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Building a Future Free of Age-Related Disease

Death Clock

The “Death is Inevitable, Why Bother?” Argument

It might be inevitable that everyone dies eventually, but that doesn’t actually matter as to whether or not rejuvenation is worth pursuing.

Getting to the heart of this particular argument against life extension

There’s a fundamental similarity between the questions “Why rejuvenate your body if it’s going to die anyway one day?” and “Why clean your house if it’s going to crumble to dust one day?” An obvious answer to the latter question would be: “Because in the meantime, I’m going to live in that house, and for as long as I do, I’d like it to be clean.” This makes for a pretty accurate answer to the first question as well, so long as you replace “house” with “body”.

The implied assumption behind this concept seems to be that, as long as life doesn’t last forever, improving its quality and quantity is pointless. (It doesn’t make much sense to distinguish between quality and quantity in the case of life, because as we have discussed elsewhere, it really isn’t possible to extend the average lifespan without significantly improving health and vice versa.)

If this assumption were true, it would also apply to many other commonplace things and situations that we wouldn’t ever dream of considering pointless: if death is inevitable, why get a flu shot? If death is inevitable, why undergo heart surgery? If death is inevitable, why looking before crossing the street? If death is inevitable, why eat? And so on.

Even if death is inevitable, that is no reason not to develop life extension technology

The answer to all these questions is the same: for as long as we’re going to be alive, we’d like to make our lives as enjoyable as possible; and not only do all those things improve the quality of our lives, they make our lives last longer than they would otherwise. Maybe it won’t last forever, but a longer, more enjoyable life seems preferable to a shorter, more unpleasant life.

As an extreme example, if improving and extending a finite life is pointless, then since the universe seems doomed to die in one way or another, perpetuating the human race and improving the lives of its members is also pointless, which would be a seriously pessimistic outlook on life.

If life is finite, there’s no reason to make it shorter than it has to be, and, moreover, there’s no reason to make it less pleasant than it could be. If rejuvenation biotechnologies reached their full potential, we could be able to always enjoy youthful health no matter our age for as long as we live, however long that may be. Regardless of this length, there is no reason why the final years of our lives should be spent in the company of disease and decrepitude.

If, one day, the Big Crunch or something else comes to put an end to our lives, so be it. Death of the universe preceded by good health sounds like a better deal than the death of the universe preceded by cataracts, for example. At least we’ll be able to see what’s going on!

Mikhail Batin from Openlongevity

Building Support for the War Against Aging

The life extension community has a number of long serving people in its ranks, and one of the longest-active of those in Russia is Mikhail Batin. His activities go way back to 2008 when the non-profit organization Science for Life Extension Foundation, which was first created with the mission to support scientific research to develop life extension techniques.

Since those early days, Mikhail also went on to co-found Open Longevity with longevity advocate Anastasia Egorova, and this is where he is most active and focusing his efforts now.

Open Longevity is a non-profit organization that emphasizes the importance of complete transparency in aging research.  The team is currently focused on three areas:

  • Open projects (including citizen science)
  • Databases (creating new ones, such as Open Genes, and improving existing ones)
  • Overall biotech industry analysis as a way of analyzing the longevity field in particular and building ground for a better strategy for the life extension community.

Today, we would like to share an interview with Mikhail that was translated from the original, which appeared recently in Republic Online Magazine.

How can you live longer?

It’s a simple question. One that has a simple answer or, rather, a myriad of simple answers. Healthy lifestyle habits. Digital healthy lifestyle habits. Technology to monitor multiple health markers. In a nutshell, we have to sleep well, exercise for an hour a day and live as far from Antarctica as possible. Having said that, this simple advice comes with a lot of nuances and refinements.

There are hundreds of anti-aging clinics around the world. I think the only good thing about them is that they distract people from eating by keeping them busy with essentially useless procedures. The real gold comes from physical exercise, reduced calories, and a calm daily regime.

On paper I’ve just answered your question, but in all honesty I haven’t.

My answer was very superficial. Just as easily, I could have advised you to become extraordinarily rich and purchase the fountain of youth. Or, rather, you could try and build this fountain by employing thousands of scientists to work tirelessly at your behest.

Furthermore, by focusing merely on a healthy lifestyle, we lose sight of other dimensions of the issue. We get derailed in comparing different healthy lifestyle methods and lose sight of the bigger picture—a truly large-scale solution. That is what I would like to focus on here. There’s a legion of health specialists out there who can elaborate on the topic of healthy lifestyles without my two cents.

Preventative medicine suffers from any lack of consolidated peer review or general guidelines for clinical trials. Frankly, the word “nutritionist” makes me sick to my stomach. I have yet to see any quality peer-reviewed papers on the subject of nutrition.

If we were to discuss nutrition, I would suggest organizing and participating in large-scale clinical trials of any given healthy lifestyle fad. This would enable us to collect large amounts of useful data about aging. The details of this trial would be scope for a separate interview in itself.

Our general anxiety about our health leads us to look for immediate and practical solutions. This is a trap that breeds ample customers for the market of useless supplements, hydrolyzed placental protein and other so-called “wellness” clinics.

I would like to highlight the fact that at present we are discussing the wellness of a generally healthy person, whose health deteriorates with age.

Let us finally leave the subject of “wellness”. The next point in our discussion is the fact that our lifespan depends on the quality of medicine and the speed of technological progress in general.

Unless there is a nuclear holocaust, we are all destined to get some sort of age-related illness. So, let me reframe the question somewhat: is there anything we can do today to outsmart the impending deadly illness by the time it arrives. Is there a way to prevent it from becoming lethal? Perhaps there will be a vaccine or certain prophylactic measures put in place. It would be great if preventative healthcare could learn to reverse the process of aging.

When we think about tackling aging, we find ourselves between the world of uncertainty and the world of endless tools and possibilities. The next step is to choose which of these tools we can use.

However, before we begin trying to change the world for the better, before we create a world without illness or suffering, we must first answer one question: who is this “we” exactly? We all have different capabilities and skills. Who exactly will tackle the issue of longevity? If we don’t decide on the “we”, this issue will remain in the realm of ideas and good intentions.

We could make a large list of necessary clinical trials, forgetting to answer one simple question: who will sponsor them?

Alternatively, we could say that the government should allocate a budget for the study of longevity. Having said that, we should be aware that the government already has its hands full with other important tasks.

Progress comes from money. It is not at all clear where we can find a superhuman who will not only raise awareness about the issue of aging but also get hundreds of billions of investment into, let’s say, regenerative medicine.

What about something simple like longevity-related promotional and educational content for Youtube? Who will create such content? Who has enough skills and funds for its production and promotion?

It comes down to this: when we ask ourselves who exactly is it that can make a change regarding the issue of longevity? No single human can overcome death alone. No amount of talent or initiative is enough to overcome social inertia. No one man.

United, however, the most regular people can achieve anything they want. This is not a novel idea. I credit Nikolay Fedorov way back in the 1900s for developing this concept in his work “Philosophy of the common cause”.

Every generation faces the same challenge: will they be able to unite against death? So far year in and year out people have failed at this task.

The so-called “blue zones”, areas where people live longer, are a credit to these very people themselves. They have organised a lifestyle that is conducive to longevity. Loma Linda in the US is a particularly interesting case. It has a very heterogeneous population: diverse in character, not in genetic make up. Their lifespan is 10 years above the US national average. This is an example of “accidental” cooperation in favor of longevity. It is our job to turn this “accident” into a large-scale, purposeful endeavor.

Part of the answer to longevity is to surround yourself with other people who are interested in your existence. To develop and test large-scale instruments of cooperation in favor of radical life extension.

Let me suggest some of these potential tools. Or rather some of the necessary tools:

  • Open Source projects analyzing and collecting data regarding aging and longevity;
  • Clinical trials based on patients’ initiative;
  • Longevity Valley or Immortality Vale (an area similar to Silicon Valley that specializes primarily on life extension);
  • Open and affordable education in biology and all sciences pertaining to life extension;
  • Government lobbies for research programs on aging and longevity.

In terms of sciences I would single out the following research:

  • Chronic inflammation
  • Mitochondrial dysfunction
  • Epigenetic rollback
  • Damage to longer-lived molecules in the body
  • The body’s ability to respond to stress
  • Sleep
  • Activity of transposons
  • Gene therapy
  • Comparative evolutionary biology of aging

These are overlapping fields. In truth, there are many ways to achieve longevity. However, it is a costly quest, one that holds no guarantees. On the other hand, a timely death is 100% guaranteed if we continue to do nothing.

Chew on this for a moment, barring Qin Shi Huang—the founder and first emperor of unified China—no one, nowhere, not a single country in the world has made life extension a government priority.

As far as governments are concerned, people are all equal and, in general, mutually replaceable. In fact, governments are founded on this disregard of individual human life.

It is enough to ignore what governments proclaim and to look at actual budget allocation. It becomes self-evident that saving lives is not of utmost priority.

“How to live longer?”—in brief, we must build a new society.

Is life extension an achievable goal?

Any scientist worth his salt working in the field of aging will be the first to tell you that radical life extension is possible. They make no hard and fast promises, but they definitely see potential in this endeavor.

We have inspiring proof in the form of life extensions of laboratory animals. Furthermore, there is no physical law that we must overcome to achieve the same result in humans.

