Irina Conboy on Academic Publishing

Date Posted: May 10, 2023

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Today, we are talking with Dr. Irina Conboy, Editor-in-Chief of the journal Rejuvenation Research about impact and other aspects of journal publishing. This journal is an important academic publication for our field and publishes many papers focused on aging and rejuvenation research.

Hi, Irina, and thanks for taking the time to talk to us. Could you tell us a little bit about yourself and the journal?

Yes. Hi, Steve. Thanks so much for this interview opportunity. During my work, I wear several hats as well. I am professor of bioengineering at the University of California Berkeley, and I’m part of the Quantitative Biosciences Consortium (QB3) between UC, Berkeley, San Francisco, and Santa Cruz.

I’m also the editor-in-chief of the Journal Rejuvenation Research. As of now, I have just completed my first year in this position.

Yes, we definitely have quite a bit in common there, and I can definitely sympathize as a fellow editor-in-chief about how busy it can be as well. Speaking of which, what does your typical day look like as the editor-in-chief?

First of all, I would like to mention that recently, there have been a flurry of journals in the field of aging and rejuvenation, which is a very promising development, of course, because it means that there is a lot of interest in this scientific area. I’m sure as a fellow editor-in-chief, you realize that as well, because your news outlet is dedicated to the same area of science and medicine.

I would like to mention Geroscience, which is an up-and-coming journal in our field and also Aging journal, which came after Aging Cell. In my opinion, it really is doing a great job, though I may be a bit biased because I’m on the editorial board. But for the Geroscience journal, we published a few papers there after reading some very interesting papers from this journal.

My typical day as Editor-in-Chief actually consists of brainstorming about how I can improve the impact of submitted manuscripts to the journal. I’m asking my colleagues in our scientific field to please send me your research papers or even reviews and perspectives.

Our goal is to be at least on par with the Geroscience and Aging journals and perhaps even supersede them at some point in the quality of rejuvenation research as a journal.

It is, of course, good news that there are more journals now dedicated to the subject.

I’m certainly noticing that there seem to be more papers about aging, in particular, those that are more focused on the rejuvenation side of things and actually doing something about aging rather than just talking about it for scientific curiosity. It would be interesting to track how many papers and mainstream media articles there have been for the past years to see if it really is rising. Do you feel they have increased?

In my opinion, absolutely. Yes, it percolates now to mainstream journals and newspapers all the time. The popular highlights are distributed widely and frequently, but it does not mean that the scientific quality of rejuvenation research has been improved in every single publication that is highlighted.

This is a good segue to the next part and what we are looking for in rejuvenation research with respect to submissions, which is a big part of my work as Editor-in-Chief. We are rebranding the journal, with the goal of publishing innovative science and technology, moving away from the hype and silver bullets towards the hardcore science that has translational promise of additional decades of healthy life.

Is there reputable data which indicates that is possible or is it only a prediction? What does the data suggest? Basically, we want to focus on the actual science rather than flashy titles and abstracts that highlight what is currently popular and sounds exciting.

Yes, as you say, let’s get back to the hardcore science. Let’s get the evidence. That’s a great approach to take, and there is a problem with hype and snake oil in the field, of course.

It is not snake oil, per se. But it is the transmission of popularized information, which at times exaggerates the positive. Rejuvenation Research journal is moving away from that and more towards publishing high-quality, well-controlled research manuscripts with accurately interpreted, not exaggerated primary data. And, of course, excellent reviews that are not only being a cheerleader for other publications, but are critically evaluating other publications as well.

That then brings rejuvenation science into the mainstream from something that is a little bit orbiting out there, though we definitely need a certain amount of cheerleading.

Yes, it’s important to try and keep it grounded.

We don’t want a situation of overpromising and underdelivering, because it doesn’t do the field any good. It’s about striking that balance. That way, people are not disappointed and then they don’t dismiss the field as nonsense, which is good.

I also want to briefly mention Aubrey de Grey, the previous Editor-in-Chief, to say that he did a marvelous job in starting Rejuvenation Research back when “rejuvenation” was not really a mainstream or acceptable term and everybody was saying “aging” instead. He basically concluded that we know enough about aging to think about rejuvenation.

When I came on board as the new Editor-in-Chief, it was great that the journal was already established and on Pubmed.

The key thing that I decided to do is to change the trajectory, pushing Rejuvenation Research to a different orbit, making it a forefront in the mainstream of the aging field.

We want to focus not on anecdotal things, like, some people ate a secret mushroom and became younger by some prediction or a testimonial. Rejuvenation Research aims to publish novel, high-impact phenomena and mechanisms that are directly or indirectly related to the aging process and approaches for attenuating, reversing and possibly even preventing age-related diseases. This scope sets us apart from other so-called specialized journals.

That is a good segue to our impact factor discussion. The best high-impact articles are generalizable. What people discover in those papers can then be repeated throughout the world in different experimental systems and broadly improves health when applied translationally.

That could be said about induced pluripotent stem cell technologies or CRISPR technologies or in the way exposure to a young systemic environment rejuvenates aged progenitor cells, which we published back in 2005. When other research groups do the same or similar studies, they not only repeat the discovery but build on it, which opens new horizons.

That’s what I call the high impact of the manuscript. My goal for Rejuvenation Research is that we publish such manuscripts. High-impact manuscripts speak for themselves, regardless of the journal where they are published.

Exactly, and of course, journals are not without their problems. So, let’s talk about the elephant in the room, journal impact factor.

For those unfamiliar with this, journal impact factor (JIF), which was launched about 40 years ago and has shaped academic behavior ever since. Impact factor is used to gauge the relative importance of a journal and to also measure the frequency with which the “average article” in a journal has been cited. However, impact is not without its controversy and issues, as you will see.

Firstly, alongside research and literature reviews, which is typically citable content, journals often also publish things like letters to the editor, editorials, news, and other kinds of similar content. These types of articles tend to increase journal citation due to some scholars choosing to cite them. This then inflates the impact factor score.

Do you agree that academic bloat from non-research articles is a problem? And if so, what are the kinds of ways that we can try to minimize this issue in the journal?

Yes, absolutely. The perceived impact factor reflects mainly one parameter: citation number that is assigned to the publications of the journal, and it can be artificially inflated. A way to inflate it is the one that you mentioned, which is to publish bits and pieces of information that you know will be cited often.

Another one is to unfortunately redirect the future citations towards the same journal and further increase the impact factor. For example, many people find it easier to cite something that has been highlighted in the popular press rather than reading the specialized papers that give a foundation to what was published in the so-called high-impact journals.

As a result, we have this circle where the articles published in high-impact journals cite other articles published in high-impact journals, which sways the information stream and impact from the foundation of discovery through redirection of scientific citations.

Another example is that often people cite reviews when they want to make a point, and within that review, there are one or two actual papers that may, and not exactly, reflect what they want to say in their reference. It’s easier to just cite the whole review on the topic. That’s another example of redirection of information or swaying the impact factor.

Yes, everything tends to get buried. I’ve seen people citing reviews, which can have a hundred or more referenced papers in them, as a way of supporting their case. I usually ask which part of the 8,000 or more word review am I supposed to be looking at here?

Exactly. I know that there is a lot of disappointment in the scientific community that we give awards, promotions, and tenures based on something that we know to be less than optimal.

Indeed, it’s a real problem. So, another problem with impact factor is typically, not always, but usually based on a two-year citation window. Some people suggest that this really isn’t enough time for a published paper to gain enough traction.

For example, the average biomedical research paper gathers up to 50% of its citations somewhere around the eight-year mark. Not two years. Or even longer, depending on the field. I believe for sociology and or psychology that can be even longer, maybe 10 years. So this short two-year window really doesn’t give an accurate reflection of the journal’s true impact.

Clarivate actually does an annual journal citation report in which they don’t just publish the journal impact factor on the current two-year method, but they also use their own in-house calculation based on a five-year timescale. But unfortunately most journals do continue to stick to this two-year window. How can we potentially address this problem?

I noticed firsthand as the Editor-in-Chief of Rejuvenation Research, which started with a low so-called impact factor of around four; it discouraged the submission of excellent manuscripts to the journal.

Right now, our editorial board is brilliant. For example, we have Tom Rando and Judy Campisi who are household names in the field, but because the so-called impact factor of a journal makes a difference in people’s careers, they will not submit high-impact studies to Rejuvenation Research. Even if those studies are about rejuvenation, they try to publish them in Nature, Cell or Science journals instead. Even though Rejuvenation Research is the appropriate journal, and even if they’re rejected by those other journals, they will still expend resources and efforts to publish there.

In terms of two years being not enough time, absolutely, because then people who reference certain papers right away in two years might overlook the implications of the work, the connections of the work to previously published literature. It’s only later on when those connections emerge, and these could be positive or negative.

So, even with a rigorous scientific approach, a two year publication scoring kind of sways it again subjectively towards the journals which already have a high impact score because people tend to browse through these and the popular highlights on these.

“Have you read about this work in Cell, Science, or Nature that is highlighted by Times Magazine?” people say. And of course that will be the first thing that they’ll start referencing. Meanwhile, there could be a paper that really gives a foundation for that Cell, Science, or Nature paper that was published a few of months before but it was not appropriately cited and is deprived from subsequent citations because everybody will keep citing the one in the higher-impact journal.

That is unfortunately not an infrequent phenomenon; deciding what to cite in their papers, authors sometimes seem to exclude the so-called specialized work that is published the same year or the year before so that what they’re doing appears more novel.

It takes a field more than two years, maybe five or six years to reconcile all these points and to say, “Hey, wait a minute, the same key discovery was already on PubMed the year before you published your work”. Meaning there was actually less innovation than suggested and eventually the citation stream might start to change years later to more accurately reflect this.

A two-year citation score might be too soon, and at the same time, it reflects the general phenomenon of redirecting citations because once 50 people have cited a recent Nature paper, 500 other people might be influenced to do the same.

Very few of us actually read every single paper in depth, look at every single figure, and then do a search on PubMed to see what was already known in the field. Some of us do, but not all of us.

I don’t think anybody’s got the time to read it all, really, unless they’re an AI, perhaps, because AI is becoming more sophisticated and it’s great at analyzing lots of bulk data.

I know they’ve been experimenting with AI to look at research papers in the past to find connections that were not made by humans because they can’t be everywhere and read everything. I know that AI is often hyped up, but it might actually be used in a way to try and mitigate this problem.

I totally agree. I think AI could be used to mitigate this problem, but there are also journal clubs which can also help. Most of the laboratories of the world have journal clubs where they look through a list of so-called high-impact journal papers that were recently published, and together they work a bit like an AI.

We are a collective of natural intelligences, and through that we do identify technical demerits, scientific demerits, lack of innovation and the positive things too. Unfortunately, that takes place at a very specialized level and often remains there, not spreading to the broader community.

My goal as the Editor-in-Chief is to see what we can do to shift focus from the impact of the journal to the impact factor of the individual publications, because then, the impact can be assessed in a couple of years.

Yes, it does seem strange, and it’s clear at least from my perspective that it has a lot of problems.

It’s also the opinion of maybe the maximum of four people that decide on whether a paper will be published or not. Four out of thousands of scientists in the field.

That means that the paper was not really scrutinized by the scientific community or by all of the experts. It is just the opinion of the handling editors whether they want to send it for review. That is the first threshold: how much that editor understands the field, a lot, a little bit, or not at all. When a paper is in peer review, the reviewers can have non-obvious biases or conflicts of interest.

These are not the obvious things, like you are not from the same school as the author or you do not have collaborations with an author, but do you dislike that person? Did they ask you a tough question when you presented a scientific talk? Do you dislike that person because what they’re publishing goes against what you published and have funding for? Those are non-obvious conflicts of interest. There are 3-4 of these reviewers, which decide if the paper is published or not, and even one bad recommendation can block the paper, at times, through scientifically erroneous critique.

I also think there’s another problem with just publication in general, and that is the reporting of negative experimental results.

I’ve written about this in the past, that researchers or certainly many I’ve encountered are often reticent to publish anything negative. That’s a huge problem, because it can lead to repetition of experiments and people going down the same wrong path. One thing I did suggest, as a bit of a joke but also slightly serious, is to have a journal that doesn’t publish anything but failures. We could call it “Failures, the Journal”.

I was always taught that you can learn as much from failure as you can from success, but if the system is geared up to punish failure, then something has to be done about the system because it’s not helping overall progress in the field. It means people are going to repeat the same mistakes, they’re going to waste time and money doing the same experiments when the information is already known but not published.

Yeah, that’s a good thought, because I mentioned in some of my editorial pieces for Rejuvenation Research that we do welcome work that did not produce a confirmation of hypotheses. We don’t even call them failures, by the way. There is a hypothesis and a null hypothesis, and they should be given equal weight.

Unfortunately, many people try to pull the weight towards confirming their hypothesis, but showing that your hypothesis and perhaps the one shared by others is incorrect and instead that the null hypothesis seems to be true is super important.

We welcome such submissions at Rejuvenation Research, as they are like the canary in the coal mine. We published one of the Conboy Laboratory papers in Rejuvenation Research about the large false positives in one of the commonly used methods of comparative proteomics: how to find these false positives, and how not to make conclusions erroneous.

We did not get any referencing of that paper at all for the whole year, which for the Conboy group is unusual. Yet, at the same time, we published other pieces of scientific work, which were referenced hundreds of times.

This could be because it shows that many of the previously published manuscripts were not entirely accurate and the field should perhaps do more control experiments going forward. Or, it could be because we published in Rejuvenation Research and it was just overlooked based on the venue: the scientific journal worth referencing.

