Behind the Study: Second Interventions in Aging Conference

Following the Second 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
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 Aging YouTube channel for more insights from outstanding authors.

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.

WATCH: AGING VIDEOS ON LABTUBE

Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

Behind the Study: Potential Reversal of Epigenetic Age Using Diet and Lifestyle

Dr. Kara Fitzgerald details her publication by Aging, entitled, “Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial“.

Researchers explain their studies that were published in Aging

Behind the Study is a series of transcribed videos from researchers elaborating on their recent oncology-focused studies published by Aging. A new Behind the Study is released each Monday. Visit the Aging YouTube channel for more insights from outstanding authors.

Listen to an audio version of this post

Hi, I am Kara Fitzgerald. I’m on faculty at The Institute for Functional Medicine. I have a clinic practice in Newtown, Connecticut. The title of our paper is “Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial“.

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 hired Helfgott Research Institute out of National University of Natural Medicine to run our study. So I, myself and my colleague Romilly Hodges who designed the program, we were not involved in the execution of the program. So that’s a little bit of the background. And what we did was we had a pilot study. We looked at men between the ages of 50 and 72.

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.

I want to thank Metagenics for their grant. I want to thank our team. Again, we worked with Helfgott Research Institute, National University of Natural Medicine in Portland, Oregon. My Co-PI from Helfgott is Ryan Bradley, statistician from Helfgott is Douglas Hanes. Emily Stack was the study manager. My team included Romilly Hodges, who is the nutrition director here at our clinic. She helped design. She and I designed the program. The other nutritionists involved are Janine HenkelMelissa TwedtDespina GiannopoulouJosette Herdell and Sally Logan. At McGill are Dr. Moshe Szyf and David Cheishvili, both helped with data analysis, particularly of the Illumina EPIC array. And Dr. Szyf also helped with study design.

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.

Click the links below for more information on corresponding author, Dr. Kara Fitzgerald:
Biological Aging Summary | Instagram | Facebook | Twitter | General Site | Younger You Program

Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

TRENDING WITH IMPACT: EFFECTS OF EXERCISE ON AGING

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.

Figure 4. Conceptual overview. Created in BioRender.

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.

Listen to an audio version of this article

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.
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.

Aging is an open-access journal that publishes research papers monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

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

  • Follow Us