What can I say; evolution is excellent at creating “life extension”. Life expectancy within a species can differ 20 times, and between species—in the millions.

Man is learning to do many things better than evolution itself. Just look at the creation of the wheel, not to mention space exploration.

I began to notice hundreds of biotech startups, mostly in California, primarily targeting mechanisms closely related to aging. I don’t believe any of them will be successful in creating the “elixir of immortality”. However, their mere existence is a good sign. They can act as initiators of large-scale governmental programs, although I would be delighted if free enterprises were able to tackle this exceedingly difficult task.

To state the obvious, the best argument in favor of potential radical life extension would be the very act of radical life extension itself. However, at the moment, we are just at the initial stages of data collection, creation and testing of theories. The scale of these current endeavours is dwarfed by the enormity of the task.

We are nowhere close to having done everything possible to extend the lives of the maximum number of people for the longest period possible. This fact is irrefutable. Many scientists failed to conduct experiments due to lack of funds. Others left science altogether. The number of Master’s and Ph.D. programs in the biology of aging is insignificant.

On the other hand, it would be dangerous to underestimate the enormity of the task itself. There is no simple solution to aging and there cannot be one. It could very well be possible that the solution to aging is comparable in its complexity to terraforming on Mars.

It could even end up to be an insurmountable task. But wouldn’t it be nice to know this for sure? Our folly is that we are not even trying to find out if we stand a chance at all.

What are the biggest obstacles in the war against aging?

Here we face the Great Wall of Death as a derivative of human culture itself. Throughout our history, humans have been aware of our mortality and have tried to come to terms with it. In a way, the fight against aging is absolutely counter culture. It suggests putting all our plans aside and solely focusing on fighting death. This is very similar to what Nietzsche said about the creation of the superman.

The idea of immortality goes against all our traditions, rituals, and stereotypical behaviors. I can name a hundred reasons why we are moving so slowly. Let me elaborate on one: people don’t believe they can live long enough to witness the technologies of radical life extension. They don’t believe that any of this can depend on them.

It is just easier to not dwell on dying. It is easier to take the familiar beaten path of death.

The fight for life is not a question of faith. It is a game of low odds but with incredibly high gains. Mathematical expectation will be on your side if you value your life high enough. Don’t you find it strange that I find myself having to talk people into paying attention to life extension?

In regards to our biological makeup, the hard part is that we are made much like a disposable, useless thing, whose single evolutionary task is to spread its genetic material and disappear.

This likens our personality to a kind of parasite that resists the power of its own genome. So far, we are not even sure what exactly this personality, that we are trying to save from death, really is. We are as yet not aware of how our inner experiences work.

Yet another necessary task is the modeling of our brain functions.

What exactly do you do, and what are the aims of Open Longevity?

We are always trying to understand what is the most important thing we can do to increase research.

First and foremost, we are a conscription service: we recruit people to fight death. We create and distribute a lot of content egging people on towards action. This creates a lot of mutual or independent projects. It’s a growing field.

In a sense, we are old fashioned and believe in the power of books to change the world. I hope to soon see the publication of our work “Aging: it’s complicated”.

In the realms of science, we are interested in targets that can be manipulated to retard aging. Our next priority is the creation of an open database focused on aging.

By the way, the fight for longevity has its own trends. Last season was cellular senescence. Today it is transposons, which we are also interested in.

However, first and foremost, we are looking for future project leaders. Not so much in the fields of research as in projects aimed at changing public opinion and mentality.

What’s happening in the field of anti-aging at the moment?

A lot, actually.

There are quite large-scale efforts to create a method to diagnose aging. After all, we need to understand this process in a numerical format. We must have a reliable system for measuring age-related changes. The priority here today lies in various epigenetic clocks (a set of epigenetic DNA tags that can determine the biological age of a tissue, cell, or organ).

These diagnostics-related ideas breed a host of various advisory services. Instagram is littered with advice on rejuvenation. Occasional accounts even reference scientific articles. None of it looks particularly salubrious. There are no large-scale human clinical trials that can confirm or disprove the veracity of this advice. There are no consolidated opinions from the medical profession, nor are there any clinical recommendations. It’s necessary for us to first and foremost agree on standards for diagnostic tools and preventative medicine.

The number of applications for mobile devices and various health-related gadgets is growing exponentially. Obviously, collecting and processing an avalanche of new data will bring tangible benefits. You don’t have to be a big futurist to assume that disease prevention gamification is the next big step.

The emergence of longevity tech is another important trend. A hundred biotech startups with capital ranging from $10M to $3B have addressed hot topics in aging and are conducting clinical research.

Gene therapy and molecular design are gaining ground. The idea behind molecular design is to come up with unusual molecules with desired properties. For example, we need to come up with new ways to get rid of the crosslinks in collagen.

Also, I really hope that aging will soon attract people and technologies from the field of cancer research.

HARPA (Health Advanced Research Projects Agency) is a wonderful new initiative of this year, and it would be great to have this in healthcare. Perhaps the US Congress will give them $6.5B.

By the way, I can recommend the book “Immortality, Inc”. There’s quite a fascinating description of how the smartest and richest people came to grips with death. Surprisingly, the leaders of Google and Amazon are in on it.

Longevity lacks good big data. Therefore, I like the INSPIRE project, which aims to collect functional and omics data on aging and create a biobank in France.

Singapore has announced a life extension program, but little has been heard of it since.

As usual, there are some technologies which carry hopes for a slight increase in life expectancy. For example, transfusion of young blood plasma with albumin solution. However, putting one’s hopes on simple solutions is not worthwhile.

What tasks do you think are most pressing?

Today, it’s blockers of retrotransposons and inhibitors of reverse transcriptase. I will name a couple more areas: blockers, antibodies to oxidized phospholipids; fatty acid synthase inhibitors; we have yet to hear the last word regarding the field of senolytics and senomorphics.

Senolytics are drugs designed to kill senescent cells that interfere with the normal functioning of tissues. Senomorphics are drugs designed to act indirectly, blocking the actions of senescent cells.

Decaying cells were almost unknown to science 15 years ago. Today, not only are they being studied, approaches have already been proposed to block this aging mechanism. Let me say a few words about the three most unexpected solutions that have emerged over the past three years.

In the first case, American oncologist Scott Lowe and his colleagues used specially modified immune T cells to remove senescent cells, which express the so-called chimeric antigen receptor (CAR). As a result, they got the very same CAR-T cells that are now much talked about in professional circles.

Previously, they were actively used in immuno-oncology to remove degenerated cells. Now we are seeing a real boom in clinical research on CAR-T cells. According to ClinicalTrials.gov, several hundred clinical trials of related therapies are underway. Since the end of the 90s, there have been 5 generations of CAR-T cells designed.

Now, CAR-T cells have been successfully tested by oncologists as senolytics.

In the second case, scientists have shown the ability of extracellular vesicles to fight senescence. Vesicles are bubbles surrounded by a membrane. They are secreted by cells, in large numbers by stem cells.

Today, these vesicles are very actively studied as therapeutic agents for the transfer of healthy biological cargo, proteins, nucleic acids, and low-molecular-weight drugs. Their recently described role in senescence is interesting.

Back in 2019, English and Spanish scientists described how decrepit cells secrete vesicles with the IFITM3 protein, which literally infect normal cells with senescence, causing them to age.

There was a recently published study about the reverse process: vesicles from young cells reduced cellular aging in an old body, reducing lipid peroxidation. The key molecule carried by the “young” vesicles was the antioxidant enzyme GSTM2, a large amount of which is characteristic of long-lived species, for example, naked mole rats.

Before that, in 2019, there was the work of American biologists from Johns Hopkins University. They found an important antioxidant enzyme, peroxiredoxin, in extracellular vesicles from induced pluripotent stem cells (iPSCs). Most importantly, iPSCs are champions in the number of extracellular vesicles. They secreted them almost 20 times more than the other type of stem cells, the mesenchymal.

In my view, vesicle therapy is likely to become a fundamental new type of therapy.

The third approach to combat senescence was described quite recently, in May of this year. The Americans from the University of California were able to activate special immune cells that fight aging—invariant natural killer T cells (NK cells).

Tested in two animal models, obese mice with fibrosis, the activation used alpha-galactosylceramide (a-GalCer), a well-known lipid antigen that specifically activates these immune cells.

As a result, senescent (decrepit) precursors of fat cells were removed in obese mice. This is a potential approach to fighting obesity in old age and to prevent the development of diabetes.

And in the fibrous model, cleansing from senescent epithelial and mesenchymal cells led to a slowdown in profibrotic processes. This will allow virtually all older tissues to perform better.

I have just considered a small but important topic in aging—the fact that cells become decrepit and damage tissues and that cells can be cleaned.

There is potential for new therapies here, but there is no single institute for the exclusive study of senescence, there is no single-state program—the study of aging is as yet terra incognita. Even Nature thinks so, publishing in May another article, “An aged immune system drives senescence and aging of solid organs”.

We will talk about scientific problems in more detail in our new book. Hopefully, it will come out this year.

The possibility of slowing it down or reversing human aging has been the focus of researchers for over a decade. What results have they achieved, and could it be possible in the near future to increase one’s youth by at least a few years?