Going forward, I would like to emphasize that we always welcome the negative findings that you call failures. We don’t consider them to be failures, we consider them successes. They are successful in warning people against doing research in the wrong direction or doing research that is not rigorous because certain controls were not included.

The way that one finds that something is not working really is by doing many more control setups and those controls: both positive and negative. If one then does the comparisons and discovers that what a paradigm turns out not to be accurate, this would be an example of superb research and excellent publication.

This is an important point, that there should be a difference between the impact of a journal and the impact of an individual paper. Many excellent scientists, including Nobel Laureate Professor Randy Scheckman, share this opinion.

There have been several papers published in high-impact journals and then later retracted by the journal in part because the researchers really made it their goal to publish in Nature or Science. For example, the paper on STAP cells, the pluripotent cells that were claimed to be induced by acid treatment, was retracted.

If researchers actually did the controlled experiments that reviewers told them to do and discovered that there was no such cell, which could be pluripotent simply because it is exposed to an acidic environment, it would be publishable in a so-called specialized journal. But instead, the stressful pressure to publish in a high-impact journal was so high that they fabricated the results.

That’s the problem, isn’t it? Because of that motivation, research can be sensationalized just like some newspapers try to grab attention using hype and sensationalized headlines.

Regarding the word failure, as you say, I think that is the wrong word. I was sort of paraphrasing what other people say. They say failure though I do not see it as failure either as we can learn from all results.

Now I’m a fan of an artist from the seventies, early eighties, called Bob Ross. You may remember Bob Ross.

Oh, yes, absolutely.

He was a wonderful artist and very peaceful, and I always liked the way he described if you’d failed or made a mistake. He said “We don’t make mistakes, we have happy accidents”. I think that’s a fantastic way of framing it. Perhaps we should have a Journal of Happy Accidents.

Haha! I don’t think there should be such a journal, but there should be a collection in every journal dedicated to the negative findings and critical reviews of findings and discoveries. Does the research need more controls? What is the true innovation of the research? Or are researchers repeating something that was published in 1996 but with new instruments and technologies?

Or, perhaps, there was an honest mistake? It could be that the researchers simply overlooked the possibility of doing an additional set of experiments and once they did them, it turns out that their conclusion does not generalize.

Another issue that I and my colleagues encountered is that if you try to publish so-called negative data that suggests something that was previously published underestimated or overestimated something, it is super difficult to pass by the editors.

Possibly, because after a peer review by a couple of scientists, there is an impression of an established paradigm, and it is physiologically unpleasant to admit that there was a mistake.

As a result, there is a certain pressure on science to move in the direction of a dominant paradigm and a counter-pressure on the new data questioning it.

Yes, it’s a massive problem. I’m beginning to have one of those “tip of the iceberg” moments where the more you explore, the bigger you find out the iceberg is and before you know it, your Titanic is metaphorically steaming towards it, which is a problem.

I would say that this problem is not only true of our field but almost certainly true of most if not all other scientific fields. In fact, I’d be amazed if there was one scientific field that didn’t have this same issue because it’s a problem that’s inherent with the journal system and not limited to a single area of science. I really don’t know how to fix it, but it is definitely a major concern.

Yes, and at Rejuvenation Research, we will try to fix it. In our journal we will not have that block for publishing experiments that started out to prove that A was true and then found it’s actually B and the researchers then understood why A wasn’t correct. We welcome such submissions. I think it should not be a separate journal, but I think it should be a legitimate part of any scientific publication.

Yes, definitely, and just in what we’ve covered today, it shows you how many sorts of hurdles and pitfalls there are. It really plays into personal biases, which is something we all have.

As journalists, we often encounter biases, and part of being a good journalist is to acknowledge that no matter what we do, we all have personal bias of some kind. In accepting that and acknowledging it, we can do our best to keep it in check and report fairly and with this in mind.

I don’t think you can ever really completely remove biases because relationships are complicated. Friendships, rivalries, pet hypotheses can all color our judgment. I’ve seen it in our field, and it definitely has an impact. This could even potentially mean if one researcher on a journal editorial board, who doesn’t like another researcher who is trying to publish a paper, could potentially try to strike their paper down.

You are absolutely right, it is biased, but I don’t think it is hatred. I think it’s just a subjective thing that we all want to be correct.

It kind of tags onto the financial part, but very indirectly, and you are right. What I think is important is that we cannot get rid of the biases, but we can dilute them. If we are making decisions about the impact of a paper, then it should be by many people in a field that make this decision, not just three, four individuals. People always discuss scientific papers after the fact that they’re published but are, at times, timid in providing a negative opinion.

Some think that the main problem is that peer reviewing is single-side blinded. If you express negative opinions about someone’s science, those same people could be reviewing your papers and grant proposals.

For our readers who might not be familiar with how journal review works, single-blind peer review is the traditional method of reviewing papers. This means that the reviewers know the identity of the authors, but authors don’t know the identity of reviewers. This can lead to problems of bias, both intentional and unintentional.

If it could be done anonymously and could involve the opinions of hundreds of people, this would help to dilute personal biases. Which would then help to make more accurate decisions about the impact of individual papers.

I think that will make a big difference because it is less subjective. I potentially see it happening in the future, but it will be super difficult to do because it goes against what scientists have been doing traditionally.

It touches on your point that you cannot get rid of the biases, positive or negative. My solution would be we can dilute them by increasing the number of judges, so to speak. Like in Olympic figure skating, in the past, there were few judges and 0-6 scoring, but it was a very small panel, and there were some scandals. So, they increased the number of people who are judging and also changed the scoring system to make it larger.

Yes, which means the larger cohort you have, the less outliers are going to influence that data strongly and skew the figures. That touches upon decentralized science, or DeSci, which is something that lifespan.io is very involved in.

Currently, in the traditional grant giving systems, the promising moonshot projects that have a potentially high risk of failure are being turned away from funding in favor of less-ambitious projects that have a higher chance of a positive publication.

That ties into risk aversion in journal publication. So, DeSci actually uses a large collective group of people to evaluate and determine which projects get funding. This creates these granting opportunities that are disconnected from traditional systems with their risk-aversion problems and helps ambitious projects avoid languishing without funds.

Because they are directly controlled by the community, it means that the kinds of experiments that they would like to see are actually getting funded through this system of decentralized science. In other words, Desci is helping to democratize science and break out of the rut it is currently in.

DeSci could also potentially play a role in the future of how journals are. Perhaps there could even be a DeSci journal.

Absolutely. You are totally right that high-innovation, paradigm-shifting science is often overlooked and funding agencies realize that as well. For the evaluation of scientific papers, I don’t think that it should be a journal’s obligation. It should be, I think, an initiative where journals publish after several years, the impact factor of individual research.

Or, perhaps there could be a community of people like lifespan.io that can publish the impact of individual papers. Maybe something to think about as a collaboration. We need to understand and evaluate what was published, not focusing mostly on where it was published.

For that, you have a perfect platform already, I don’t think it’ll be really costly or require anything else except for the tabulation of professional opinion. So, all of us are the judges, and once a paper is published, it’s fair game to critically evaluate it both positively and negatively. That information should help establish the impact of the work outside of its publication venue.

It almost sounds like film reviewing on the website Rotten Tomatoes, where there is an audience and critic rating.

Yes, I always look at Rotten Tomatoes to decide whether to watch movies or not, so absolutely. And it’s more or less accurate, right?

Yeah, it doesn’t make any sense at all. If you had that collective reviewing and confirmation, you could have that core of professionals reviewing it, but then other professionals who are not on the review board but are confirmed could also collaborate by rating the paper as it were almost like how Rotten Tomatoes works.

That would be your canary in the coal mine as well. Because if the review panel gives it like 30%, but the audience who are actually consuming the paper gives it 90%, then you know something might not be right.

Yes that happens on Rotten Tomatoes all the time, both ways. Sometimes movie critics give it like 90%, and the audience has this overturned bucket of popcorn icon giving it a 30% score. In such a metaphor, thousands of scientists can determine that a paper is strong or weak, adding to the opinion of a couple of peer-reviewers who like it.

That will allow us, instead of reading everything that is done, redone and published on Pubmed, to use the judgment of the collective scientific community. As a collection of human beings, we currently supersede artificial intelligence, in my view.

The DeSci movement uses active community participation to fund and operate large-scale projects but also potentially could apply to reviewing things. I could easily see this being applied to journal clubs to facilitate the evaluation and sharing of information.

You could even use AI as a third layer to evaluate papers and review them. So, you would have your professional reviewers, the professional public, and AI. Doing that would potentially help to truly assess the impact of a paper and steer away from where it was published being the most important factor. Of course, the tools to do this already exist today if such a system was something we wanted to develop.

Yes, absolutely, and AI could be instrumental there because it could synchronize the diverse opinions and languages into something that is a scoring system. This could really help to shift the focus from the venue where the content is published to what is being published.

Yes, something like that would be really useful.

The final point about journal impact factor I want to touch upon is that a small number of highly popular papers, which get cited a lot, can also give a false impression of how popular a journal is. A journal’s impact factor is based on an average number of citations that papers have attracted in a two year period. which we talked about earlier.

This means that these highly popular papers are basically outliers that can skew the calculation of what that average is. What can we do about these sort of disproportionately popular papers?

What can we do about that? I don’t think there is much. I think it again goes back to this foundation of basing the quality of the paper and the quality of the scientist on where it was published. At times, there are controversies and papers come out later on, to say that previous work is not generalizable or not reproducible to other systems of methods of analysis.

So, everything that you said is accurate, but I don’t think it can be solved trying to treat symptom after symptom. We all say that the system is not optimal, but we keep using it.

Yes, It’s almost like being in an abusive relationship. You know it’s bad for you. You know you shouldn’t be involved with it, but yet you keep coming back for more.

I think it is a great comparison. Journal impact factor is like an abusive relationship that academia has with itself. Why are we doing this to ourselves? Is this because there is no alternative? I think the remedy is to find an alternative using metrics, which people agree are fair, for ranking the impact factor of individual publications.

Then, if a journal publishes 10 high-impact papers that are ranked highly by the critics of the world in a year, then yes, it’s a good journal and others will try to submit to it. In summary, I don’t think we should pay supreme attention to the venue where a paper is published.

Yes, it’s a problem for sure, but hopefully with all these new tools and the Desci movement, we can replace what is broken. No point in trying to fix a system that does not work, as you suggest; better to sink our energy into making something better to replace it.

On that final note, I would like to thank you for taking the time to talk with us today and for sharing your thoughts and insights on the journal system.

Lastly and importantly, to make sure that there is no misconception, Cell, Science, Nature, etc. are excellent journals published and continue to publish groundbreaking research that is justly considered to be on top of scientific fields. The goal is to diversify and optimize the stream of scientific information in the arena of aging and rejuvenation, have more ease in publishing negative data and paradigm shifts, and do not equate the value of a paper with the impact of a journal.

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Date Posted: May 9, 2023

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Vera Gorbunova on Long-Lived Species

Dr. Vera Gorbunova is a famous geroscientist who, for the last several years, has worked mostly on uncovering the amazing biological mechanisms that are responsible for the enviable longevity and resilience of long-lived species such as the naked mole rat. We talked about those feats of evolution and how they can be harnessed to increase human longevity.

How did you end up studying the biology of aging and long-lived species in particular?

It was a serendipitous occurrence. I wanted to study biology from very early on, probably from some time in middle school. I remember when I was at St. Petersburg University, we had a guest lecture dedicated to cell aging and the Hayflick limit. That concept seemed so fascinating to me, that there’s some kind of regulation of the aging process, and that it can be studied using cells and organisms. From that moment on, I was hooked.

I wanted to understand it. It was more of a scientific question for me: how does this work? I wasn’t able to start working on it right away because, at the time, there weren’t many groups working on aging. Even when I was looking for a group to pursue my PhD at the Weitzmann Institute, there was no one there who worked on aging, so I had to work on something else. But for my postdoc, I made a promise to myself to finally dive into aging. I joined the laboratory of Olivia Pereira-Smith, where we were studying senescence. Later, I worked with John Wilson on DNA repair and aging.

These were very interesting topics but more on the conventional side of things. Those groups didn’t study long-lived organisms. Somewhere in the second half of my postdoc, I started thinking about how to really address this question head-on, how to understand longevity.

I was somewhat disappointed with the existing models based on very short-lived creatures like worms, flies, mice and so on. Whatever we are trying to learn from them would be limited. We might be able to understand something but maybe not the mechanisms that we really want to find.

That’s when I got this idea to study long-lived organisms. We started with long-lived rodents because I thought, well, there’s the mouse, which is very well-studied. There are many tools available for it. What if we work with an animal that is similar, but long-lived?

Actually, the first rodent that we dissected in the lab was a beaver. Beavers live over 20 years. The official record is 24, but anecdotal evidence suggests they can live up to 50 years. From there, we moved to the naked mole rat, and I realized that it contains a treasure trove of information about the biology of longevity. This is what I have been doing until this day.

We don’t really know the actual maximum lifespan of long-lived species, right?

Yes, the definition of a maximum lifespan is the longest lifespan documented for any individual of the species, so it’s difficult to say whether we know with certainty that this really is their maximum lifespan. This could be said with confidence for species where many individuals were followed from birth to death. Hence, this is something that we know for humans and mice, even though, for humans, there’s still some debate. But for most less-studied species, we probably underestimate their maximum lifespan.

For the naked mole rat, this is currently 41 years. Those numbers come mostly from the colony of Shelley Buffenstein, because she studied those animals for a very long time, and that’s how long she kept them. However, most lifespan figures for other species come from zoo records.

