of biomedical science.
The MEND (Bredesen) protocol to treat neurodegeneration associated with Alzheimer’s disease was tested in a small cohort. In 2016, researchers followed up with objective results.
Blue synapse and neuron. 3D rendering
The Top-Performer series highlights papers published by Agingthat 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.
Precursors to the onset of early Alzheimer’s disease (AD) include mild cognitive impairment (MCI) and subjective cognitive impairment (SCI). Many have viewed this looming neurodegeneration as an unavoidable fate that accompanies aging. However, in a 2014 study, a novel precision medicine treatment approach, termed the metabolic enhancement for neurodegeneration (MEND) protocol, yielded unprecedented results. Nine out of 10 participants with memory loss associated with AD, amnestic MCI, and SCI, were treated using the MEND protocol. Participants displayed subjective improvement in cognition within 3-6 months of this protocol. The study claims their only failure was one patient with very late stage AD.
“In each of these cases, obvious subjective improvement, noted by the patient, his/her significant other, and his/her co-workers, was accompanied by clear, quantitated, objective improvement.”
THE MEND PROTOCOL
The MEND protocol, also known as the Bredesen Protocol (named after the creator of the protocol, Dr. Dale Bredesen), consists of a multifaceted, tailored approach to treating each AD patient for their individual symptoms of cognitive decline—and not only a few symptoms. This strategy uses a combination of diet, lifestyle, and therapeutic interventions. Treatment is based on the hypothesis that AD occurs due to an imbalance in an extensive plasticity network in the brain. The authors note that the MEND protocol is an iterative process and designed to improve with continued patient visits.
“The therapeutic system described in this report derives from basic studies of the role of APP signaling and proteolysis in plasticity, and the imbalance in this receptor proteolysis that reproducibly occurs in Alzheimer’s disease.”
Upon clinical assessment and lab testing, the patients’ physical and cognitive health were evaluated. Based on this assessment, patients were prescribed a lengthy personalized therapeutic system. Among other objectives, the MEND protocol recommends treating diabetes; improving sleep and digestive health; reducing stress, inflammation, and blood sugar; increasing physical exercise, intellectual stimulation, antioxidants, and vitamins; and optimizing hormone balance, synthesis of acetylcholine, nerve growth factors and mitochondrial function.
ANECDOTAL AND OBJECTIVE RESULTS
“The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective.”
Before participating in the MEND protocol, most of the 10 participants reported a family history of AD, confusion, difficulty with word finding, following instructions, remembering, reading, concentrating, driving, completing work related tasks, and other cognitive struggles. Over the course of between five and 24 months on the MEND, nine of 10 patients and their families or caregivers reported improved cognitive function. Some patients were able to go back to work, play games, and even babysit their grandchildren. One spouse of a patient mentioned that her husband had stopped following the protocol for a period of time, which resulted in him leaving the car in the driveway idling with the keys in the ignition. After he resumed the protocol, no such instances were reported.
Bearing in mind that this study used an extremely small cohort to test this very expensive protocol, the objective results observed by the researchers were still considerably significant. Quantitative neuropsychological testing showed improvements of up to three standard deviations. One patient showed an increase in hippocampal volume from 17th percentile to 75th percentile. These results must be verified in a larger sample size to validate efficacy.
CONCLUSION
“The initial results for these patients show greater improvements than have been reported for other patients treated for Alzheimer’s disease. The results provide further support for the suggestion that such a comprehensive approach [3] to treat early Alzheimer’s disease and its precursors, MCI and SCI, is effective. The results also support the need for a large-scale, personalized clinical trial using this protocol.”
Click here to read the full research paper, published by Aging.
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 AgingListen to an audio version of this post
Dr. Kara Fitzgerald:
I am thrilled with our study being accepted into the journal Aging. I think it’s the perfect home for it.
The process of submitting and our peer review journey was actually, it was actually a lot of fun! I found our peer reviewers, they really move our study forward and help us to articulate our findings and inquisitive, appreciative of what we’ve done. And so that whole piece of it was good.
Dr. David Sinclair actually suggested that Aging would be the right home for us and I couldn’t agree more.
What else? It’s open access. I think open access is essential. Having our study behind a paywall and inaccessible to other scientists and just the community who might be interested in the longevity research that’s happening, particularly this, which is a diet and lifestyle program so, it’s something that people could actually do if they wanted to. We want that available. So I’m all for open access.
I enjoyed working with Aging. I thought that they were good across the board. And I just appreciate David’s recommendation that we go here.
Click here to read the full study published by Aging.
Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.
Researchers tested antiviral, anticancer, and immunosuppressive drug combinations that may aid in treating neurodegenerative disorders, including Alzheimer’s disease.
Figure 5. Neratinib and AR12 combine to reduce the expression of HSP90, HSP70, GRP78 and HSP27 via autophagy.
The Trending with Impact series highlights Aging publications that attract higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Aging-US.com.
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Heat shock proteins (HSPs), also known today as stress proteins, were first observed in fruit flies in the 1960s. After Dr. Ferruccio Ritossa inadvertently subjected a preparation of fruit fly salivary glands to a non-lethal increase in temperature, he discovered a new pattern of chromosomal “puffing.” In 1974, researchers identified the proteins that were encoded by the “puffs” recorded by Dr. Ritossa, and named them heat shock proteins.
These newfound proteins appeared to only become detectable when the cells were heated. Researchers later learned that HSPs can also be induced by oxidants, toxins, heavy metals, free radicals, viruses, and other stressors. Since its discovery, variations of this genetic system have been found in all bacteria, plants, and animals—including humans. HSPs have been well-studied since this revelation, and researchers now believe these molecular chaperones play important roles in protein refolding, aging-related diseases, and overall longevity.
“Toxic misfolded proteins are key drivers of AD [Alzheimer’s disease], ALS [Amyotrophic lateral sclerosis], HC [Huntington’s Chorea] and other neurodegenerative diseases.”
“In this paper we examined using isogenic colon cancer cells [with] several existing drugs that function by increasing autophagy and degrading misfolded proteins.”
THE STUDY
“Aberrant expression of chaperone proteins is found in many human pathologies including cancer, in virology and in AD, ALS and HC.”
In this study, researchers tested drugs that have been used preclinically and clinically in several anticancer studies. The drugs used were: AR12, an antiviral chaperone ATPase inhibitor; Neratinib, a tyrosine kinase inhibitor; a combination of AR12 and Neratinib; Fingolimod, an immunosuppressive sphingosine l-phosphate receptor modulator; MMF, monomethyl fumarate; and a combination of Fingolimod and MMF.
The cells they tested these drug combinations on in vitro included Vero cells (African Green Monkey kidney cells), isogenic HCT116 colon cancer cells (genetically manipulated colon cancer cells), and GB6 cells (glioblastoma cancer stem cells). They also used plasmids, antibodies, and siRNAs. Researchers acknowledged that the use of non-neuronal cells may be a limitation of this study.
“Our present studies were performed in non-neuronal cells and as a caveat, it is possible that our data in HCT116 and Vero cells will not be reflective of the same processes in neuronal cells.”
Despite this caveat, results from their research were promising. Some combinations of these drugs were capable of knocking down many disease specific proteins that form toxic aggregates inside cells and in extracellular environments via autophagy.
CONCLUSION
“As the mechanism of drug-action became clearer it was apparent that these agents should also be tested in neurodegenerative diseases. The entire neurodegenerative field needs rapid translational methods that target the underlying cause of disease, toxic misfolded protein. The findings from this work warrant further testing with a focus on clinical utility.”
Click here to read the full research paper, published by Aging.
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.