We can say that this has been a hot topic for over a century, but, so far, there is no consensus on any issue. Even on the existence of aging itself, there is no consensus; maybe it is best to avoid using a term that could not even be defined?

When they say that aging is an increase of the likelihood of death, and they do not describe what happens physically, this reveals a lack of understanding of the very process.

It so happens that theories of aging follow the major discoveries in biology. They discovered immunity—there will be an immune theory of aging, hormones—the hormonal theory of aging, epigenetics—the epigenetic theory of aging.

Now, there are many works in the field of alternative splicing—we can totally put forward an isoform theory of aging in response.

At the same time, there are a lot of ethics involved in our understanding of aging: aging is something bad. It is a violation of physiological functions, a breakdown. Thus, aging begins to cover everything we know about the body. As a result, we begin to get bogged down in all this comprehensiveness.

Maybe, in order not to drown, we need to focus our attention on something: here is a chronic non-infectious inflammation, let’s study it and do something with it; here is mitochondrial dysfunction, this subject is also clear; let’s lower the level of non-enzymatic glycation and see what happens.

I emphasize that we do not yet know which strategy will be the most effective. There are roughly twenty branches of aging studies, and our knowledge is increasing.

The science of aging has achieved the following: we have learned a lot and are more confused. Since the dominance of the oxidative theory of aging, there has been less clarity. We can say that our ignorance is growing exponentially.

Basically, you need to take the most important interventions of the past twenty years, from rapamycin to IGF-1 inhibitors, and ask yourself why they didn’t work? We need to focus on the inefficiencies and side effects of potential geroprotectors. What is it that is always in our way?

So far we have found out that a mouse is not a human and that 30% of life extension in mice does not carry over to humans. We need to understand why that is so.

At the same time, of course, we should avoid negative spell casting: “everything is so complicated, tangled and difficult”. Yes, it is difficult, but we must rush head on into this complexity. All knowledge about aging should be well structured.

Human stem cells for growing organs are beginning to be increasingly used in medicine. It is also likely that the depletion of stem cells is one reason we age, are there any methods that exist today that can address this problem?

You can add stem cells. The first bone marrow transplant was performed 62 years ago by Georges Mathé, a French oncologist, but these are alien cells, of course, and if you just inject donor stem cells, rejuvenation does not occur. What does occur is profiteering off gullible patients. I wonder why there are still no high-profile criminal trials in Los Angeles regarding all of these procedures.

As for organ growing, I think we need to focus on therapeutic cloning. That is, growing clones of our own organs. After all, we can roll back a cell to a pluripotent state, and if so, theoretically there exists a combination of influences, including various growth factors, enabling the desired organ to grow from this cell. Of course, a new generation of bio incubators will be required. Regenerative medicine needs to move in this direction.

Yes, stem cells are shrinking, and this is true aging. If we could effectively increase their quantity (without losing quality), this would be a solution to one of the problems of aging, blocking one of the harmful mechanisms. The problem is that the existing products on the market do something completely different: foreign stem cells almost never take root, even the host’s own cells rarely take root, since this process requires complex factors and conditions.

If such therapies do have an effect, then it is achieved due to the molecules secreted by these cells in those hours and days before they have died.

In particular, we are talking about the development of exosomal therapy. The cell can release into the surrounding space both free molecules and exosomes packed in special bubbles, also called vesicles (I have already spoken about them). Modern science is very interested in this delivery method. And by clinical research, I mean Longeron, not what is happening in the Bahamas, of course.

Perhaps there is a possibility of a non-trivial alternative approach. Aging is an extremely complex thing, and it is not yet clear how we can create a cocktail of drugs that prolong life. The idea is to try it out blindly. We need to organize and train a certain biological system that can have a suppressing effect on the aging of the body. Yes, the topic is quite speculative, but I think we need to go in this direction as well. Michael Levin suggests something similar.

When can we expect a cure for old age?

Let’s ask ourselves a question: what must happen before a cure for old age is found? Since the task is large-scale, probably some huge project should be created. When can this happen?

Let’s consider the arrival of billionaires in this field as a marker of progress. Their number is growing, but they are focused on commercial projects, which seems to me to be a mistake. At some point, I think the concept of radical openness will prevail in aging research. To be precise, I am sure of it. It is necessary to build such a schedule and see at what point in time there will be 100 major players.

It will probably take another 10 years to create a megaproject. Then 10 more years for us to extract the first results on human life extension from the colossal amount of data. It will be sometime 2040–2045. The very same dates coincide with the forecasts on the possible emergence of a strong AI.

I would turn the conversation from predictions of when we learn to extend a person’s life to talking about a plan to make it happen.

Who has the best plan in the world, and how long does it take to get it done? Calico? It seems unlikely, no. Facebook with its cell atlas? So far, no results have been heard of.

The clearest position has been and remains with Aubrey de Grey. Regardless of how we may feel about him, on the topic of aging, he is the most intelligible dude in the world. Until this year, he had a budget of $5M a year. When will he have 5 billion? This does not mean that it is he who will create the technology, but the budget of his SENS foundation is a marker of society’s attitude towards the fight against aging.

Creating a cure for old age is about implementing a clear plan, a clear strategy. Create a strategy, and you have a deadline.

This is a very important thought: we need to be clear about the chain of events that must occur before the creation of technologies for radical life extension. It is on them that we must focus our attention. Let’s say we believe that a cure for old age cannot be created without a major international project.

This means that in, let’s say, the EU itself, some political processes must take place that will lead to the expansion of the Horizon program. What could drive such an initiative? First and foremost, civic engagement.

What steps do you think should be prioritized?

A large part of the fight against aging is in the collection of databases. If we are talking about the control of genes over lifespan, then we must have all these “lifespan” genes collected. We carry out a small part of this work, although it is subject to criticism. They say it is impossible to formalize all knowledge about genes associated with aging. Our position is quite simple: let’s look at the whole picture, to the extent that it is available to us now. And then we will see how useful it is, for example, in selecting a combination of potential geroprotectors.

All DAMP, SASP, changes in immunity, lipid, various omics data, cell atlas, and the actions of potential geroprotectors and their side effects must also be transferred to the databases. Transcriptomes of different tissues of people, of different ages.

Datasets are needed to develop diagnostics of aging to understand the early pathogenesis of age-related diseases. We need open data on human aging.

As I said, the fight against aging is about getting good new data and careful processing of the data that has already been obtained. In particular, we need data on changes in the transcriptomes of every human organ, in different ages. Such work has not yet been carried out anywhere in the world. It costs several hundred million dollars. But without it, we would not know how a person grows old. It must be an open dataset. Who will pay for this? Who will pay for open-source aging projects? For all the primary data to be published and not to be under any patent protection.

I think, without open-source projects, we will not be able to revolutionize aging.

Why so categorical? Doesn’t the current system of thousands of pharmaceutical and biotechnological companies work on prolonging human life?

Of course they do. Research is ongoing on all fronts. If the technologies that are now being created in the fight against tumors can be used in the partial removal of senescent cells, and these, in turn, still turn out to be a serious cause of aging, then this will be a breakthrough. The same goes for epigenetic retracement. Pharma is working, and we are closely monitoring everything that happens, but we want more. What approach can overtake all biotech? Open data. Then there will be no hiding of data due to commercial interests, and we will have an increase in the speed of development and the level of expertise on what needs to be done in the first place.

We will proceed thusly: We initiate an open non-profit project in aging that we will declare as being the best. This will be true because it will be one of a kind. Then, we will propose others to create a project that would be better. Perhaps we will announce a prize. Thus, we want to launch an avalanche of non-commercial projects.

The point is that life extension is valuable in itself. It’s nice to make money, of course, but it’s better to stay alive. Therefore, we need to remove this weight of compulsory commercialization. Korolyov would not have launched Gagarin into space if he was required to pay off the flight around Earth.

Our task is to convince philanthropists that this approach is correct. The amount of money in a non-profit approach is generated from the number of volunteers who are willing to spend their personal time on the goals and objectives of the NGO. We have a big-enough problem here. Research on aging itself requires a lot of knowledge. This is not a volunteer garbage collection, when everyone can go clean up the park. We want volunteers to perform non-trivial tasks. What solutions can there be?

Raising awareness of how aging works. Timofey Glinin gave 12 lectures on the biology of aging and posted them on YouTube. There should be a thousand lectures of such that would most fully cover the field of aging research. There should be a unified course following the example of the Khan Academy.

Another approach could be patient-driven clinical trials. Of course, it is not the patients themselves who should conduct the research, but initiate it, and the research would take place in an organized manner. Perhaps what is now called biohacking may turn into patient research.

Nevertheless there is still no strong solution out there for those who would like to invest their time into radical life extension. We have to keep on experimenting.

If aging is so difficult, are there alternative solutions? For example, organ growing?

There are many alternatives. For example, cyborgization of organs, artificial blood. We would get rid of half of the problems if we learned to artificially deliver oxygen and nutrients to the brain.

I think a head transplant, or rather a body transplant, is a good alternative. There is a rather important stage here: the maintenance of the vital activity of the head of a large mammal outside the body. It would be great to set a world record in this area. A simpler step is the exchange of circulatory systems between animals, so that the heart of one pumps blood for another. I wonder what would happen if these animals were clones.

Are such experiments ethical?