Which traits or abilities of long-lived species do you personally find most fascinating?

I think the most important one is that all these species are not just chronologically long-lived, but they also stay very healthy, because to live for a long time, and especially to survive in the wild, species must be able to avoid getting sick. Their longevity comes with resistance to most age-related diseases.

This is really important, because whatever mechanisms we find there will be associated with better health. When people perform screens on short-lived organisms and find something that allows these organisms to live longer, this perturbation often comes with negative side effects. But whatever we find in naturally long-lived species comes hand in hand with better health, because it was optimized by millions of years of evolution.

What do you think are the evolutionary reasons for some species developing those superior anti-aging mechanisms, but not other species? Why can’t we humans have nice things like superior double-strand break repair or antioxidant protection?

In a nutshell, longer lifespan evolves in the conditions where it’s beneficial. Many long-lived species have particular traits that protect them from accidental death due to predators or other environmental factors. If an animal lives in a certain ecological niche where it can live longer, it will evolve molecular mechanisms to support this long life.

For example, for a mouse, there’s no point in evolving longevity mechanisms, because it just can’t live very long, it has too many predators. But many long-lived species will either occupy particular ecological niches where it’s difficult for predators to get them, or they are very large, or they have a hard shell, etc.

This is, in general, where longevity evolves. What particular mechanisms start to be regulated in any given species is a more difficult question, and maybe there’s some level of randomness here. It’s whatever is available. For instance, in naked mole rats, we discovered hyaluronan that seems to protect them from cancer. Recently, it dawned on us that it’s a common trait for subterranean animals. It seems important for those living in subterranean tunnels, probably because hyaluronan makes the skin stronger and more flexible.

So, it’s sort of a side effect?

Yes, you might say so. Animals already had this upregulated, and it came with an opportunity to evolve a longer lifespan, so this trait became co-opted. You mentioned double-strand break repair, which is quite interesting, because this seems to be a conserved feature of long-lived organisms. Basically, any organism that is long-lived would have very good double-strand break repair.

Maybe we can classify all those longevity mechanisms into something more “private” that evolved only in certain lineages and something that is more conserved, that we keep finding again and again. DNA repair would be in that second group.

That’s what you are mostly working on, right?

We are interested in both types of mechanisms. It’s really fascinating to find conserved mechanisms, and it also means that if we manage to tweak it, it should probably work across species, including in humans. Although, a word of caution would be that if it’s already upregulated in all long-lived species, and humans are quite long-lived as we are, it would be difficult to make it work even better, because we already have it quite optimized.

Right, we tend to forget that we humans already are a long-lived species.

Yes, we are quite privileged in this regard.

Still, many species have far superior mechanisms, such as a more effective SIRT6, which is something that you study as well.

Yes, while our SIRT6 is already quite good, we probably can make it work even better. We are currently studying what probably is the longest-lived animal, the bowhead whale, and we find that in many respects, it outperforms humans.

There are many factors that correlate with longevity across species, such as body size, the rate of mutations, epigenetic drift, retrotransposons. Do you think all those might be somehow related?

Those are definitely related. Let’s take double-strand break repair and epigenetic drift. Some enzymes that we study, such as SIRT6 that you mentioned, are involved in both, because to repair double-strand breaks, you need to rearrange the chromatin. These processes are happening at the same space and time. Aberrant double-strand break repair accelerates epigenetic drift, and recent work from Sinclair Lab reinforces this idea. This is something we keep seeing, because when we compare different types of DNA repair, double-strand break repair always seems to be the most critical for the aging process.

Retrotransposons are a part of the same epigenetic drift situation because they make up the majority of DNA in the cell. When they become activated, things really begin drifting away, because it disrupts transcription patterns in the cell and probably drives many age-related dysfunctions downstream, because when cells don’t express what they are supposed to express in each tissue, it leads to loss of function.

These three processes are very much related to each other, and this might be the most fundamental underlying mechanism of aging, when the epigenome gets disrupted because of double-strand breaks or because of retrotransposon activation. That’s when all other problems begin.

I was actually going to ask you about your thoughts on Sinclair’s paper where they claim that aging is caused by the loss of epigenetic information.

I really like it. I wholeheartedly agree with that. That loss of epigenetic information is probably what drives other hallmarks of aging. Which of the hallmarks are causal is a good question, and I’d say that epigenetic drift is probably the causal one, and it drives other dysfunctions downstream.

Can you think of a process of aging that’s unrelated to this?

People tend to assign a lot of importance to the accumulation of protein aggregates in some tissues, especially in the brain. Everyone who’s working on proteostasis would probably say – wait, but what about proteins? Damaged proteins have a very profound impact on aging. You can view it as an aging process that is separate from epigenetic drift, but people find more and more relationship between DNA damage, inflammation, and neurodegenerative diseases.

It’s difficult to say whether there are processes of aging that are completely uncoupled from epigenetic drift. It’s speculation at that point, but it seems to me that this is the causal one, and the rest can be linked to it.

Some evidence for this is provided by the fact that you can rejuvenate the cell completely by rejuvenating its epigenome. That happens repeatedly when a new life is conceived. You put the cell through the zygote, and everything gets restored to its youthful state.

Let’s move on to translation. All those superpowers that long-lived species possess look very tempting, but how can they actually be translated into humans?

There are many different avenues that are being explored. That’s what makes our field so exciting, because once we find and understand the mechanism, we can look for ways to target it. Right now, we are pursuing several of these directions, and maybe the most translatable is the one we found in the naked mole rat. People already use hyaluronan in the beauty industry for skin rejuvenation, or at least to make the skin look better, but we also see its anti-inflammatory effect. We generated mice with the naked mole rat’s hyaluronan synthase, and they live longer. Right now, we are looking for pharmacological ways to increase hyaluronan in human tissues, and this is a very straightforward path to translation.

Epigenome, DNA repair: how can we make it better? This is a bit more difficult, because hyaluronan is just one molecule. You increase its level, and things get better. DNA repair, on the other hand, is a process that involves multiple enzymes.

Looking at various ways to improve DNA repair, we found that among different enzymes involved in DNA repair, SIRT2 and SIRT6 can activate it very effectively. That was quite unexpected, because most other enzymes we tried just made things worse; after all, this is a process where exact balance is very important.

We found that SIRT6 can stimulate DNA repair, and then we found that long-lived species’ SIRT6 is more active. Even in human centenarians, we found a variant that was more active in certain ways, and it was improving DNA repair. Now, we are looking for chemical activators of SIRT6, and we actually found one, which is exciting. It’s a natural product called fucoidan, and it comes from brown seaweed.

Fucoidan is very safe, people consume it as food, especially in Japan and South Korea, two of the countries with the longest life expectancies. In preclinical studies, where we gave fucoidan to aged mice, it improved their frailty scores. So, we are very excited about this safe way to activate SIRT6, but we’re also pursuing other strategies, for example, gene therapies that may provide a much stronger SIRT6 activation and also can be targeted to particular tissues. It is ongoing research, but as you can see, it is possible to translate those mechanisms.

I didn’t know that you were also working on gene therapies for SIRT6 activation. Do you have any preliminary results or insights?

Like I said, this is ongoing, so I don’t have a lot of results, but we’re exploring this using different models and targeting different organs. Hopefully, we’ll have the results soon, but just based on genetic models of SIRT6 overexpression, we expect to see a rejuvenating effect, because if we simply overexpress SIRT6, mice live longer.

It’s not an easily translatable system, but if we can deliver SIRT6 and even express it transiently, we hope to see improvement. I can share one type of results, which is in cell culture, not in animals. When we overexpress SIRT6 briefly in cultured human cells, we see epigenetic age going down.

You have found that exposure to cold also improves DNA repair. So, should we all start taking ice baths?

Maybe. Of course, we have to be careful about it, because ice baths for someone who’s in less than perfect health might actually be detrimental. But there’s a lot of evidence that a brief cold exposure can have beneficial effects. We can see it in traditional folk medicines, such as cold-water swims that are very popular in Russia and in Scandinavian countries. It hasn’t made it into the mainstream, but right now, there are many scientific works, especially in sports medicine, that show cold exposure having a potent anti-inflammatory effect. The mechanisms were not very well understood.

We found that this protein called CIRBP, cold-inducible RNA-binding protein, which is induced by cold as its name suggests, also improves DNA repair. This is a very exciting connection, and cold exposure is something that many people can easily practice without any major complications.

Do you have human data to back it up?

No, the human data that we have comes not from our lab but mostly from observational studies. There have been small trials of swimmers versus non-swimmers where cold exposure was found to have generally beneficial effects, but nobody has measured its effect specifically on DNA repair. The DNA repair work comes from our cell culture studies, where we expose cells to cold and then we see an improvement in DNA repair.

In one of your talks, you said that calorie restriction works in both directions, upregulating both pro- and anti-longevity genes. We know that CR is a potent anti-aging intervention, so how does this square with this finding of yours?

You’re referring to a result from our transcriptomic study, where we established a signature of longevity based on about 30 species of animals, short-lived to long-lived, and we identified which pathways were more highly expressed in the long-lived species. Then, we used this transcription signature to evaluate interventions such as calorie restriction.

This way, we can identify interventions that can move our transcriptome towards those of more long-lived species. This doesn’t necessarily mean that this is how every intervention should work. For instance, you can tweak certain processes that make a mouse live longer but don’t necessarily make every other species live longer.

This signature is not absolute: it only tells us whether this particular intervention works in the same direction as the evolutionary process of evolving a longer lifespan. For instance, we found that rapamycin worked exactly the way we wanted it to work, meaning that it upregulated and downregulated the same genes that are upregulated or downregulated in long-lived species.

With calorie restriction, we saw that it worked both ways, which perhaps tells us that it has a more mixed effect. We know from mouse studies that, yes, it definitely extends lifespan, although even in mice, it works in some strains but not in others. Perhaps this reflects the complexity of this intervention. It may shape the transcriptome in some ways that are similar to what’s going on in long-lived animals, but there may be some detrimental effects as well.

Of course, the question is, does calorie restriction really work for lifespan extension in humans? Clinical data up to now seems positive, although less dramatic than what’s been observed in mice. It could be that for humans, the effect is less pronounced.

My explanation of it is that mice have a very fast pace of life. They live fast, they eat a lot, they reproduce copiously. We are somewhat slower creatures. So, maybe for mice, just slowing them down a bit with calorie restriction can increase their lifespan by a lot, while for us humans, the effect might be smaller. There probably is some benefit, clinical studies support this, but it may not be as dramatic as in mice.

Obviously, it’s not easy to work on long-lived species in a lab, but some prominent figures such as Steven Austad think that we really should be expanding our repertoire of lab animals with long-lived ones. Where do you stand on this?

First, Steve Austad is a great inspiration to all of us. I remember reading his review when I was just starting my lab, and I thought, this is exactly how I should address all the questions to convince people that this is the right way to go.

This process of introducing long-lived species to labs is already happening. I’m happy to say that my group contributed to that, because we demonstrated that by using long-lived species, we can actually identify molecular mechanisms. We’re not just doing some descriptive zoological work. We can drill down to mechanisms! This encouraged the field, and now, many more groups are moving in this direction.

Regarding the difficulties, it may not be that difficult, depending on what type of questions you ask. Because if you envision a naked mole rat or, if we go for an extreme example, a bowhead whale, used in the same way we use mice, it’s not going to work. You can’t do a lifespan study on a creature that lives 40 years, let alone 200 years.

You cannot breed transgenic whales or naked mole rats, but this may not be necessary, because the strategy we adopted is to use these long-lived animals as a discovery platform. We study them from the -omics perspective, we do cell culture experiments. We can also do some limited in vivo experiments in naked mole rats, which we can keep in a vivarium, but any further genetic characterization and manipulation is done back in mice. Once we find a candidate gene, we just move it into mice, where we can manipulate it. Then we can test whether it extends lifespan in a short-lived organism.

So, you still have to go through mice, with all their limitations as a model animal?

Yes, and that actually makes it convenient. Of course, we can try using different models, which is what Steve Austad advocates for. That’s something we’re always considering. But as of now, mice are still the most useful model with the largest toolbox available for them.

We do collaborate with people who use zebra fish or killifish, which is another vertebrate that is easy to manipulate, and you can keep a lot of fish in one tank, which makes large studies affordable. But if the whole idea is to find a longevity intervention and then test whether it can be used to increase lifespan in a short-lived organism, mice are the ideal way of doing it. Then, if it works in mice or in killifish, we can start thinking about doing the same in humans.

Neurodegeneration is one of the most important processes of aging in humans. Do long-lived animals experience it too?

We don’t know a lot about that, because to study neurodegeneration, you must have access to aged animals. Especially when you’re studying wild animals, aged animals are very rare. We mostly deal with young adult animals.

For naked mole rats, because they are kept in research colonies, people observe that they do not develop similar signs of neurodegeneration as we humans do. Their brains don’t seem to form similar plaques and tangles. Although their amyloid-beta sequence is such that it should be prone to aggregation, it is not. That means they have some mechanism that helps them avoid it.

Right now, we’re doing something quite interesting: we’re developing a new model of neurodegeneration using a rodent that’s somewhere in the middle in terms of lifespan. It’s called the degu. Some people keep them as pets because they are cute and smart, but at a fairly early age, around five, they begin to develop dementia. They come from South America, Argentina. So, researchers in Argentina were the first to notice that these animals develop Alzheimer’s-like dementia.

We acquired several degus and we’ve been breeding them for the past four years, because they may be a great model of sporadic Alzheimer’s disease. All mouse models don’t reflect sporadic Alzheimer’s, which is a big reason why interventions are so slow in coming. We just don’t have good models to test them on. Whatever works in these mice doesn’t translate into humans, because the disease etiology is different.

Do you have any preliminary data from your fucoidan trial?

The human trial is ongoing, we’re recruiting patients, so there’s not a lot of data as of now. In the mouse trial, we observed a quite significant reduction in frailty scores in aged mice. We started at 14 months of age, and the effect still was impressive.

Do you or will you have data on lifespan from these mice?

There is a trend towards a longer lifespan, but I’m careful to say that, because we’re not powered enough for a proper lifespan study. But we’ll have data, and I hope it will reach significance. We started with only 20 animals of each sex, so that might not be enough, but we do see a trend.

As a veteran of geroscience, what do you think about its current state? What do you find exciting or maybe disheartening?

Right now, the field is growing so fast. It’s just blooming. Ten, twenty years ago, we started with some foundational discoveries showing that aging can be genetically controlled and manipulated. Then, there was this era of model organisms. Now, it’s moving towards long-lived species that are becoming generally accepted as models for longevity studies.

There are also many interventions in development. We see new startups popping up very quickly. Finally, I see that society as a whole has realized how important aging research is, and that this is the proper strategy to address many health issues instead of going after individual diseases.

This is a great time. It excites me a lot. Those epigenetic therapies that we just discussed are very promising, because if we can find a way to address the underlying cause of aging, there’s huge potential there. I think we’re coming close to that.

I remember that at our conference last year, Ending Age-Related Diseases 2022, when answering a question from the audience, you said, and I hope I’m not misstating, that we will have anti-aging therapies in about 20 years from now.

Frankly, I don’t remember what I said back then, but I think 20 years actually sounds too long. I would say therapies may be available in the next five years. The question, of course, is the magnitude of life extension they will provide. After all, interventions that can give a small but significant lifespan extension are perhaps already available, such as certain lifestyle modifications that are based on large epidemiological data. If we are talking about pharmacological interventions, I would say, we should have something broadly available in five to ten years from now.

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Date Posted: May 8, 2023

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Gene Therapy Ameliorates Sarcopenia in Old Mice

A paper published in Aging has detailed how gene therapy has been used to treat sarcopenia in wild-type mice, and the results are positive.

A lack of effective treatments

As expected with papers of this kind, the researchers begin by discussing frailty and sarcopenia, the age-related loss of muscle tissue that is associated with decreased mobility and an increased risk of falls. The researchers note that there are not yet any real medical treatments for sarcopenia and that current attempts to intervene only involve exercise and nutrition, which are moderately effective in slowing this disease but cannot stop its basic causal factors.

We have previously written about the development of gene therapy for sarcopenia focusing on the enzyme PCYT2. These researchers use a similar approach, but they focus on a different target: neurotrophin-3 (NT-3), which has been previously shown to improve muscle fiber thickness and many other parameters in mouse models [1, 2]. That previous work, however, used mouse models of a genetic disease. This experiment used naturally aged wild-type mice.

Straight to the muscles

The researchers selected a skeletal muscle-specific promoter to make sure that this gene therapy affects only the right kind of tissue. The treatment was injected directly into the gastrocnemius, a calf muscle that is a major part of locomotion. The mice used in this experiment were 18 months old when it began and were tested two, four, and six months after injection.

These mice were put on a treadmill and run to exhaustion. As expected, the treated mice lasted significantly longer than the untreated mice at all three tested time periods, with the strongest results being four months after injection: the treated mice ran roughly twice as far. In a rotarod experiment, which is used to evaluate motor control, treated mice performed better, and their twitch strength was also found to be higher. The mice’s total weight was almost entirely unaffected.

Interestingly, although male mice still received a substantial benefit, female mice seemed to respond much better than males at four months in the treadmill experiment. This was accompanied by sex-specific fiber changes in different muscle groups. Some muscle groups in females were found to change in their proportions of fast-twitch and slow-twitch fibers, while the same groups in their male counterparts changed in an opposite way or did not change at all.

Nerves and mitochondria more like those of young mice

However, despite the muscle-specific nature of the treatment, the nerves of the treated mice were found to be substantially more youthful in at least one key respect. Myelin, the protective and functional coating of nerves, decreases with age. In the distal tibial nerve, which is connected to the muscle tissue that is the focus of this study, two-year-old untreated mice had substantially thinner myelin than their one-year-old counterparts.

This age-related problem was almost completely reversed in the treated group. In this specific nerve, two-year-old treated mice had myelin thickness that was very close to one-year-old untreated mice. Neuromuscular junctions in the area were also found to be improved.

The mitochondria of the treated group were also found to be more youthful in their overall prevalence, although carbohydrate use was found to be sex-specific in a way that matched the changes in fiber type. This was connected to the aging-related factor mTORC1, which was affected substantially more in females than males.

Conclusion

Some of this study’s findings are puzzling and poorly explained, some aspects of the basic biology are not fully eludicated, and it is not known why this approach is so much more effective in female mice than male ones. However, the results of this study were still significantly positive. Combining this target with other genes that affect aging, developing a gene therapy combination, may be the right path for effectively treating sarcopenia in human beings.

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Literature

[1] Yalvac, M. E., Amornvit, J., Chen, L., Shontz, K. M., Lewis, S., & Sahenk, Z. (2018). AAV1. NT-3 gene therapy increases muscle fiber diameter through activation of mTOR pathway and metabolic remodeling in a CMT mouse model. Gene therapy, 25(2), 129-138.

[2] Ozes, B., Moss, K., Myers, M., Ridgley, A., Chen, L., Murrey, D., & Sahenk, Z. (2021). AAV1. NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice. Brain Communications, 3(4), fcab252.

Date Posted: May 4, 2023

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Using Machine Learning to Find Senolytics

Research published today in Nature Aging has described a machine learning algorithm that finds senescent cell-removing drugs (senolytics) and compared the algorithm’s discoveries to existing compounds.

A quest for effective therapeutics

Removing senescent cells with senolytics may reverse some aspects of aging.

What Are Senolytics? Senotherapeutics for Senescent Cells

Senolytics work by targeting one of several pro-survival pathways that senescent cells use to evade apoptosis and cling onto life. One of the challenges in dealing with senescent cells is that there are a number of different populations of these cells in our tissues and organs, each using different pro-survival pathways. It could be that multiple senolytic drugs need to be used to remove senescent cells using different pathways to survive.
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After covering familiar territory regarding senescent cells, this paper begins with a discussion of existing senolytic compounds, such as the well-known dasatinib and quercetin combination. Most of these compounds were found through bioinformatics approaches that investigated how these cells stay alive long after they should have died by apoptosis [1].

While some senolytics have shown a certain amount of effectiveness in animal models [2], there are relatively few of these drugs, some were found to be ineffective against the diseases they were meant to target, and some have significant side effects. For example, a Phase 2 clinical trial has found that navitoclax causes blood platelets and some immune cells to decline [3].

Even with these disappointing results in mind, researchers have still found merit in the base principle of senolytic development, that senescent cells are valid targets and that removing them with the right compounds would show clinical effectiveness in treating diseases. Finding these compounds, however, is the problem.

Machine learning methods have been used for drug discovery in other areas, including antibiotics [4], but this team notes that there has been no previous progress in using them to find senolytics. Therefore, they sought to meet that need, training an artificial intelligence system from the ground up to find them.

Working on a very large dataset

The researchers took a well-established graph model of machine learning and trained it with detailed information on 2,352 compounds, which they tested themselves for senolytic activity against human lung fibroblasts that had been chemically driven senescent with etoposide. 45 of these initial 2,352 were selectively effective against senescent cells. The researchers then applied this trained model to a full 804,959 compounds.

The results the model returned were highly diverse; it determined that some compounds were highly likely to be senolytic and that others were not. After applying a filter against compounds that are too similar in structure to existing senolytics, the researchers selected 216 compounds that the algorithm chose and that they had on hand along with an additional 50 as negative controls.

The preliminary analysis was favorable: 25 of the initial 216 were found, by initial experiment, to have senolytic properties in the real world. While this is a relatively small percentage, it is clear that the algorithm had effectively narrowed down a very large search space. None of the negative controls had senolytic properties.

Comparison to a gold standard

The team then compared the effectiveness of these candidates to ABT-737, a drug that has significant senolytic properties but is unsuitable for clinical use due to its low bioavailability and side effects. At the 10-micromole dose, the researchers narrowed down the field further to three particular compounds that are roughly as effective and specific as ABT-737. Critically, none of these compounds decreased the viability of control cells, which ABT-737 is known to do.

The researchers note some appealing characteristics of these compounds: they are druglike compounds with no current clinical use, they do not resemble the compounds used in the training dataset, and their chemical properties make them good candidates for oral administration. Further testing revealed that they do not excessively harm healthy liver cells and that they are senolytic against cells that were driven senescent with doxorubicin.

All three of these compounds were found to bind Bcl-2, a mechanism of action that is common to multiple senolytics. This is a critical achievement in AI-guided drug discovery: despite the fact that they don’t look like other senolytics, these algorithmically discovered compounds have been determined to work the same way.

Finally, one of these compounds was tested in naturally aged mice, and the results were positive. The treated mice did not seem to suffer from side effects, and their expression of the senescence markers SA-β-gal and p16 were substantially lower in the kidneys. This, again, represents a critical achievement: an artificial intelligence had successfully discovered a compound that reduces a key biomarker of aging in an animal model.

Conclusion

There are, of course, limitations to the model used in this study and the data used to train it. The initial training data consisted only of a specific cell population that was driven to senescence in a specific way. Senescent cells are highly heterogenous, and other types of senescent cells might be vulnerable to entirely different approaches that this trained model cannot discover.

However, this was an effective proof of concept, and it certainly appears that AI drug discovery applies to senolytics. It is likely that a more robustly trained model on different types of senescent cells can offer even more useful information, discovering potential therapeutics that unassisted people would never have found themselves. Determining whether or not any of these drugs are truly effective in human beings is, as always, a matter of clinical trials.

Yes I will donate❤️

Literature

[1] Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[2] Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., … & Kirkland, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. Nature medicine, 24(8), 1246-1256.

[3] Rudin, C. M., Hann, C. L., Garon, E. B., Ribeiro de Oliveira, M., Bonomi, P. D., Camidge, D. R., … & Gandhi, L. (2012). Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer. Clinical Cancer Research, 18(11), 3163-3169.

[4] Stokes, J. M., Yang, K., Swanson, K., Jin, W., Cubillos-Ruiz, A., Donghia, N. M., … & Collins, J. J. (2020). A deep learning approach to antibiotic discovery. Cell, 180(4), 688-702.

Date Posted: May 3, 2023

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AI Better Than Humans At Healthcare Questions

Scientists have compared doctor-written and chatbot-generated responses to healthcare-related questions, and the results don’t look good for Team Human [1].

Ask your doctor?

Access to healthcare has been linked to longer lifespan, and good healthcare often starts with a good initial consultation. A group of researchers, including scientists from the University of California, San Diego and from the company Human Longevity, has set out to determine if AI might be able to do this better than human beings. The results were published in JAMA Internal Medicine.

The researchers based their study on 195 real-life exchanges from the Reddit forum r/AskDocs. In all instances, the initial questions asked by users were answered by verified physicians. Questions answered by other healthcare professionals were omitted on the premise that a response by a licensed physician constitutes a better benchmark. The researchers then posited same questions to the 3.5 version of ChatGPT that’s been around since November last year. Each question was asked in a new chat session.

Both the responses provided by human physicians and those provided by the AI model were then evaluated by a team of licensed healthcare professionals using several criteria. The evaluators considered “the quality of information provided” (very poor, poor, acceptable, good, or very good) and “the empathy or bedside manner provided” (not empathetic, slightly empathetic, moderately empathetic, empathetic, and very empathetic). The responses were, of course, randomized, stripped of any identifying information such as “I am an AI model”, and labeled “Response 1” and “Response 2”. To decrease the possibility of bias, each case was presented to three different teams of healthcare professionals for a total of 585 evaluations.

The machine prevails

The differences between the human-generated and the machine-generated responses began with their length. The AI gave significantly longer answers on average (211 words vs 52 words). Human professionals were not inclined to engage in a prolonged conversation: 94% of the exchanges contained a single response from the physician.

The evaluators preferred the chatbot response in a staggering 78.6% of cases. Chatbot responses reached the average score of 4.13 (better than “good”) and human responses 3.26 (worse than “good”). Moreover, 27% of human responses, but only 2.6% of machine responses, were rated “unacceptable” (less than 3). ChatGPT also cleanly defeated human physicians in the percentage of responses rated “good” or “very good”: 75.5% vs only 22% on Team Human.

As if this wasn’t enough, chatbot responses were also found to be significantly more empathetic (3.65 vs 2.15). A full 80.5% of human responses and just 15% of chatbot responses scored below “slightly empathetic” (less than 3). Chatbot responses were also almost 10 times likelier to be rated “sympathetic” or “very sympathetic”.

Let’s ask the chatbot

To explain these staggering results, we asked ChatGPT version 4.0 for its own analysis.

The chatbot then offered several important caveats:

Moreover, ChatGPT was empathetic enough to provide some comfort to us, humans, and show understanding of the circumstances many healthcare professionals find themselves in:

The researchers mention several limitations of their study, the most important being that an exchange on an online forum does not recapitulate a face-to-face dialogue between a patient and a physician. In such dialogue, the physician can expand on the topic, ask follow-up questions, provide increasingly more relevant information, and probably be more empathetic as well.