Let’s think about this. If we make the value of human life absolute, then inaction, missed opportunities to prolong life, becomes the true evil.

Religious figures often hide behind talk about bioethics in order to slow down progress. Just look at the ban on human cloning. Naturally, we should not clone a person if we are not sure that the clone will be healthy. But to prohibit cloning because of the assumption that a clone will not possess a soul is going too far.

Experiments on animals are a necessary evil, otherwise we would not have medicines and medical technologies.

You follow the ideas of Russian cosmists, who believed that in the future, people would be able to preserve their youth. How relevant are the ideas of Vernadsky and Tsiolkovsky in our time?

Talking about heritage. If today, we were to set up a major international conference on aging in Europe, attended by participants from many countries, do you know what the most frequently asked side question would be? Why are there so many Russians? 30% of the participants would be Russian speakers.

This is that kind of continuity. The Russians are very much in favor of the idea of ??physical immortality. We do not notice this in Russia, but actually we are very strong in transhumanism. I think that in the next few years, organizations with Russian roots will reveal themselves.

Who in the world do you think has come closest to life extension?

I don’t know about the result per se, but I began to like Sergey Young’s activity more. It is picking up momentum.

I would like to believe in Gero’s company, but I take it partially on faith, as I do not understand their complex physics.

Michael Greve from Germany announced today that he will invest $362M in rejuvenation startups. He comes across as the most competent investor in Europe.

Many scientists are doing interesting research.

I’ve just read Rochelle Buffenstein’s article on epitranscriptomics today. Another universe of aging research has been discovered.

Separately, I would mention the main fighters against protein crosslinking in the extracellular matrix, David Spiegel and Jonathan Clark. These stitches are one of the key barriers separating us from longevity. Extracellular matrix proteins are crosslinked by sugars and stop working normally. The matrix becomes rigid and triggers entire chain reactions of pathological processes associated with epigenetics, genomic instability, mitochondrial dysfunction, stem cell depletion, and more. Spiegel and Clark, with the support of Aubrey de Grey’s company, are actively studying this cross-linking of matrix proteins.

Last year, they managed to create an antibody that specifically binds to glucosepane, one of the main matrix cross-links. This will enable us to measure the amount of glucosepane in tissue.

A year earlier, Spiegel and his team tested the bacterial enzyme MnmC in action. Their work has shown positive results in breaking down two key glycation end products (AGEs) that also contribute to aging: carboxyethyl lysine and carboxymethyl lysine.

At the same time, we know that bacteria and fungi have a considerable evolutionary arsenal to combat AGEs: glycopeptides, metalloproteases, amadoriasis, and deglycases.

Let this be my refrain, but here too we need an institute, an international research program, and not just five laboratories with small budgets.

It is customary in our region to scold Calico, but I think they should finally be able to get somewhere with $3B.

You know, I also like what is happening in the Russian segment of Facebook on this subject. It seems to me that the right processes have been set in motion there, and wonderful collective intelligence is being created. I am one of the chefs in this kitchen of immortality. Subscribe to my Facebook account.

What advice would you give someone wanting to invest in life extension? How to choose a company, which fund to finance?

First of all, I would recommend spending 10% of the proposed investment on open research and on a non-profit approach. Or better, 100%.

Longevity startups are now dominated by an aggressively naive approach. These people believe they’ve caught God by the beard, so money is poured on simple solutions: like now we will remove bad cells or add a “longevity gene”. There is no lack of funding for this kind of approach. Any given Stanford professor promising to find a cure for old age sometime a little later, but for now needing to conduct clinical research on a different nosology, albeit closely related to the mechanism of aging, will easily find funding.

There is little money available for the establishment of cause-and-effect relationships in aging, for the evolutionary-comparative biology of aging, for open data on human aging.

You can make money off the hype, but is this what we want? We need true life extension.

Aging as a problem is huge. There is no need to worry that you will not have time to profit from selling the elixir of immortality. If you’re late and someone else is making money on radical life extension, that’s great. This means your life expectancy has increased. Now there is time for further enrichment.

Nevertheless, I admit that I could be mistaken, and it is businesses who will prove capable of creating at least a weak cure for old age. Perhaps the conditions for particular financing are as follows: either commerce or nothing.

Then we have to answer the question: what do we, as startups, know that Calico or Pfizer does not know? They have no problems with money, they have the best specialists, and they work all the time. What is our strength?

First of all, you need to invest in improving the competence of the analysts who work for you. A very strong American full-time professor costs $200–300K a year. There should be several such people working exclusively for you.

Second step. Use the stock exchange as a way to test your competence. If your team is focused on research related to inflammation, then you should probably pick up a good package on the NASDAQ by reading the results of clinical studies. In pretty much every direction, wherever you go, there are already listed companies working on similar tasks.

Third step. It sounds strange. Choose a totem animal. It is possible that evolution has already solved the problem that you are solving in prolonging life. Maybe learning how she did it for a particular organism will help you develop technology.

I also think that when investing, you need to keep a certain focus. Don’t get scattered into dozens of different directions, but invest in companies from the same sector working on similar tasks. This will increase the investor’s own competence. Yes, it is better to know one topic than spread yourself too thinly. On the other hand, avoid depending on one single company; work with several different ones.

So then what areas of investment seem more promising to you?

I naturally do not provide investment advice. I can only speculate about interesting research areas in which technology can be created.

We already mentioned splicing when we talked about the theories of aging. I should mention the main researcher of changes in splicing during aging, an English biologist Lorna Harries.

The story of splicing and aging began recently, in 2016, when several publications came out describing age-related changes in splicing in different species, from worms to humans. Before that, they already knew about the changes in splicing in various diseases.

What is splicing, and why is it important? RNA splicing is when introns and exons derived from a gene’s DNA sequence are removed and combined into the final RNA sequence from which the protein will then be synthesized.

Introns are usually discarded, exons remain. They can be shuffled in a clever way, making it possible to synthesize different proteins from a single gene. This is called alternative splicing.

All these processes are disrupted during aging, which, of course, negatively affects the functioning of the body, and, as studies show, it may be one of the causes of aging.

Despite the complexity and importance of this area in the fight against aging, only one team, led by Lorna Harries, is engaged in this research. The biotech startup SENISCA was created for this. I must say, they already have had some successes; they were able to identify the key molecular players in these aging processes.

Of course, in the naked mole rat, splicing processes are very stable throughout almost its entire life. How could we leave it out of this discussion?

Another team of scientists who are doing a lot in the fight against aging are the Spanish biologists Reinald Pamplona and his colleagues. They became known in the early 2000s as the first to show that limiting the amino acid methionine has a positive effect on health and longevity, and then they actively studied the processes of lipid peroxidation.

Lipid peroxidation is when the lipids of cell membranes attack free radicals. Then, chain reactions occur, when some oxidized molecules oxidize the next, and so on. The metabolites of these reactions can form the end products of glycation.

The most susceptible to lipid oxidation in membranes were polyunsaturated acids. Scientists have traced an interesting correlation. The less unsaturated docosahexaenoic omega-three fatty acid there is in the membranes, the longer the species lives.

So, in mice, this acid in the membranes was 9 times higher than in naked mole rats. Based on this data, Pamplona and colleagues have put forward their membrane theory of aging. This suggests that the composition of membrane fatty acids, through its effect on lipid peroxidation, is an important factor in life expectancy. It sets the pace of aging and links metabolism to longevity.

Fighting lipid oxidation is a very promising topic, and I think new blockbusters will be created here. In general, there are many areas of work.

You probably want me to name the tickers of all the promising companies? I need to think more about this. We are currently conducting an in-depth analysis of all the biotech companies associated with longevity

Am I correct in my understanding that you feel that the real culprit is the underfunding of academic science?

Academia too has its problems. Its structure is wildly archaic. It is like some sort of feudal slavery system. Graduate students from all over the world, young postdocs are humiliated. They essentially act as “science slaves” to their master, the “serious scientist”. Low wages, lack of freedom, and a strict hierarchy make 90% of people leave science.

We are left with a lucky 1% who happen to be good at marketing and self promotion and have an eye for legal subtlety.

Basically, by the age of 40, a scientist feels he’s been deceived: there’s few perspectives and a lot of lost hope. Academia’s efficiency is extremely low. The rat race for survival results in lots of trashy work; a lot of experiments cannot be reproduced in part because of false data that was supplied for the sake of receiving further funding.

Novel organisational solutions are the super task. A very good example is how Elon Musk created Neuralink.

There are still so many problems to solve. Do we even stand a chance?

In spite of all this, I am not only a longevity optimist, I also believe that we must strive for an unlimited lifespan, for the physical immortality of mankind. I believe in the incredible power of the human mind and the unquenchable desire to live. At the end of the day, the work of tens of thousands of people will bear fruit.

We need to closely monitor potential drivers of social processes. For example, it might be transhuman art. Art that evokes the desire to act in favor of extending the human potential.

As for the odds. We will stand a good chance when we have a good strategy. Look, the fight against aging is extremely difficult at the molecular level. But it is no less difficult at a social level. We need to press thousands of levers, spin millions of wheels of public order, to be able to radically change the situation in favor of prolonging life.

Enumeration won’t solve these tasks.