Additionally, the sample size was limited, and some of the co-authors were also on the evaluation team, which might have created bias despite the study’s blind design. Finally, it is possible that not all human physicians in the study were native English speakers, and the language barrier could have added to the impression of brevity and dispassion.

Conclusion

Based on the results of this study, the researchers call for an evaluation of the possibility to integrate chatbots into clinical settings. While chatbots cannot replace human healthcare professionals (at least for now), they might, the authors suggest, be employed in drafting messages to the patients to be edited and approved by the human staff.

In developing countries, where people often have only limited access to human healthcare professionals, chatbots might be even more important for providing initial assessment and assistance. Last but not least, chatbot-generated responses to healthcare questions might be able to counteract the copious amounts of incomprehensible, contradictory, or plainly misleading information that a regular web search often yields.

Yes I will donate❤️

Literature

[1] Ayers JW, Poliak A, Dredze M, et al. Comparing Physician and Artificial Intelligence Chatbot Responses to Patient Questions Posted to a Public Social Media Forum [published online ahead of print, 2023 Apr 28]. JAMA Intern Med. 2023

Date Posted: May 2, 2023

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Certain Medications Appear to Improve Aging Biomarkers

A twin study published in GeroScience has yielded results suggesting that calcium channel blockers, drugs that are commonly used to treat hypertension and other diseases, slow down epigenetic aging and may lengthen healthy lifespan.

A wide field

The researchers begin this paper by noting that over 400 compounds, as found in the DrugAge database, have been reported to extend lifespan in model organisms [1]. However, getting human data for the efficacy of these drugs against any of the processes of aging is considerably more difficult. Therefore, researchers normally try use surrogate endpoints that correspond to lifespan (biomarkers) [2].

Some drugs, however, already appear to be associated with lifespan. The researchers placed their focus on antihypertensive, antidiabetic, and lipid-lowering drugs, which are widely consumed by a substantial fraction of the US population [3], have been reported to have beneficial effects against other age-related diseases: statins are linked to a reduced incidence of dementia [4] and metformin is linked to a decrease in cancer incidence [5].

Previous studies have attempted to examine the relationship between these sorts of drugs and DNA methylation clocks [6]. However, while these clocks are valuable, they are not always comprehensively robust, and so these researchers aimed to use considerably more biomarkers.

A robust twin study with multiple layers of information

This paper uses data from SATSA, a Swedish twin study that focuses on twins that were raised together or apart. Participants who were at least 50 years old received in-person examinations for 3 years between 1986 and 2014, creating a wide body of evidence. After exclusions for contradictory or incomplete information, 672 people with 2,746 measurements were included in the results analyzed here.

There were a total of 12 different biomarkers, including measurements of DNA methylation (including DunedinPACE and GrimAge), telomere length, physical frailty, functional age, and cognitive decline. Many of these biomarkers were composites of related biomarkers. The medications taken by the participants were self-reported, which was corroborated by purchase data.

Advanced statistical analysis was performed on these results, controlling for confounding variables and correlating multiple drugs. As this was a long-term study, it was possible to conduct individual analyses, comparing people’s measurements before and after they were consuming certain medications. The researchers’ model also took into account the diseases that had caused the participants to be taking such medications in the first place.

A confluence of factors

Unsurprisingly, the people who did and didn’t take medications of all types had significant demographic differences. Medication takers were older and had higher BMIs and blood pressure.

Depending on how the researchers analyzed their measurements at the individual level, certain patterns began to emerge. The number of participants who took antidiabetic drugs was too low to draw any significant conclusions. However, in a model that controlled for individual biases, antihypertensive drugs were found to be associated with a lower GrimAge.

While some antihypertensive drugs were individually found to be associated with better cognition but negative effects on epigenetic aging, calcium channel blockers were associated with multiple functional biomarkers along with decreased methylation aging according to multiple epigenetic clocks.

Conclusion

This study is interesting for both its positive and negative results. With statistical results such as these, the biological effects of calcium channel blockers on human beings warrant further investigation. On the other hand, these results make it clear that while they are effective against the specific disorders that they are prescribed for, the vast majority of drugs do not appear to have any noticeable effects on biological aging.

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Literature

[1] Barardo, D., Thornton, D., Thoppil, H., Walsh, M., Sharifi, S., Ferreira, S., … & de Magalhães, J. P. (2017). The DrugAge database of aging‐related drugs. Aging cell, 16(3), 594-597.

[2] Lohman, T., Bains, G., Berk, L., & Lohman, E. (2021). Predictors of biological age: The implications for wellness and aging research. Gerontology and Geriatric Medicine, 7, 23337214211046419.

[3] Hales, C. M., Servais, J., Martin, C. B., & Kohen, D. (2019). Prescription drug use among adults aged 40–79 in the United States and Canada.

[4] Jick, H. Z. G. L., Zornberg, G. L., Jick, S. S., Seshadri, S., & Drachman, D. A. (2000). Statins and the risk of dementia. The Lancet, 356(9242), 1627-1631.

[5] Gandini, S., Puntoni, M., Heckman-Stoddard, B. M., Dunn, B. K., Ford, L., DeCensi, A., & Szabo, E. (2014). Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and ConfoundersMetformin Meta-Analysis. Cancer prevention research, 7(9), 867-885.

[6] Gao, X., Colicino, E., Shen, J., Just, A. C., Nwanaji-Enwerem, J. C., Coull, B., … & Baccarelli, A. A. (2018). Accelerated DNA methylation age and the use of antihypertensive medication among older adults. Aging (Albany NY), 10(11), 3210.

Date Posted: May 2, 2023

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Flavonols, Especially Quercetin, Linked to Less Frailty

In a new prospective cohort study, a higher intake of flavonols, and quercetin in particular, was linked to a significant decrease in the risk of frailty [1].

Flavonoids: not just flavor

Flavonoids are a class of polyphenolic compounds that include flavanols, flavonols, flavones, anthocyanins, and some others. Flavonoids are abundant in plant-based foods, including fruits, vegetables, berries, grains, tea, and wine. They have been studied extensively for their potential health benefits, including antioxidant, anti-inflammatory, and anti-cancer effects. In a recent study, flavanols found in cocoa extract were found to reduce cardiovascular mortality.

One flavonol called quercetin has been an object of increased interest for geroscientists. Its combination with the cancer drug dasatinib, D+Q, is a popular senolytic approach that has shown some success in preclinical and clinical trials [2]. Quercetin reduces oxidative stress and even increases lifespan in several organism models [3]. Quercetin is the most abundant in onions but most bioavailable in berries.

Flavonoids and frailty

This new prospective cohort study attempted to elucidate the role of flavonoids, their subclasses, and quercetin in particular in the prevention of frailty, a clinical syndrome that is characterized by a decline in physiological reserves and function across multiple organ systems. This decline contributes to morbidity and mortality by leaving the person vulnerable to sudden changes in health status triggered by relatively minor stressor events. Frailty is also a major cause of falls and impaired mobility in the elderly.

A recent meta-analysis has found that a healthy diet rich in flavonoids (such as the Mediterranean diet) might decrease the risk of frailty by 50% to 70% [4]. There have been also some interventional studies that showed a positive effect of flavonoids on frailty-related symptoms. In one such study, supplementation with blueberries, a rich source of flavonoids, led to gait improvements in elderly people [5].

Quercetin lives up to expectations

This new study was based on the Framingham Heart Study and encompassed 1701 participants with no frailty at baseline (1998-2001). Frailty was then re-evaluated in 2011–2014. Levels of flavonoid intake were estimated using a food intake questionnaire. The sample was roughly equally distributed by sex, and the mean age at baseline was 58.4. Over an average of 12 years of follow-up, 13.2% of the participants developed frailty.

In a model adjusted for sex, age, energy intake, smoking status, cancer, cardiovascular health, and diabetes, the association between frailty and overall flavonoid intake was insignificant. However, when researchers dug deeper into individual subclasses of flavonoids, the picture became clearer. Each 10 milligram per day increase in flavonol intake was associated with a 20% decrease in the risk of developing frailty. Even more impressively, each 10 milligram per day increase in quercetin intake was associated with 35% lower odds of frailty onset.

Another significant result was age-dependent: among the participants younger than 60 years old, each 10 milligram per day increase in the intake of anthocyanins, another subtype of flavonoids that gives many fruits and vegetables their blue, purple, or black color, was associated with 52% lower odds of frailty onset. However, for participants aged 60 years and older, no significant association was observed.

Like any populational study, this one was laden with limitations, such as using a questionnaire to assess nutrient intake at a single time point along with having a relatively small sample size. However, such studies allow researchers to assess the effects of long-term dietary habits, which is nearly impossible in interventional studies.

In this prospective cohort study, although flavonoid intake was not significantly associated with the odds of frailty onset in middle-aged and older adults, higher intake of the flavonoid subclass, flavonols, was associated with reduced odds of frailty onset, which appeared to be driven by the specific flavonol, quercetin. The protective association between anthocyanins and frailty onset was primarily seen in participants below the age of 60 y. Although hypothesis-generating, this study highlights the potential of dietary flavonols and quercetin as a strategy to prevent frailty onset. Future research should focus on dietary interventions of flavonols or quercetin for treating frailty.

Conclusion

This interesting study suggests that not all flavonoids are equally protective against the onset of frailty, but some might have a robust effect. It confirms the known role of quercetin as a protector against various age-related conditions, which is likely due to its antioxidant activity. The results also highlight yet again the overall relevance of diet for healthspan.

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Literature

[1] Oei, S., Millar, C. L., Nguyen, T. N., Mukamal, K. J., Kiel, D. P., Lipsitz, L. A., … & Sahni, S. (2023). Higher intake of dietary flavonols, specifically dietary quercetin, is associated with lower odds of frailty onset over 12-years of follow-up among adults in the Framingham Heart Study. The American Journal of Clinical Nutrition.

[2] Hickson, L. J., Prata, L. G. L., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., … & Kirkland, J. L. (2019). Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine, 47, 446-456.

[3] Proshkina, E., Lashmanova, E., Dobrovolskaya, E., Zemskaya, N., Kudryavtseva, A., Shaposhnikov, M., & Moskalev, A. (2016). Geroprotective and radioprotective activity of quercetin,(-)-epicatechin, and ibuprofen in Drosophila melanogaster. Frontiers in pharmacology, 7, 505.

[4] Wang, Y., Hao, Q., Su, L., Liu, Y., Liu, S., & Dong, B. (2018). Adherence to the Mediterranean diet and the risk of frailty in old people: a systematic review and meta-analysis. The journal of nutrition, health & aging, 22, 613-618.

[5] Schrager, M. A., Hilton, J., Gould, R., & Kelly, V. E. (2015). Effects of blueberry supplementation on measures of functional mobility in older adults. Applied Physiology, Nutrition, and Metabolism, 40(6), 543-549.

Date Posted: May 1, 2023

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Dr. Peter Attia on How to Outlive

Peter Attia, M.D., popular host of The Drive, has nearly a million followers across his social media platforms. In his first book, OUTLIVE The Science and Art of Longevity, he summarizes much of the evidence and wisdom that he has delivered to his audience over the years by providing a no-nonsense evidence-based tactical manual for optimizing healthspan.

A matter of risk

The book opens with a brief recounting of the practice of medicine through the ages, emphasizing how the system has evolved to address acute illness and injury but not sensibly assess and manage the risks associated with the major metabolic diseases that account for 80% of deaths in people over 50 who do not smoke: atherosclerotic disease, cancer, neurodegenerative disease, and metabolic disease.

Attia reinforces this point by noting that once we account for people who were spared from death by infectious disease, life expectancy has only changed marginally since 1900. From here, Attia introduces the basic concepts of what he terms Medicine 3.0: prevention, personalization, and intelligent risk assessment.

The failure to estimate risk over longer time horizons is cited as a major fault of traditional medical practice, which does not address the major metabolic diseases at their inception but waits until those diseases are developed to the point at which the costs of intervention are much higher and more likely to fail.

A roadmap to healthspan

Attia unfurls a tactical roadmap to optimize healthspan. The first step is to concretely envision our future centenarian selves. What functional capacities do we imagine we’re going to have at 90 without a plan? Is our current trajectory likely to take us there? Attia explains how those answers are obtained through a thorough process of risk assessment, functional testing, and education.

Attia’s strategy of optimizing healthspan requires a focus on its three primary vectors: cognitive ability, physical function, and emotional health. If any of these component parts of healthspan are neglected, the idea of meaningful longevity is lost.

Part II discusses the strategy for optimizing lifespan in greater detail and the science that informs it. Attia addresses what we can learn from centenarian studies and how it is possible to capture the cognitive, functional, and emotional characteristics of centenarians without necessarily having the best genes.

Next, the author tackles the topic of caloric restriction before moving on to sharing his insights into the mechanisms underlying aging and how they are related to the development of diabetes, cardiovascular disease, and neurodegenerative disease. How and when do they begin? What forces drive them? Most importantly, how can they be delayed or even prevented entirely?

The strategy in detail

In Part III of OUTLIVE The Science and Art of Longevity, Peter Attia presents a comprehensive set of tactics in five main areas to optimize healthspan and longevity. These tactics, based on evidence and practical wisdom, are designed to help people achieve their envisioned future selves at 90 and beyond.

Exercise: Attia emphasizes the importance of incorporating a balanced mix of aerobic and anaerobic exercises, including Zone 2 and Zone 5 training, strength training, and flexibility/mobility workouts. These diverse exercise routines contribute to improved cardiovascular health, increased muscle mass, enhanced flexibility, and reduced risk of chronic diseases.

Nutrition: Attia advocates for a whole-foods-based diet rich in vegetables, lean proteins, healthy fats, and complex carbohydrates, with a focus on limiting processed foods and added sugars. He also discusses the potential benefits of intermittent fasting, time-restricted feeding, and caloric restriction in promoting cellular repair, metabolic health, and longevity. Personalization of dietary plans based on individual needs and genetics is a key aspect of his recommendations.

Sleep: Recognizing the critical role of sleep in overall health, Attia provides strategies for optimizing sleep quality and quantity. These include maintaining a consistent sleep schedule, creating a sleep-conducive environment, and addressing sleep disorders through appropriate medical interventions.

Emotional Health: Attia underscores the necessity of nurturing emotional well-being for a fulfilling, long life. He suggests practicing mindfulness techniques, such as meditation and gratitude journaling, prioritizing social connections, and engaging in leisure activities to foster emotional resilience and reduce stress.

Exogenous Molecules: Attia explores the potential benefits of carefully selected drugs, hormones, and supplements in addressing nutrient deficiencies, optimizing hormone levels, and promoting overall health. Some examples include fish oil, vitamin D, magnesium, and metformin. He advises consulting a healthcare professional before starting any new supplement or medication regimen.

Conclusion

Peter Attia’s OUTLIVE The Science and Art of Longevity offers a practical and evidence-based manual for people who want to to optimize their healthspan and achieve meaningful longevity. Through the application of Medicine 3.0 principles—prevention, personalization, and intelligent risk assessment—readers are empowered to take control of their health trajectories and work towards realizing their envisioned centenarian selves.

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Date Posted: May 1, 2023

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Rejuvenation Roundup April 2023

As the second month of spring, April is often associated with rebirth, and we’ve added rejuvenation to the mix with cryptocurrency donation initiatives, biotechnology company progress, and plenty of science.

LEAF News

A Busy Spring for Rejuvenation Research and Advocacy: lifespan.io’s birthday was in April, and we proudly celebrated nine years of being a non-profit organization that advocates, educates, and fundraises for healthy life extension.

An Opportunity to Support Aging Research with Gitcoin: We have two scientific research projects in the new Gitcoin fundraising round. Help us to combat Alzheimer’s disease or improve how clinical trials are conducted today! Gitcoin is a decentralized science (DeSci) platform that utilizes blockchain technology to support the development of open-source projects using Web3 technologies.

Team and activities

Cardio Diagnostics Announces Strategic Engagement With Us: Cardio Diagnostics Holdings, Inc (Nasdaq: CDIO), an artificial intelligence-powered precision cardiovascular medicine company, has announced a strategic engagement with lifespan.io.

Rejuvenation Roundup Podcast

Ryan O’Shea of Future Grind hosts this month’s podcast, showcasing the events and research discussed here.

Journal Club

Reducing DNA Damage With DREAM: In Journal Club this month, we explored a new study published in Nature Structural and Molecular Biology, where researchers demonstrated that by manipulating the DREAM protein complex, a major regulator of DNA damage response, it may be possible to reduce the number of DNA mutations accumulated with age.

Advocacy and Analysis

Bryan Johnson’s Race Against Time: Bryan Johnson is an enigma in the longevity space, someone who is difficult to place in a familiar category or determine the net impact of. Johnson is a successful tech entrepreneur of humble origins who sold his company Braintree Venmo to PayPal in 2013 for 800 million dollars.

What AI Technology Is Doing for Longevity Now: In March 2023, MIT Technology Review revealed that Sam Altman, the CEO of OpenAI (ChatGPT), was the mystery investor behind the $180 million investment into stealth startup Retro Biosciences, a biotech company with the ambition of “adding 10 years to the human lifespan.”

Research Roundup

Cold Temperatures Stimulate Lifespan-Associated Protein: A paper published in Nature Aging describes how cold temperatures stimulate the production of PA28γ, a protein that appears to increase lifespan in worms and cells.

Young Microbiomes in Very Old People: Research published in Nature Aging has illustrated how the gut microbiomes of the longest-lived people are more likely to have bacterial populations associated with youth.

Low Carb Intake Linked to Insulin Resistance: Scientists have published a new study suggesting that low carbohydrate consumption is significantly associated with increased insulin resistance in healthy, lean people.

Reducing Axonal Death and Inflammation in Mouse Brains: Researchers have published a study in Aging Cell on how inhibiting the death of axons in the brain protects the brains of old mice from inflammation.

Air Pollution May Drive Lung Cancer via Inflammation: Researchers have concluded that airborne fine particulate matter, which has been consistently linked to cancer, promotes lung cancer via inflammation and not necessarily via mutagenesis.

Physical Activity, Sleeping, Sedentary Behavior, and Aging: Regular exercise, getting enough sleep, and avoiding sedentary behavior are frequently reported as being important in determining how slowly we age. A team of researchers recently set out to determine the link.

Examining a Factor in the Diabetic Heart: Research published in Heliyon has outlined the effects of F-Klb, a signaling molecule receptor that is released under metabolic stress, on the hearts of diabetic patients. It is the receptor for fibroblast growth factor 21 (FGF21), a regulator of metabolism that is produced both by adipose (fat) cells and the liver.

Age-Related Changes in RNA Transcription Speed: Research published in Nature has described transcriptional elongation changes in the cell with age and how they may be linked to lifespan. Transcriptional elongation is a fundamental biological process that affects the basic steps involved in the production of RNA, which is responsible for executing DNA instructions.

Comparing Mushroom and Animal Protein for Muscle Building: Scientists have reported that protein derived from mushrooms (mycoprotein) has a similar impact on muscle mass and strength as animal-based protein in young, healthy people undergoing resistance training.

Review: Moderate Drinking Doesn’t Lower Mortality: A new comprehensive meta-analysis failed to find any protective effect of moderate drinking on mortality risk. There is an ancient idea that while excessive drinking will kill you, moderate alcohol consumption is actually good for you, and until recently, it seemed to be supported by scientific evidence.

Heart Organoids May Change Future Research: Researchers publishing in Nature Biotechnology have generated epicardioids, which are pluripotent, self-organizing stem cells that allow for better understanding, research, and potentially prevention and treatment of heart disease. The epicardium, a layer of cells surrounding the heart, plays a major role in human embryonic development.

Rapamycin Rescues Age-Impaired Blood Flow in Mice: Scientists have concluded that rapamycin treatment started in early mid-life can prevent age-related blood flow impairment, peripheral artery disease, in the hindlimbs of wild-type, atherosclerotic, and Alzheimer’s model mice.

Amyloid-β Clearance by the Liver Might Help with Alzheimer’s: Chinese scientists have found that the liver removes amyloid-β from circulation in mice, which also decreases its levels in the brain. The age-related impairment of this process might offer a new clue for fighting Alzheimer’s disease.

Case Reports of Sclerotic Fibrosis in the Heart: A pair of case reports published in Heliyon have shed more light on the connection between systemic sclerosis and fatal heart failure, highlighting a need for early diagnosis and treatment.

Uncovering a Predictive Biomarker for Alzheimer’s: Researchers publishing in Alzheimer’s and Dementia have published a correlation between the Alzheimer’s-linked protein tau and another protein, bisecting N-acetylglucosamine (GlcNAc), which suggests its usefulness as a biomarker.

Sleep Quality and Duration Associated with Stroke: Showing yet again that sleep is a serious matter, scientists have reported that short sleep duration, snoring, and long naps are linked to a significantly elevated risk of acute stroke.

Increased Energy Efficiency Might Drive Weight Regain: Scientists have discovered that formerly obese mice that became leaner have greatly improved energy efficiency, which might be preventing their complete return to normal weight.

Examining Cellular Stemness as a Tissue Attribute: In a preprint paper published on bioRxiv, researchers including João Pedro de Magalhães have gotten a glimpse at how stemness declines across tissues with aging.

Reprogramming Fibroblasts in Vivo for Heart Repair: Scientists from Duke University have found a way to make adult fibroblasts differentiate into cardiomyocytes, which might help develop better heart attack treatments.

Simply Being Overweight May Not Be Harmful in Aging: According to a new large-scale populational study, being overweight is not associated with either significant risks or benefits between the ages of 45 and 85. Obesity, however, is a clear risk factor.

Hair Pigment Stem Cells May Work Differently: Researchers publishing in Nature have made the surprising discovery that pigmentation cells (melanocytes) can naturally transition back into the stem cell state in a process called dedifferentiation.

Netrin-1 Rescues Blood Stem Cells in Mice: Scientists have discovered that the protein Netrin-1 alleviates the age-related decline in hematopoietic stem cell function in mice, enhancing HSC transplantation and protecting these mice from the harmful effects of chemotherapy.

Ketone bodies: A double-edged sword for mammalian life span: Endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival.

High-Intensity interval training reduces transcriptomic age: A randomized controlled trial: A low dose of HIIT can reduce an mRNA-based measure of biological age in sedentary adults between the ages of 40 and 65 years old. Other changes in gene expression were relatively modest.

Physical activity is associated with slower epigenetic ageing—Findings from the Rhineland study: These findings suggest that regular physical activity slows epigenetic aging by counteracting immunosenescence and lowering cardiovascular risk.

High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: This study’s results suggest that dietary spermidine is presystemically converted into spermine, which then enters systemic circulation.

Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction: TA-65 increased all major lymphocyte subsets and reduced C-reactive protein in elderly patients 12 months after a heart attack.

Senolytics rejuvenate the reparative activity of human cardiomyocytes and endothelial cells: These results open the path to further studies on using senolytic therapy in age-related cardiac deterioration and rejuvenation.

Engineering longevity—design of a synthetic gene oscillator to slow cellular aging: These results establish a connection between gene network architecture and cellular longevity that could lead to rationally designed gene circuits that slow aging.

AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans: TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo.

Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging: Calcium channel blockers may decrease biological aging as measured by epigenetic and functional biomarkers.

Vitamin D Supplementation and Its Impact on Mortality and Cardiovascular Outcomes: It appears to lower the risk of all-cause mortality while not showing a decrease in specific cardiovascular morbidity and mortality risk.

News Nuggets

Longevity Prize Announces First Winners: The winners of the Hypothesis Prize have been announced as part of the Longevity Prize initiative. This is an important step for funding rejuvenation research and sets a great precedent for future longevity-focused prizes and open science.

The Maximon Longevity Prize 2023: 50,000 CHF (56,000 USD): Maximon, Europe’s first longevity company builder, is pleased to announce that applications for the Maximon Longevity Prize 2023 are now open. This prestigious prize is awarded to translational longevity research projects that demonstrate exceptional potential to extend human healthspan and lifespan.

Life Biosciences Claims Visual Restoration in Primates: Life Biosciences, a company co-founded by the well-known Dr. David Sinclair, has recently claimed that it has reversed a form of neuropathy in nonhuman primates through gene therapy and epigenetic reprogramming.

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Date Posted: April 28, 2023

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An Opportunity to Support Aging Research with Gitcoin

We have two scientific research projects in the new Gitcoin fundraising round. Help us to combat Alzheimer’s disease or improve how clinical trials are conducted today!

An alternative way to fund science

Gitcoin is a decentralized science (DeSci) platform that utilizes blockchain technology to support the development of open-source projects using Web3 technologies, with the purpose of providing resources to projects that will improve the public good.

The DeSci movement describes a collective of individuals from scientific, independent, building, developing, activist, and organizing backgrounds that collaborate to construct support systems and push for distributed governance to advance scientific discovery.

lifespan.io is thrilled to participate in this round of funding, and we have two proposals in the current round, demonstrating our dedication to advancing progress in the aging field.

lifespan.io is developing a therapy for Alzheimer’s

The first of these is the Mindset project, a project to create a light and sound headset that may address Alzheimer’s disease.

Through the generous contributions of approximately $17,000 from previous Gitcoin funding rounds, we have been able to construct an initial hardware and software system. Early tests reveal that it can influence the brain with the light and audio stimulation it produces.

Our system has, so far, generated preclinical data that suggests that neural entrainment, which is when brain activity responds and adjusts to a pattern of external signals such as audio or visual elements, works on humans.

We began the process of developing the Mindset system based on the idea that utilizing entrainment therapy may help reduce the loss of critical connections in the brain, increase cognitive capability, and alleviate the symptoms that typically accompany Alzhemeir’s disease.

This new funding round will help us reach our $50,000 goal, when we will be able to buy the equipment needed to build a cost-effective production prototype. Once we have that, we can then move forward and produce a low cost headset at scale to benefit the greatest number of people possible.

Web3 crowdsourced clinical trials

The second project is the lifespan.io Web3 program, which has the goal of improving how aging research and clinical trials are funded.

Your contribution can enable us to develop a novel blockchain-based crowdfunding platform. This could provide additional resources for ambitious projects, such as creating treatments to reduce or even reverse the effects of aging.

Existing forms of financing, like grants, have intense competition and are likely to be conservatively invested, so the innovative studies that we are attempting may not receive the money they need. Your assistance can help us create an alternative approach to financing daring, revolutionary initiatives that could be highly impactful.

Need help donating to these projects?

If you are new to the technology, we have made a step-by-step guide on how to donate.

Get a MetaMask wallet.
Acquire $100 (or whatever amount you want) worth of ETH via Coinbase or other methods.
Send this ETH to your MetaMask from Coinbase (or wherever): this could incur a significant gas fee.

Once you have done that, this video (at 4 minutes, 20 seconds) will show you the steps you need to take to donate and ensure that your donation benefits from the matching fund.

Donate today, and help us to make age-related diseases a thing of the past!