What is the current solution for raising funds? By increasing the amount of content related to scientific achievements. It is believed that people with resources will read a lot about aging and start spending private and public money. It is working, but not at all to the extent that we would like it to.

There are no strong longevity lobbyists in the world because no one pays for such work. Private funding goes to venture capital.

We need some sort of devious strategy. We must use the scientific method not only in the laboratory but also in the organization of social change. Here, we also need big data, but of a different nature: what role the struggle for life holds in public minds and what the factors that can influence public opinion are.

Now, these are the direct tasks of our organization, Open Longevity.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Red coronavirus

COVID-19 Spike Protein Shown to Increase SASP

New research published in the journal Science has shown that the spike protein of SARS-CoV-2, the virus that causes COVID-19, causes senescent cells to secrete more of the senescence-associated secretory phenotype (SASP), causing hyperinflammation and weakening the body’s defenses against viruses.

An established link

The researchers of this new study cite previous research linking the known symptoms and risk factors of COVID-19 to the factors involved in cellular senescence. Many of the symptoms associated with severe COVID-19, including myocarditis, organ failure, respiratory distress, and the infamous cytokine storm, are also associated with factors known to be part of the SASP [1]. The SASP factors IL-6, IL-10, and IP-10 can even be used to predict the outcome of COVID-19 patients [2].

However, this is merely correlation. The researchers sought to show a more direct link between senescent cell accumulation and the effects of COVID-19.

A weakened defense

The researchers treated human tissue with conditional media from senescent cells; in other words, they exposed healthy human cells to the SASP. In kidney tissue, two key viral defense genes were suppressed; antibodies against several of the SASP factors partially restored the expression of these genes. In human lung, kidney, and endothelial tissue, the gene TMPRSS2, which is critical to the virus’ entry into cells, showed greater expression upon exposure to the SASP; lung tissue also expressed greater ACE2, a well-known factor in SARS-CoV-2 infection.

Tissue taken from elderly patients supported these results, showing that cells expressing the senescence marker p16ink4a were often adjacent to cells expressing TMPRSS2.

Collectively, these data further support the conclusion that SnC could promote SARS-CoV-2 pathogenesis by decreasing viral defenses and increasing expression of viral entry proteins in neighboring non-SnCs through amplified secretion of SASP factors.

Pathogens and senescent cells

To determine the effects of pathogen exposure on senescent cells, the researchers exposed generally pathogen-free laboratory mice to pet store mice, which are carriers of many common murine diseases. 89% of young mice survived, but nearly 100% of 20-month-old mice died within two weeks of this exposure. SASP factors were significantly increased in these exposed older mice compared to younger mice exposed to the same array of pathogens. The researchers note that this is consistent with their hypothesis that existing senescent cells become hyperactive upon pathogen exposure.

The researchers also show data suggesting that a particular coronavirus, mouse hepatitis virus (MHV), is largely responsible for the mortality seen in old mice. Immunizing old mice against MHV protected them against death due to microbe exposure.

The researchers then tested to see whether reducing senescent cells would also allow mice to survive MHV. By dosing 20-month-old mice mice with fisetin, a well-known senolytic, the researchers found that half of them survived exposure to MHV. All of the 20-month-old mice without fisetin in their diet died.

Additional experiments, including a short-term fisetin regimen and treatment with dasatinib and quercetin, showed the same results: removing the senescent cells of aged mice gave them a 50% survival rate rather than a 0% survival rate upon exposure to MHV. Therefore, as the researchers conclude, it is possible that removing senescent cells through senolytics is a viable approach towards ameliorating the cytokine storm of SARS-CoV-2 infection.

Two separate human clinical trials, NCT04476953 and NCT04537299, have already been initiated to investigate the effects of fisetin on COVID-19.

Abstract

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse ß-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting SnCs using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

Conclusion

One defining feature of SARS-CoV-2 infection is that it very seldom kills young people; mortality due to COVID-19 rises dramatically with age. This study provides strong evidence that senescent cell accumulation, one of the hallmarks of aging, is at least partially responsible for its lethality among older people.

If senolytics such as fisetin or other methods of removing these harmful cells can be shown in a human clinical trial to reduce the hyperinflammation and cytokine storm brought on by COVID-19 infection, then it may be possible to create a therapy that significantly reduces the fatality rate of this deadly disease – as well as any future pandemic that causes these effects.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., & Manson, J. J. (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. The lancet, 395(10229), 1033-1034.

[2] Laing, A. G., Lorenc, A., Del Barrio, I. D. M., Das, A., Fish, M., Monin, L., … & Hayday, A. C. (2020). A dynamic COVID-19 immune signature includes associations with poor prognosis. Nature medicine, 26(10), 1623-1635.

Rendering of chromosomes

Human Genome Fully Sequenced

In a preprint paper, scientists have announced the completion of the first full, telomere-to-telomere, sequencing of the human genome, more than two decades after the first draft of its sequencing. This was made possible by new sequencing technologies [1].

Mind the gaps

The human genome was first reported as being sequenced two decades ago by the Human Genome Project and Craig Ventor’s company Celera Genomics. This original draft was announced with great fanfare from the White House lawn on June 26, 2000. It included roughly 90% of the genome, which took scientists ten long years to achieve. The task was declared completed three years later, in 2003, but almost 8% of the genome remained undeciphered.

Certain hard-to-read DNA regions were left out due to technological constraints. The problem with the previous generation’s sequencing technologies was that scientists had to shred multiple copies of the DNA into small chunks several hundred base pairs long and sequence them separately. After the sequencing, the scientists would try to recreate the order of the fragments by looking for unique overlaps: that is, if two chunks overlap, they probably contain adjacent sequences. It worked for most of the regions but not all of them. The regions that defy this old type of sequencing are rife with multiple tandem repeats – such as AGAGAGAG – sometimes spanning over thousands of bases [2]. Until recently, there was no way to recognize where these sequences overlap.

These regions are located mostly near centrosomes – the “knots” that tie homologous chromosomes together into the familiar X-form, and near telomeres, i.e., at the ends of the chromosomes. This is the reason why the initiative that gave us this final reading of the human genome is called the Telomere 2 Telomere (T2T) Consortium.

New kids on the block

In recent years, several new technologies emerged that were able to sequence longer chunks of DNA. With the help of these technologies, the sequencing of the human genome has been inching slowly towards completion. For this last push, the scientists used methods developed by two companies: PacBio from California and Oxford Nanopore from Oxford, UK.

Both methods allow sequencing long chunks of DNA, with Oxford Nanopore claiming a seven-digit limit. In this technology, a single DNA molecule is sequenced while being slowly driven through a nanopore, like a thread through a needle. Oxford Nanopore’s technology sacrifices accuracy for length with a 15% error rate, while PacBio’s method, though capped at 20 thousand base pairs per string, is 99.9% accurate, which makes these two technologies complementary.

200 million new base pairs

The researchers have fully sequenced all 22 autosomal (non-sex) chromosomes and chromosome X (the male-exclusive chromosome Y was not sequenced). This added almost 200 million base pairs of novel sequence that contain more than 2000 paralogous gene copies. Paralogs are copies of an original gene that were inserted into other places in the DNA. Most of these copies become defunct, while others can retain their original functions or develop new ones. A small but considerable portion of the newly found genes – 115 – are predicted to code for proteins, and many more probably code for RNA that is not translated into proteins but is still used in gene regulation in what is known as RNA interference.

Short arms matter too

Five of our 23 chromosomes are highly asymmetric, with one arm on one side of the centromere being much shorter than the other arm. These are called acrocentric chromosomes. These short arms are particularly rich in repeats and duplications, so they have not been adequately sequenced until now. This new technique provides highly accurate sequencing of the short arms of all acrocentric chromosomes.

The researchers note that genes on these short arms are known to affect such important cellular processes as ribosome biogenesis and nucleolus formation. They have also been implicated in genetic conditions such as Down syndrome. A full sequencing of these regions can bring us closer to understanding these aspects of cellular life and human health.

We need more references

In addition to gaps that have been all but eliminated now, the human reference genome has yet another problem: it is a mosaic assembled from the genes of 13 anonymous volunteers. It does a decent job as a genomic map that helps sequence new genomes and can tell us where particular genes are located, but it fails to take into account some differences that exist between real-world genomes. Scientists have been arguing for a while that we need more reference genomes that are fully derived from people of various ethnic backgrounds. New sequencing technologies can make this task easier.

Conclusion

Full sequencing of the human genome, if confirmed, is an important milestone that opens the door to many new discoveries. Soon, we will be able to better understand how our centromeres work and discover the role of long-tandem repeats. Scientists will also be able to look deeper into genetic differences between people of various backgrounds, which is important for studying ethnicity-based genetic diseases.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Nurk, S., Koren, S., Rhie, A., Rautiainen, M., Bzikadze, A. V., Mikheenko, A., … & Phillippy, A. M. (2021). The complete sequence of a human genome. bioRxiv.

[2] Warburton, P. E., Hasson, D., Guillem, F., Lescale, C., Jin, X., & Abrusan, G. (2008). Analysis of the largest tandemly repeated DNA families in the human genome. BMC genomics, 9(1), 1-18.

Two mice

The Two Kinds of p21 Expression

A team of researchers led by Dr. Judith Campisi of the Buck Institute has discovered valuable information about how cells express the senescence marker p21 [1].