Yes I will donate❤️

Date Posted: April 28, 2023

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Netrin-1 Rescues Blood Stem Cells in Mice

Scientists have discovered that the protein Netrin-1 alleviates the age-related decline in hematopoietic stem cell function in mice, enhancing HSC transplantation and protecting these mice from the harmful effects of chemotherapy [1].

(Not) a niche problem

Stem Cell Exhaustion

Stem cell exhaustion is the age-related deficiency of stem cells. This particular hallmark is directly responsible for many of the physical problems associated with aging, such as frailty and a weakened immune system.
Read More

Declining stem cell function (stem cell exhaustion) is linked to numerous aging phenotypes [2]. Stem cells reside in so-called “niches” – microenvironments whose role is to support stem cells’ viability and function. However, stem cell niches themselves are prone to accumulating age-related damage [3].

In this new study, the researchers “sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow”. The health of hematopoietic stem cells, which give rise to differentiated blood cells, is especially important in the context of blood cancer, with patients often requiring hematopoietic stem cell transplantation (HSCT). HSCT effectiveness diminishes with age, probably due to age-related changes in the bone marrow niche, although the exact mechanisms of this deterioration remain unknown [4].

Target: Netrin-1

The researchers used a mouse model that recapitulates premature aging of the immune system. Transcriptomic analysis revealed multiple genes that were differentially expressed in this model compared to wild-type mice, and the researchers focused on the one that encodes Netrin-1. Since this protein has been linked to angiogenesis (blood vessel building) and osteogenesis (bone building), it seemed plausible that it might be relevant to the BM stem cell niche.

Perusing existing RNA sequencing databases revealed that in bone marrow, Netrin-1 is expressed mostly in mesenchymal stromal cells (MSCs) and epithelial cells (ECs), both of which are important components of the niche. Conditional deletion of Netrin-1 in those cells led to impaired vascular integrity and accumulation of adipocytes (fat cells), both of which are known features of BM niche aging.

More importantly, Netrin-1 deletion seemed to impair stem cell function. In mice with Netrin-1-deficient MSCs, more HSCs were “stuck” in the nonproliferative G0 phase of the cell cycle. This decrease in progenitor activity was accompanied by impaired engraftment capacity when HSCs from Netrin-1-deficient mice were transplanted into wild-type mice. In mice with Netrin-1 knocked down in ECs, similar effects were observed, albeit of a lesser magnitude. An increase in the number of quiescent stem cells and a decline in their engraftment capacity are characteristic of hematopoietic aging.

DNA damage responses restored

The researchers performed RNA sequencing to elucidate the effect of Netrin-1 deletion on gene expression. In MSCs and ECs of Netrin-1-deficient mice, they detected significant upregulation of pathways associated with adipogenesis, cell cycle, and, importantly, DNA damage responses (DDR). Consequently, those cells accumulated more DNA damage than controls.

Accumulation of DNA damage is central to cellular aging. In this experiment, DNA damage was greater in MSCs and ECs taken from aged wild-type mice than those taken from their young counterparts. Strikingly, a two-week Netrin-1 treatment was enough to significantly reverse DNA damage in aged mice. The treatment also resulted in improved bone marrow vascular health.

Protection from chemotherapy-induced damage

However, the important question was whether Netrin-1 supplementation would improve the function of an aged hematopoietic system, which it did. The treatment increased the number of functional HSCs following bone marrow transplantation four-fold. Moreover, HSCs from treated aged mice were almost as fit and competent as those derived from young controls.

The researchers also learned that not all beneficial effects of Netrin-1 supplementation on HSCs result from improvements in the bone marrow niche. Many of those effects were recapitulated when HSCs were co-cultured with Netrin-1 in vitro, showing that Netrin-1 probably exerts its benefits both directly and indirectly, via niche improvements.

Netrin-1 treatment also significantly protected mice from the detrimental effects of chemotherapy. Treated mice demonstrated preservation of body weight and much more robust hematopoietic recovery. When mice were subjected to an especially damaging multiple-dose chemotherapy, the difference in survival was striking, with the treatment group not losing a single mouse:

Conclusion

This study identifies Netrin-1 as a regulator of BM niche health and HSC fitness that at least partially works by restoring DNA damage responses. This discovery might prove important for protecting patients from the harms of chemotherapy and improving HSC transplantation, and it might also apply to the wider context of aging.

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Literature

[1] Ramalingam, P., Gutkin, M. C., Poulos, M. G., Tillery, T., Doughty, C., Winiarski, A., … & Butler, J. M. (2023). Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response. Nature Communications, 14(1), 2018.

[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[3] Brunet, A., Goodell, M. A., & Rando, T. A. (2022). Ageing and rejuvenation of tissue stem cells and their niches. Nature Reviews Molecular Cell Biology, 1-18.

[4] Ho, Y. H., & Méndez-Ferrer, S. (2020). Microenvironmental contributions to hematopoietic stem cell aging. Haematologica, 105(1), 38.

Date Posted: April 27, 2023

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Hair Pigment Stem Cells May Work Differently

Researchers publishing in Nature have made the surprising discovery that pigmentation cells (melanocytes) can naturally transition back into the stem cell state in a process called dedifferentiation.

A kinship with hair follicle cells

These researchers begin their study by discussing stem cells and their proliferation. In the common understanding, which appears to be true for blood cells [1], the human body maintains a stem cell population that divides either into identical stem cells or partially differentiated cells that divide into functional, somatic cells [2].

Hair follicle cells have commonalities with melanocytes. When hair regenerates, both follicle stem cells and melanocyte stem cells act, bringing growth and pigmentation to the hair [3]. Melanocyte stem cells are commonly known to occupy a specific niche, and previous work has suggested that this niche becoming depleted is the key cause of hair whitening. We have previously published an interview with this idea in mind.

However, these researchers disagree with the basic essence of that idea, as their results suggest that the stemlike state of hair pigmentation cells can switch back and forth.

The bulge and the hair germ

This research separately examines the bulge and the hair germ, which are known to be the niches associated with hair pigmentation and growth. This research corroborates previous research demonstrating that melanocyte stem cells can sometimes be found in the bulge [4].

However, according to this study’s volumetric analysis, these cells aren’t usually in the bulge at all; instead, they normally reside in the follicle’s hair germ area. When the mature melanocytes are at the part of the hair cycle when they express pigmentation, the stem cells migrate to the bulge and migrate back before the next cycle. This does not occur with hair follicle cells.

No dedicated stem cell niche

The authors developed a fluorescent reporter to track the fate of cells expressing Oca2, which is associated with differentiated, active melanocytes. This is where they confirmed their key discovery: instead of their reporter gene being gradually flushed as the somatic pigmentation cells went away, the gene was being expressed in cells that were displaying more stemlike charcteristics. Therefore, according to this study, these cells had dedifferentiated from a somatic state into a stem cell state.

Furthermore, after repeatedly administering their reporter and checking for the presence of unreported melanocyte stem cells that never became pigment-producing cells, these researchers discovered no such population group. Therefore, they came to a shocking conclusion: there is no truly dedicated niche that contains a reserved population of melanocyte stem cells.

There is also an explanation for how and why melanocytes decline with aging. Using a population of genetically engineered mice, the researchers found that Wnt signaling is crucial to melanocyte stem cell fate. If Wnt is always on, the cells stay differentiated and die off; if Wnt is off, the cells cannot differentiate and hair turns white. This is in accordance with previous research [3].

Conclusion

The researchers note two different downstream consequences of their findings. Cells that regularly transition back into stem cells appear to be rejuvenative at first glance, but this could cause accelerated aging instead, as these transitory cells aren’t able to protect themselves from damage in the way that a dedicated stem cell population can. The second consequence is considerably more dire: this paper offers at least a partial explanation for the aggressiveness of melanoma, which occurs when out-of-control melanocytes become cancerous.

While this is a mouse study and these findings fly in the face of the widely held understanding of the melanocyte stem cell niche, this was a peer-reviewed study published in a major academic journal, and it certainly warrants further investigation. If these researchers’ results are confirmed to be true in human beings, they may offer an entirely new set of approaches to hair graying with age.

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Literature

[1] Seita, J., & Weissman, I. L. (2010). Hematopoietic stem cell: self‐renewal versus differentiation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2(6), 640-653.

[2] Cockburn, K., Annusver, K., Gonzalez, D. G., Ganesan, S., May, D. P., Mesa, K. R., … & Greco, V. (2022). Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer. Nature Cell Biology, 1-9.

[3] Rabbani, P., Takeo, M., Chou, W., Myung, P., Bosenberg, M., Chin, L., … & Ito, M. (2011). Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell, 145(6), 941-955.

[4] Nishimura, E. K., Jordan, S. A., Oshima, H., Yoshida, H., Osawa, M., Moriyama, M., … & Nishikawa, S. I. (2002). Dominant role of the niche in melanocyte stem-cell fate determination. Nature, 416(6883), 854-860.

Date Posted: April 27, 2023

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Zuzalu: The Experimental Pop-Up City With a Longevity Focus

The decentralized autonomous organization VitaDAO is supporting longevity realated initiatives at Zuzalu, a pop-up mini-city event in Montenegro, which aims to create a unique jurisdiction for medical innovation within a more effective regulatory framework.

A platform for longevity events and workshops

VitaDAO is hosting unique, longevity-oriented events and workshops in Zuzalu which are designed to accommodate 200-300 longevity enthusiasts.

While establishing industry connections, participants will be coming together to explore the possibility of deepening the ecosystem surrounding longevity and solidifying its regulatory structure. There are also health-improving activities available during this long-term event’s health track.

Held between March and May 2023, the mini-city experiment is hosting several workshops and events. The topics will include cryptography, synthetic biology, the concepts of pop-up cities and digital tribes, and multiple facets of the DAO ecosystem and longevity.

Participants have the opportunity to learn about longevity innovations, take part in workshops and initiatives to improve their own longevity, engage in the latest discourse in biotech, and engage in the conference’s primary topic of a new jurisdiction and regulatory framework for longevity.

In addition, the event’s health track takes a holistic approach to health, allowing participants to check their biomarkers while exploring diets and exercise routines designed to help improve health.

The mini-city experiment was created by Vitalik Buterin, founder of Ethereum and an avid supporter of aging and rejuvenation research. The event is being attended by some of the industry’s most well-known figures, such as Aubrey de Grey, President and CSO of the LEV Foundation; Joe Betts-LaCroix, CEO of Retro Biosciences; Nathan S. Cheng of Healthspan Capital; Laurence Ion and Tyler Golato of VitaDAO; and Stephanie Dainow, lifespan.io’s Executive Director, among many other noteworthy industry names.

Personal connections to decentralized ideas

Driving deeper connections and establishing an environment of learning is at the heart of this pioneering event. The Zuzalu mini-city is meant to be a holistic experience that creates an atmosphere in tune with longevity. Participants have the opportunity to discuss lifespan-related topics and can dive deeper into the ecosystem with health programs, community activities, workshops and hackathons, immersing themselves in the experience. A step away from VitaDAO’s virtual decentralized format, Zuzalu intends to capitalize on human connections over the two months of its existence.

Apply to visit the main Longevity Biotech Conference at Zuzalu in May.

Yes I will donate❤️

Date Posted: April 26, 2023

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What AI Technology Is Doing for Longevity Now

In March 2023, MIT Technology Review revealed that Sam Altman, the CEO of OpenAI (ChatGPT), was the mystery investor behind the $180 million investment into stealth startup Retro Biosciences, a biotech company with the ambition of “adding 10 years to the human lifespan.” This investment marks the latest tech entrepreneur expressing their interest in longevity science and a new connection with innovative AI technology.

According to February 2023 reports, AI is continuing to gain traction in healthcare applications. Currently, the market is estimated at $14.6 billion (USD) with a compound annual growth rate (CAGR) of 47.6%, with solutions spread across various healthcare fields, such as patient data and risk analysis, precision medicine, cybersecurity, lifestyle management, and drug discovery.

AI is currently being used in longevity and healthcare

The increasing convergence of AI technology and longevity science is sparking advancements in the sector, with established businesses, start-ups, and researchers utilizing the technology. Most recently, scientists explored how ChatGPT, an AI-based language model, was able to predict Alzheimer’s in 80% of cases when analyzing speech. However, it is not the only implementation.

Due to its capabilities of analyzing a vast range of data, AI is proving instrumental in the discovery and development of new compounds. One such application is Insilico Medicine’s ChatPandaGPT integration, which allows researchers to ‘talk’ to its PandaOmics target discovery platform, thus analyzing and navigating large datasets in order to discover new biomarkers and therapeutic targets.

Atificial intelligence models are currently being used to conduct genomic analysis and identify specific genes associated with healthy human lifespan. One such project is Calico Labs’ collaboration with the well-known platform AncestryDNA, which analyzes a vast range of data to establish hereditary factors in longevity.

Personalized medicine

By using AI technology, researchers may be better able to detect iomarkers for disease early, facilitating prompt interventions. BioAge Labs’ partnership with Age Labs AS seeks to analyze samples and health records from the Nord-Trøndelag Health Study (HUNT) biobank to develop novel therapeutics.

The precise impact of diet and exercise on the individual level is still not completely understood, and AI may change that by analyzing a wider range of data. Nutrino’s personalized AI platform is a predictive glycemic response algorithm that can help optimize eating habits and potentially reduce diabetes.

On a similar note, pecision medicine allows for tailored medical solutions. AI can be employed to analyze relevant data and help design and deploy these strategies. For example, Deep 6 AI’s clinical trial matching system connects participants, patients, and researchers for clinical trials in order to broaden databases.

Occasionally, AI has been known to spot what a human cannot due to its ability to analyze data more closely and at greater volumes. Zebra Medical Computer Vision AI medical imaging tool can be used to analyze data, including medical imaging, to diagnose diseases, such as bone, liver, lung, and cardiovascular illnesses. This start-up was recently purchased by Nanox for a rumored sum of $200 million.

Using AI in longevity research

Recent advancements in the sector and widespread application across various industries have shown the technology to be effective. Although each AI implementation is different, in longevity, it is finding its application due to its capabilities for analyzing and working with the immense range of data in the healthcare sphere, allowing researchers to identify patterns, relationships, and evaluate factors in age-related diseases. In turn, they are better able to develop potential solutions and test them, at least in the initial stages, to ensure their feasibility.

Despite the achievements, AI isn’t a flawless solution, and people who apply the technology in their work are advised to do so with caution to ensure that any solutions created operate efficiently and can be used responsibly. For example, biased data introduced into AI datasets can discriminate against or favor certain groups. In addition, such models may contain incomplete or inaccurate data, making them ineffective.

For AI in longevity to work effectively, it must have access to expansive datasets. This creates an issue wherein sensitive data could be breached or exposed. In addition, it raises concerns of consent, as people may be unaware of when and how their data is used. These risks could be minimized by the responsible application and security of AI.

Although this isn’t exclusive to AI, the risk of geographical and economic disparities in access, as with most state-of-the-art technology, means that access may be limited. This raises ethical concerns about how datasets are used, whom they are used for, and who will benefit from the solutions. As artificial intelligence technology advances, more benefits and challenges to its usage will become apparent.

Summary

Recent implementations of artificial intelligence in the longevity sector have presented some impressive results, including the power to harness data in order to deliver tangible suggestions for therapeutics development and to analyze medical images. As AI continues to advance, its potential appears to grow in tandem. However, scientists should be careful to avoid data-related ethical concerns and pitfalls when onboarding this new technology.

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Date Posted: April 26, 2023

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Simply Being Overweight May Not Be Harmful in Aging

According to a new large-scale populational study, being overweight is not associated with either significant risks or benefits between the ages of 45 and 85. Obesity, however, is a clear risk factor [1].

BMI plus fat mass index

While obesity is widely recognized as a life-long risk factor, several studies suggest that people who are simply overweight might be at a lower risk of death than their lean counterparts [2], especially at older ages [3]. However, many scientists attribute these results to a failure to account for variables such as body shape and long-term shifts in BMI (body mass index). The debate is far from settled, and this new study provides yet another angle.

The authors used UK Biobank, a vast repository of health data on almost half a million British citizens, to analyze the association between being overweight or obese and the risk of death at various ages, from 45 to 85. To address another common claim, that BMI does not always reflect body composition (muscular people can have high BMIs without actually being obese), the researchers used an additional metric: fat mass index. This is calculated the same way as BMI but using only fat mass.

The researchers adjusted their model for an impressive array of potential confounders, including physical activity, dietary patterns, smoking, history of disease, socioeconomic status, educational attainment, and even salt consumption and leisure-time screen use. The final analysis included about 370,000 people. The participants were categorized by BMI as underweight (under 18.5 kg/m^2), normal weight (18.5–24.9 kg/m^2), overweight (25.0–29.9 kg/m^2), obesity class 1 (30.0–34.9 kg/m^2), and obesity class 2 (at least 35 kg/m^2).

A bit of extra weight seems benign

The results showed that being overweight, both according to BMI and fat mass index, was only moderately associated with mortality risk at any given age. While an inverse association was indeed observed at ages 45 to 55, the statistical power in this age group was considerably lower due to fewer deaths. The graph shows a small bump in mortality risk for overweight people between ages 55 and 75, but this association vanishes according to BMI and is reversed according to fat mass index in older people. The researchers add a caveat to this last observation, saying that “the magnitude of association was small and may not be clinically meaningful”.

The picture was much clearer for obesity, especially extreme obesity, which was highly associated with mortality, even at younger ages. When measured by BMI, the association barely changed across all age groups, and it became only slightly attenuated with age when measured by fat mass index:

The main upshot of the study, according to its authors, is that obesity should be prevented at any age, while the association between being overweight and mortality is more nuanced. The researchers also note that while BMI and fat mass index showed a slightly different picture, those differences were small, and the correlation between the two indices stood at ≥0.93. Hence, BMI can be safely used as a measure of adiposity in future studies.

Surprising high lean mass results

Regarding the attenuation of the relationship between fat mass and mortality in the oldest participants, the researchers suggest a methodological explanation. First, people who reach old age despite their obesity might be genetically well-protected from its harmful effects. Second, at this point, the risk of cancer, cardiovascular diseases and frailty is so high that body composition becomes a relatively less important factor.

Interestingly, the researchers found the group with the highest lean mass (i.e., the most muscle) at a 20% to 30% higher risk of mortality from 55 to 75 years, which is consistent with some previous studies [4]. If these results are accurate, they pose an interesting question of why supposedly fit people with very high lean mass are at an increased risk. According to the researchers, “previous authors have suggested that muscle quality matters more than quantity when it comes to cardiometabolic health, and future research should consider factors such as microvasculature, muscle fiber type distribution and size, fat infiltration, and fat-free mass function.”

Conclusion

By adding stratification by age, this study paints a clearer picture of the relationship between adiposity and mortality risk with aging. According to the results, being overweight neither significantly increases nor decreases mortality risk. Obesity, however, seems to be equally harmful at all ages. While this might be the largest such study to date, it still has all the usual limitations of a populational study and cannot establish causation.

Yes I will donate❤️

Literature

[1] Sanchez-Lastra, M. A., Ding, D., Dalene, K. E., del Pozo Cruz, B., Ekelund, U., & Tarp, J. (2023). Body composition and mortality from middle to old age: a prospective cohort study from the UK Biobank. International Journal of Obesity, 1-8.

[2] Flegal, K. M., Kit, B. K., Orpana, H., & Graubard, B. I. (2013). Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. Jama, 309(1), 71-82.

[3] Doehner, W., Clark, A., & Anker, S. D. (2010). The obesity paradox: weighing the benefit. European heart journal, 31(2), 146-148.

[4] Lagacé, J. C., Brochu, M., & Dionne, I. J. (2020). A counterintuitive perspective for the role of fat‐free mass in metabolic health. Journal of Cachexia, Sarcopenia and Muscle, 11(2), 343-347.

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The Blog

Building a Future Free of Age-Related Disease

Hi, Irina, and thanks for taking the time to talk to us. Could you tell us a little bit about yourself and the journal?

Yes, we definitely have quite a bit in common there, and I can definitely sympathize as a fellow editor-in-chief about how busy it can be as well. Speaking of which, what does your typical day look like as the editor-in-chief?

It is, of course, good news that there are more journals now dedicated to the subject.

Yes, as you say, let’s get back to the hardcore science. Let’s get the evidence. That’s a great approach to take, and there is a problem with hype and snake oil in the field, of course.

Yes, it’s important to try and keep it grounded.

We don’t want a situation of overpromising and underdelivering, because it doesn’t do the field any good. It’s about striking that balance. That way, people are not disappointed and then they don’t dismiss the field as nonsense, which is good.

Exactly, and of course, journals are not without their problems. So, let’s talk about the elephant in the room, journal impact factor.

Do you agree that academic bloat from non-research articles is a problem? And if so, what are the kinds of ways that we can try to minimize this issue in the journal?

Yes, everything tends to get buried. I’ve seen people citing reviews, which can have a hundred or more referenced papers in them, as a way of supporting their case. I usually ask which part of the 8,000 or more word review am I supposed to be looking at here?

Indeed, it’s a real problem. So, another problem with impact factor is typically, not always, but usually based on a two-year citation window. Some people suggest that this really isn’t enough time for a published paper to gain enough traction.

I don’t think anybody’s got the time to read it all, really, unless they’re an AI, perhaps, because AI is becoming more sophisticated and it’s great at analyzing lots of bulk data.

I know they’ve been experimenting with AI to look at research papers in the past to find connections that were not made by humans because they can’t be everywhere and read everything. I know that AI is often hyped up, but it might actually be used in a way to try and mitigate this problem.

Yes, it does seem strange, and it’s clear at least from my perspective that it has a lot of problems.

I also think there’s another problem with just publication in general, and that is the reporting of negative experimental results.

That’s the problem, isn’t it? Because of that motivation, research can be sensationalized just like some newspapers try to grab attention using hype and sensationalized headlines.

Regarding the word failure, as you say, I think that is the wrong word. I was sort of paraphrasing what other people say. They say failure though I do not see it as failure either as we can learn from all results.

Now I’m a fan of an artist from the seventies, early eighties, called Bob Ross. You may remember Bob Ross.

He was a wonderful artist and very peaceful, and I always liked the way he described if you’d failed or made a mistake. He said “We don’t make mistakes, we have happy accidents”. I think that’s a fantastic way of framing it. Perhaps we should have a Journal of Happy Accidents.

Yes, it’s a massive problem. I’m beginning to have one of those “tip of the iceberg” moments where the more you explore, the bigger you find out the iceberg is and before you know it, your Titanic is metaphorically steaming towards it, which is a problem.

Yes, definitely, and just in what we’ve covered today, it shows you how many sorts of hurdles and pitfalls there are. It really plays into personal biases, which is something we all have.

As journalists, we often encounter biases, and part of being a good journalist is to acknowledge that no matter what we do, we all have personal bias of some kind. In accepting that and acknowledging it, we can do our best to keep it in check and report fairly and with this in mind.

Yes, which means the larger cohort you have, the less outliers are going to influence that data strongly and skew the figures. That touches upon decentralized science, or DeSci, which is something that lifespan.io is very involved in.

Currently, in the traditional grant giving systems, the promising moonshot projects that have a potentially high risk of failure are being turned away from funding in favor of less-ambitious projects that have a higher chance of a positive publication.

Because they are directly controlled by the community, it means that the kinds of experiments that they would like to see are actually getting funded through this system of decentralized science. In other words, Desci is helping to democratize science and break out of the rut it is currently in.

DeSci could also potentially play a role in the future of how journals are. Perhaps there could even be a DeSci journal.

It almost sounds like film reviewing on the website Rotten Tomatoes, where there is an audience and critic rating.

That would be your canary in the coal mine as well. Because if the review panel gives it like 30%, but the audience who are actually consuming the paper gives it 90%, then you know something might not be right.

The DeSci movement uses active community participation to fund and operate large-scale projects but also potentially could apply to reviewing things. I could easily see this being applied to journal clubs to facilitate the evaluation and sharing of information.

Yes, something like that would be really useful.

This means that these highly popular papers are basically outliers that can skew the calculation of what that average is. What can we do about these sort of disproportionately popular papers?

Yes, It’s almost like being in an abusive relationship. You know it’s bad for you. You know you shouldn’t be involved with it, but yet you keep coming back for more.

Yes, it’s a problem for sure, but hopefully with all these new tools and the Desci movement, we can replace what is broken. No point in trying to fix a system that does not work, as you suggest; better to sink our energy into making something better to replace it.

On that final note, I would like to thank you for taking the time to talk with us today and for sharing your thoughts and insights on the journal system.

How did you end up studying the biology of aging and long-lived species in particular?

We don’t really know the actual maximum lifespan of long-lived species, right?

Which traits or abilities of long-lived species do you personally find most fascinating?

What do you think are the evolutionary reasons for some species developing those superior anti-aging mechanisms, but not other species? Why can’t we humans have nice things like superior double-strand break repair or antioxidant protection?

So, it’s sort of a side effect?

That’s what you are mostly working on, right?

Right, we tend to forget that we humans already are a long-lived species.

Still, many species have far superior mechanisms, such as a more effective SIRT6, which is something that you study as well.

There are many factors that correlate with longevity across species, such as body size, the rate of mutations, epigenetic drift, retrotransposons. Do you think all those might be somehow related?

I was actually going to ask you about your thoughts on Sinclair’s paper where they claim that aging is caused by the loss of epigenetic information.

Can you think of a process of aging that’s unrelated to this?

Let’s move on to translation. All those superpowers that long-lived species possess look very tempting, but how can they actually be translated into humans?

I didn’t know that you were also working on gene therapies for SIRT6 activation. Do you have any preliminary results or insights?

You have found that exposure to cold also improves DNA repair. So, should we all start taking ice baths?

Do you have human data to back it up?

In one of your talks, you said that calorie restriction works in both directions, upregulating both pro- and anti-longevity genes. We know that CR is a potent anti-aging intervention, so how does this square with this finding of yours?

Obviously, it’s not easy to work on long-lived species in a lab, but some prominent figures such as Steven Austad think that we really should be expanding our repertoire of lab animals with long-lived ones. Where do you stand on this?

So, you still have to go through mice, with all their limitations as a model animal?

Neurodegeneration is one of the most important processes of aging in humans. Do long-lived animals experience it too?

Do you have any preliminary data from your fucoidan trial?

Do you or will you have data on lifespan from these mice?

As a veteran of geroscience, what do you think about its current state? What do you find exciting or maybe disheartening?

I remember that at our conference last year, Ending Age-Related Diseases 2022, when answering a question from the audience, you said, and I hope I’m not misstating, that we will have anti-aging therapies in about 20 years from now.

A lack of effective treatments

Straight to the muscles

Nerves and mitochondria more like those of young mice

Conclusion

Literature

A quest for effective therapeutics

Working on a very large dataset

Comparison to a gold standard

Conclusion

Literature

Ask your doctor?

The machine prevails

Let’s ask the chatbot

Conclusion

Literature

A wide field

A robust twin study with multiple layers of information

A confluence of factors

Conclusion

Literature

Flavonoids: not just flavor

Flavonoids and frailty