Two genetic loci, one protein

Cellular senescence is partially determined by two cyclin-dependent kinase inhibitor proteins: p16 and p21. The former is encoded by a genetic locus known as Cdkn2a, and p16 has been successfully used as a biomarker of senescence, as it is strongly dependent on age and responds to caloric restriction. On the other hand, p21, which is encoded by Cdkn1a, has shown less success as a biomarker; it seems to be entirely tissue dependent, and it is unaffected by caloric restriction.

These researchers have noted two different genetic loci that produce the same p21 protein. Cdkn1a variant 1 has been the most commonly studied, as it normally produces significantly more p21 than Cdkn1a variant 2.

However, the expression of variant 1 does not seem to change with age, as determined in the liver tissue of 2-month-old and 24-month-old mice. Instead, dermal fibroblast testing showed that this locus is immediately sensitive to stressors, such as radiation and doxorubicin, which is known to induce cellular senescence. Unlike variant 2, it also varies greatly with circadian rhythm; mice produce eight times as much p21 from this locus in liver tissue at 6 AM as they do at 3 PM, and its expression in fat and kidney tissue is similar.

On the other hand, variant 2 of Cdkn1a is significantly less sensitive to these stressors in the short term. Instead, this variant is much more aligned with aging, as it is more than twice as active in 24-month-old mice than 2-month-old mice, as determined by samples of multiple tissues. Its expression is strongly suppressed by the senolytic ABT-263, while the first variant is largely unaffected by this drug.

Abstract

Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16Ink4a and p21Cip1/Waf1. In mice, the p21Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues. Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.

A noisy signal

This research is highly illuminating as to the nature of p21 expression, but it doesn’t make the p21 protein itself any more useful as a biomarker. Variant 2 produces significantly less p21 than variant 1 overall; even aged mice produce less than half as much p21 from variant 2 as from variant 1. Because the average value of p21 significantly varies from sample to sample, it would be easy to lose such a signal in the general noise.

Instead, as the researchers point out, more investigation is needed to determine the effects of the ten currently known p21 loci that exist in human beings, which have been discovered by previous research [2] and may be part of determining cell fate in cancer. The researchers note that murine variant 2 and human variant 4 share certain transcriptional regulators, so it is possible that senescence-based research in that direction may bear fruit.

Conclusion

Despite the fact that its results prove an unpleasant fact for the longevity community, namely that p21 by itself is not of much value as a biomarker, this research has provided the scientific community with an enormous boon: we now know significantly more about why p21 is the way it is, and this approach might also be useful in determining the value of other biomarkers.

The potential value of this locus-based technique isn’t restricted to p21 or even to senescent cells as a whole; if multiple genetic loci are responsible for other proteins whose aging-related effects have been overlooked, such loci might also be worth studying. While searching for useful information gene by gene is expensive, time-consuming, and difficult, such exploration may help us to better determine, and ultimately combat, the root causes of aging themselves.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] López-Domínguez, J. A., Rodríguez-López, S., Ahumada-Castro, U., Desprez, P. Y., Konovalenko, M., Laberge, R. M., … & Campisi, J. (2021). Cdkn1a transcript variant 2 is a marker of aging and cellular senescence. Aging, 13.

[2] Radhakrishnan SK, Gierut J, Gartel AL. Multiple alternate p21 transcripts are regulated by p53 in human cells. Oncogene. 2006; 25:1812–5. https://doi.org/10.1038/sj.onc.1209195 [PubMed]

Life Extension – Humanity or Individuals First?

What is it that really matters: preserving individual lives or preserving humanity? Is it more important to grant individuals the option to live as long as they’d like in good health, or is it more important to ensure the preservation of our species?

This sort of question isn’t unheard of in the context of discussions of pros and cons of rejuvenation biotechnology; at times, when presented with the possibility of indefinite lifespans, some people reply that focusing on the preservation of our species is more important. This observation is reminiscent of the “other priorities” objection, and one could respond to it in the same way. However, this issue is also worth examining from other angles.

Quick comeback: the two goals aren’t incompatible

A practical remark to make here is that preserving individual lives automatically preserves the human species because the species only exists as long as there are humans. Not everyone agrees that having a population of individuals that live indefinitely is “good for the species”—be it for fear of overpopulation or of cultural stagnation—but this concept is rather vaguely defined and not objectively measurable. However, here we are stepping into a different territory, one that has been explored in other articles, so we won’t go there in this one.

Another point worth making is that some people are concerned that indefinite lifespans might, for some reason, spell the end of humanity in the sense that the species might die out. At this point, there is no evidence to think that this would be the case, and it certainly cannot be taken for granted. One thing that is granted, though, is that if somehow we knew for a fact that indefinite lifespans would inevitably lead to humanity’s extinction, with no possible workarounds, then we’d better let go of the idea. In such a scenario, presently alive people would die whether we develop rejuvenation or not; between two options entailing our death, we might as well choose the one that doesn’t entail humanity’s doom too. Thankfully, we’ll hardly have to make this choice.

Do you care about humanity? Then Don’t leave it

Some among us are very fond of the idea that our species will still be here long after they’re gone. They deem the survival of the species more important than their own. That’s very noble indeed, but there is something about that worth noting.

You can care about humanity, or value its survival more than your own, only for as long as you are alive. The moment you pass away, even if you’ve held humanity as the dearest thing to you until your very final breath, you will stop caring, because you will stop existing. Maybe you will pass away with the blissful feeling that you’ve been part of a great civilization that will go on until the end of time, but that feeling will be over in a brief moment followed by nothingness. You won’t be able to remember it or enjoy it, but this is not the worst part. The worst part is that any deathbed certainty you may have that humanity will go on beyond your death is not a certainty at all.

The only surefire way you have to know for a fact that humanity is still there is sticking around with it. Anything may happen past the point of your death, and there’s no way for you to know that humanity won’t go extinct in the future, no matter how much faith you may have in it. Worse still, if you’re dead, you can’t help in preventing the possible demise of humanity; even without dramatizing the issue so much, if you’re dead, you can’t help humanity improve. If you really care about humanity, then you shouldn’t leave it.

Humanity is not a football club

One of the innumerable romanticizations of death that we’re often presented with is that, as one generation dies out, it’s just passing on the responsibilities of life to the next. Someone else will take on the task of perpetuating the species, and in general, it doesn’t really matter who it is. Never mind that we all die; as long as there’s someone to pass the torch to, somebody who will continue to play for team humanity, that’s all it matters.

That may be a nice-sounding metaphor, but it is very inaccurate. There’s no marathon that humanity is running, no game that it is playing. Other species may just keep on reproducing for reproduction’s sake and play evolution’s game; we don’t have to.

Speaking of games and metaphors, there’s one I find rather enlightening—and timely, since, at the moment of writing, the World Football Championship is taking place. You might never have thought of it, but sports teams are mere abstractions, and I always found it odd that people would root for one or another. Members of a team—from players to managers—are only on a team for a certain time before moving on to another team, another job, retirement, or even dying. After a couple of decades, a team has completely changed, and the only thing that is probably still the same is the name.

When you root for a team, you’re actually rooting for its name, or more accurately, the idea of that particular team. Not the players, not the management; those change and may well change often during your time as a supporter of the team. Supporters often hope for this or that player to join the team, and for some other whom they dislike to leave for the good of the team itself, whose only real constant is the name—which is what you’re really rooting for.

Not that there’s anything wrong with it: it’s an innocent, completely legitimate pastime. Except that we adopt this very same model when we speak of a generation passing on the torch to the next; that, as it involves the death of millions, is a touch less innocent.

Humanity is not a football club, and neither are other, smaller groups of humans. The family of my great-grandfather, intended as himself, his wife, and their children, is dead. Their genes are still around, and other families have descended from them, in some case even bearing the same family name (another abstraction), but the specific individuals making up my great-grandfather’s family are gone, and so is that specific family.

You might argue that they’re still alive in their descendants’ memories and genes or that their name is being passed down, keeping alive the family, but these are all mental gymnastics to present the fact that they’re dead in a less unappealing fashion. They’re dead, and whether someone still remembers anything about them, or carries a few of their genes or their name, doesn’t make them any less dead.

Even if we accepted the mental gymnastics, no one in their right mind would argue that my great-grandfather’s family is still there, only with different members, like we do in the case of a football team, but that’s exactly what we do when we say that humanity will carry on without us. The whole of humanity of the 600s is dead and buried, and entirely new humanities have come and gone since then. Currently, humanity is comprised of around 7.6 billion individuals, including you and me, and as things stand, they’ll slowly be plucked out one by one and replaced by new individuals, who will collectively inherit the name “humanity”.

However, “humanity” doesn’t have goals, dreams, expectations, feelings, or desires; the people constituting today’s humanity do. Far from being unimportant, the fact that we all die matters a great deal, and even if team humanity will still exist, only with different players, it doesn’t make it any better. As conscious beings, perpetuating our species for the mere sake of reproduction should hardly be a worthy goal to us; the preservation of its members, present and future, should be.

A brief detour: of carts and horses

On the subject of future generations, one often hears that their well-being depends on our actions today, and thus we should work to leave them with a better world than we had; this is a commendable intention, and, in fact, it is one of the reasons why we should develop rejuvenation—to spare future human beings the plague of age-related diseases.

However, future generations are not here yet; we are, and it’s rather mystifying how everyone frets about the currently nonexistent needs of people yet to come but not so much about the very real needs of people who already exist. Today, people suffer from, and die of, age-related diseases; it’s a concrete problem, with tangible effects on the world at large in the present; yet many people seem to worry more about the potential problems they imagine that rejuvenation might cause to future, hypothetical people who’re nowhere near being in their potential mothers’ wombs yet.

Some people are even concerned about the opportunities taken from unborn people, who might be born thanks to the resources freed up if we kept dying of aging instead. According to this line of thinking, living, breathing human beings should give up not only their lives but also their good health so that some unspecified, imaginary people may be born. This isn’t even putting the cart before the horse; this is putting the cart before the horse before carts were invented, before anything vaguely resembling horses ever evolved, and before the concept of “before” was ever thought up for the first time.

The number of different people that could, in theory, ever be born is astronomical, and just picking one partner over another to have children with immediately “takes opportunity” from a myriad of them. The factors that lead to someone being or not being born are innumerable, and there’s no hope that any choice you make will not lead to a hypothetical someone missing the birth train. By the way, as far as we know, there are no unborn people dwelling on the fact that they don’t exist, so perhaps we can remove this from our list of things worth losing sleep over.

And the winner is…

So, who’s more important? Individuals or humanity? It should be clear by now that we’d better think in terms of individuals. This is not to say that one’s own benefit should come at everyone else’s expense; not many people would sleep soundly if they had to choose between their own lives and those of everyone else. If they chose to sacrifice themselves, it would hardly be to preserve the species; more likely, they’d do it to avoid sacrificing so many other individuals.

The good of humanity shouldn’t be about maintaining our presence in the universe just for the sake of being here; it should be about the well-being and life quality of the individuals that make up humanity—and when they’re dead, or about to die, individuals aren’t generally doing very well. Being concerned about future generations is both understandable and commendable, but it should not lead us to neglect who’s already here. As long as we exist, and our good is taken care of, the preservation and the good of humanity will be ensured as well; future humans are welcome to join.

Zalzala interview

Dr. Zalzala: PEARL Trial Could Advance the Longevity Field

We are very excited to be crowdfunding PEARL, one of the few human trials of rapamycin, which is probably the most promising anti-aging molecule known today.

Dysregulation of nutrient sensing (the ability of cells to adjust their metabolism to the amount of nutrients available) is thought to be one of the nine hallmarks of aging.

Rapamycin affects mechanistic target of rapamycin (mTOR), a complex protein involved in nutrient sensing as well as autophagy, the process that cells use for waste recycling. Rapamycin was discovered on Easter Island (Rapa Nui) and is named after it. Rapamycin is an established drug and is currently used for preventing organ transplant rejection. However, probably the most exciting feature of rapamycin is its proven ability to prolong the lifespans of various model organisms, sometimes drastically.

PEARL (Participatory Evaluation of Aging with Rapamycin for Longevity) is a relatively large-scale trial, one of the first of its kind, that aims at recapitulating the amazing effects of rapamycin in humans. If successful, PEARL could have a dramatic impact on the longevity field and, potentially, on our lifespans.

The PEARL study is run by AgelessRx, a company operating in the field of telemedicine and dietary supplements based on popular compounds with possible anti-aging qualities, such as metformin and NAD+. Last year, when PEARL was already in the works, its chief scientist Dr. Sajad Zalzala gave a fascinating talk at our virtual conference, Ending Age-Related Diseases 2020. Now, we asked him for an update on PEARL, rapamycin, and telemedicine.

Could you explain the design of the study? 

PEARL is a randomized, double-blind, placebo-controlled trial. This is the “gold standard” of clinical trials. We selected four different rapamycin dosing schedules plus a placebo group. We are hoping to enroll between 200 to 400 participants – 40 to 80 participants per group. This number was chosen based on what we think is needed for the study to be sufficiently powerful. This estimate was based on previous studies.

PEARL is a telemedicine study, which is unusual. How do telemedicine studies work? What are the benefits and potential problems, compared to conventional studies?

The major difference between a virtual and a conventional trial is the location. In conventional studies, a patient needs to leave their home and travel to the trial site (usually a clinic or a hospital).  With a virtual trial, everything comes to the patient who has almost no need to travel.

There are several advantages to virtual trials. Participants can be almost anywhere in the US. This helps resolve any geographical or environmental influences and confounders. For example, with Dr. Watson’s small rapamycin trial, he suspects that the California wildfires’ adverse effect on patients’ health may have washed out any benefit from the rapamycin. [Dr. James P. Watson of UCLA is the principal investigator of PEARL.]

Virtual trials are not just more convenient for participants but also much more cost-effective than conventional trials. Still, if planned properly, they can provide very useful data.

There are some possible downsides too. Virtual trials can be limited in the types of data that can be gathered. For instance, it is much more challenging to do things like biopsies or echocardiography if patients are remote. Same about types of interventions that can be assessed, since you obviously can’t perform a joint injection or other relatively invasive procedures.

Subjects in a telemedicine trial would also need to be technically proficient to some degree, which might exclude some participants.

Presumably, most participants are people interested in longevity, so they could be using dietary or lifestyle strategies (supplements, fasting of various sorts, keto) that might affect some of the same pathways as rapamycin. How will you control for this potentially confounding issue?

We encourage participants not to make any changes to their routine during the trial other than taking the study drug. Presumably, those in the placebo group would be just as inclined towards various supplements and lifestyle strategies as the active treatment group. In that case, the effects of rapamycin will hopefully shine through these potential confounders.

Since last year, have you recruited any new research collaborators?

The list of potential collaborators continues to grow.  Our most exciting potential collaborators include the Mayo Clinic’s Robert and Arlene Kogod Center on Aging, and the NIH’s National Institute on Aging.  We hope to have more official announcements in the months to come.  We equally appreciate all our potential partners and all their hard work and dedication.

There seems to be a major problem with repurposing existing drugs: it is not lucrative for Big Pharma, so we don’t get to have large scale trials of potentially impactful compounds, such as rapamycin and metformin. What can be done to incentivize this kind of research?

While it is true that Big Pharma may not be interested in repurposing drugs (and if they are – watch out, you can bet they will make it incredibly expensive when they are done), it is our hope that the longevity community, as well as anybody with an enthusiastic interest in longevity, will step up to support and/or participate.

Ultimately, the best incentive will be the results.  If we can show that one or more compounds can slow or reverse aging, I think that will be enough of an incentive for people to support further research.

You assume that rapamycin is a caloric restriction mimetic, but we’ve seen some research lately that suggests otherwise. Could this affect the study?

If I am interpreting these studies properly, it seems that rapamycin affects mostly, but not exclusively, some of the same pathways as caloric restriction. Actually, I think this is promising because it hints at a potential synergy between different longevity therapies.

One such combination that keeps coming to mind is rapamycin and metformin. They might both affect the mTOR system, but I hope we will find that their combination is more beneficial than either one alone, since they might have effects that do not completely overlap but rather are independent of each other.

I do not believe this new data will change the outcomes of PEARL. Rapamycin seems to stand on its own regardless of how exactly it works.

In your talk last year, you did mention combination strategies, such as rapamycin and metformin. Could you expand on that? Why might this one work, and do you have others in mind?

It is possible that rapamycin might “play well” with loads of other molecules and interventions.  I specifically mentioned metformin because it seems to be the “next best thing to rapamycin”, but it also has the potential to overcome some of the possible weaknesses of rapamycin, such as potential insulin resistance (although it is not certain that we will actually see insulin resistance in our study in any of our dose groups).

For example, the combination of growth hormone, metformin, and DHEA (dehydroepiandrosterone) seemed to work really well in Dr. Watson’s TRIIM trial.  We need that same kind of thinking to formulate better trials and therapies.

I have not yet thought that far ahead in terms of exactly which combinations to try next – it would probably require collaboration with other experts to be able to cleverly choose the combinations.  I think we would also want to wait and see what we get back in terms of biomarkers and other data to determine if there are opportunities for synergy that have not yet been explored.

Could you explain the study’s endpoints?

There are primary endpoints and secondary endpoints. The primary is the change in visceral adipose tissue (VAT) by DXA scan, while the secondary is assessing changes in various biomarkers and other age-related markers.

These are not to be confused with our objectives, which are evaluation of the safety profile of our dosing schedule for an otherwise healthy adult population, evaluation of the effectiveness of rapamycin on various markers of aging, and determining the best dose in terms of safety and effectiveness. Ultimately, we want to be able to offer rapamycin prescriptions for patients who would like to use it for its longevity benefits.

We also hope to create a foundation for a telemedicine research “machine” that churns out high-quality studies and data on all sorts of therapies and interventions.

Aren’t studies like this one, due to their combination of potential importance and cost effectiveness, ideal for crowdfunding? After all, they allow citizens to make a real impact in an important field where neither Big Pharma nor governments are currently present.

In a perfect world, governments and large institutions would realize the importance of such studies and provide all the funding that is needed – and then roll those therapies out to all their citizens as a part of a public effort to stamp out the tragedy of premature aging. But until this utopian dream comes true, crowdfunding seems to be the only viable option.

You draw a distinction between participants of a trial and citizen scientists. Can you explain this to our readers? Who are citizen scientists and how can a person become one?

Generally, citizen science is a public participation in scientific research. Participation in a clinical trial is not commonly thought of as “citizen science”. Moreover, I think that traditional trials funded by the government or Big Pharma are largely incompatible with citizen science; they violate its spirit. In my opinion, the difference between the traditional model and the crowdfunded model is like between building a house while working for a large commercial company like Pulte Houses and volunteering through Habitat for Humanity.

PEARL’s model keeps the spirit of citizen science intact in several ways: how we attract the funding and how we ask the participants to fund certain parts of the study. It’s also in our commitment to open access to the data and in how we collaborate with various organizations.

We also strongly encourage participation in our patient registry for those who are already on rapamycin (and therefore excluded from our trial), or who may not qualify for the trial for other reasons – or just anybody who has valuable data on their health and longevity.

Rapamycin research is going strong, new papers are published all the time. Have you seen anything important during this year?

I think the most intriguing and potentially promising research during the last year has been on rapamycin’s and rapalogs’ ability to bolster immunization response and protect against viral diseases, potentially including COVID-19 [which we have reviewed in this article].

A paper from Matt Kaeberlein’s lab, showing that rapamycin rejuvenates oral health in mice, also comes to mind [read our recent interview with Dr. Kaebelein].

How was your work, and the trial in particular, affected by the pandemic? You are in the telemedicine business, which has predictably expanded during this year. How much more popular has telemedicine become? How do you see its future? What role can it play in extending healthspan and lifespan?

We started planning PEARL shortly before the pandemic – but like almost everything, it was put on hold for a while during “The Great Pause”.  Fortunately, we were able to pick up the work quickly and get back on track.

Before the pandemic, telemedicine was growing steadily but slowly, and there was still quite a bit of resistance from some conventional medicine circles.  The pandemic “imposed” telemedicine on all medical providers and health care systems.

One of the most significant changes I encountered was in a state which I shall not name. Their medical board went from being one of the most anti-telemedicine in the country to essentially saying to healthcare providers during the pandemic: “Do whatever you think is in the best interest of the patient”. But isn’t this how it’s supposed to be all the time, pandemic or not? So, telemedicine is definitely here to stay – many of the changes we saw during the pandemic will be made permanent.

When it comes to things like monitoring a person’s health status and the rate of aging, I think there is so much that can be done remotely. Many tests can be done remotely (or locally for the patient). Limiting longevity therapies to brick-and-mortar locations would be a huge disservice to the millions of people who are interested in such therapies.

To conclude, I think that the only way to reach as many people as possible and to make the biggest impact on human longevity is to do it at least in part through telemedicine. When done correctly, telemedicine can be safe, effective, and cost-efficient.

Do you have a message for people thinking about donating to PEARL?

This is a unique trial which can advance the whole field of longevity. Many parties have joined forces to bring it to life: Mayo Clinic Translational Geroscience Network, Better Humans, DexaFit, TruDiagnostic, GERO.ai, Young.ai, and many others that we are not at liberty to name yet. All have come together to provide their services and products at steep discounts or even free to make this project viable. Donor support is the last missing piece that will make this a success. Yet another key point is that if this project succeeds, it will pave a way for other collaborative, speedy and cost-effective trials.

We would like to thank Dr. Zalzala for taking the time to speak with us about the PEARL project. If you would like to get involved by supporting the project you can visit the PEARL campaign page.

Antique, complicated clock

Transcriptomic Aging Clock Measures More Than Just Age

Researchers have developed a new transcriptomic aging clock that incorporates information about biological pathways. With this approach, the clock predicts not only age but also how the state of various genetic pathways changes with age, providing insight into the transcriptional changes involved in aging.

Time for a new kind of clock

In recent years, the use of molecular clocks to estimate age has become a staple of longevity research. The basic idea is to measure certain molecular features and use machine learning to correlate them with age. Aging clocks have been developed based on transcriptomic, proteomic, and metabolic data, but the most popular are probably epigenetic clocks, which estimate age based on DNA methylation patterns.

By providing accurate, reliable biomarkers of aging, these clocks have given researchers a relatively easy and straightforward method to distinguish between biological and chronological age. They can be used to measure the efficacy of therapeutic interventions. However, while these clocks provide an effective tool for estimating age, they don’t offer any insight into the processes behind aging. The seem to be reliable predictors, but they are poor guides for interpretation.

A change of design

With this in mind, a team of researchers in Germany developed an aging clock that incorporates knowledge about biological pathways into its design. They accomplished this by restricting how the neurons in an artificial neural network can connect to each other. Normally, the neurons can connect to each other freely, meaning that the network can take on any shape. This is part of the reason these networks are such powerful machine learning tools, but it’s also part of the reason why they are effectively black boxes.

By limiting the connections, the team could guide the flow of information through the network. They constructed it to reflect the pathways in 50 highly conserved and refined gene sets in the ‘Hallmark’ pathway collection. They then trained this model for age prediction using transcriptomic data from nearly 900 skin samples.

Peering into the ticking machine

The resulting model was able to predict age with an average error of 4.7 years, and it included information about the state of the different pathways. Using this, the team could evaluate how aging affected each biological pathway. For example, they report that neurons in the p53- and TNFa/NF-kB-signaling pathways were most strongly activated by age, indicating that these pathways play an important role in aging.

The team then validated their model by carrying out various in silico knockdowns and showing that they recapitulated observed changes in aging. For example, decreasing SIRT1 in the network increased the predicted age. Similar patterns held when they replicated more complex transcriptomic signatures, such as the changes involved in Hutchinson–Gilford progeria syndrome or photo-aging. The model also captured the effect of positive interventions, such as caloric restriction.

The network could do more than just replicate known results. When the researchers simulated knocking down each gene in the network, they turned up some new candidates alongside the expected culprits. For example, they found that knocking down the HK2 gene increased aging, and simulated overexpression led to rejuvenation. HK2 expression has been reported to decrease with age, but so far, the gene hasn’t been the subject of intensive longevity research. The discovery of such candidates highlights the value of building a model that accurately reflects the mechanisms underlying aging rather than simply predicting their outcome.

The development of ‘age clocks’, machine learning models predicting age from biological data, has been a major milestone in the search for reliable markers of biological age and has since become an invaluable tool in aging research. However, beyond their unquestionable utility, current clocks offer little insight into the molecular biological processes driving aging, and their inner workings often remain non-transparent. Here we propose a new type of age clock, one that couples predictivity with interpretability of the underlying biology, achieved through the incorporation of prior knowledge into the model design. The clock, an artificial neural network constructed according to well-described biological pathways, allows the prediction of age from gene expression data of skin tissue with high accuracy, while at the same time capturing and revealing aging states of the pathways driving the prediction. The model recapitulates known associations of aging gene knockdowns in simulation experiments and demonstrates its utility in deciphering the main pathways by which accelerated aging conditions such as Hutchinson–Gilford progeria syndrome, as well as pro-longevity interventions like caloric restriction, exert their effects.

Conclusion

As the researchers themselves write, this clock doesn’t perform better than existing aging clocks and might even be a little less accurate. However, it arguably offers significantly more value because it incorporates biological information rather than being optimized entirely for prediction. This makes it possible to interpret the state of the network and examine changes in different components that reflect known biological pathways. As such, it serves as a tool not only to predict the effect of longevity interventions but to understand them and thus to interrogate the processes behind aging.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Holzscheck, N et al. Modeling transcriptomic age using knowledge-primed artificial neural networks. npj Aging and Mechanisms of Disease (2021), doi: 10.1038/s41514-021-00068-5
Mitochondrion

Removing and Replacing Mitochondria in Human Cells

A new study conducted by a team of Japanese scientists and published in Scientific Reports details how cells can have their damaged mitochondria destroyed and replaced with healthy ones, offering a potential solution to the problem of mitochondrial dysfunction.

Out with the old, in with the new

In order to destroy the existing mitochondrial DNA (mtDNA) in human fibroblasts, the team engineered a plasmid with XbaIR, an endonuclease that can digest mtDNA. This caused the existing mtDNA to drop to less than 10% of its original value, showing that the vast majority of the mitochondria had been destroyed.

This treatment was followed by an injection of mitochondria from outside the cell. These exogenous mitochondria successfully replaced the existing mitochondria, and 70% of the mtDNA of the treated cells was from the new mitochondria, demonstrating the success of this approach.

Developing an intervention

After proving the concept, the researchers then turned to human fibroblasts with a known disease state. Taking cells from a baby with mitochondrially caused Leigh syndrome, a disease that leads to neurological disorders, they performed the same experiment, attempting to destroy the existing mtDNA and replacing it with new mitochondria.

The results were significant. Cells that had been treated in this way exhibited significantly more uniform, healthy mtDNA than their untreated counterparts. The mutation rate, which was 90% in the untreated cells, dropped to 25% in the treated cells. A total of 60% of the treated cells were fully healthy with replaced mitochondria.

The practical effects took time to manifest, as the treated cells needed to recover from their time with depleted mitochondria. However, after 30 cell divisions, the mitochondrially replaced cells had considerably healthier phenotypes than their unmodified counterparts.

The mitochondria are the powerhouses of the cell, and these cells were able to more efficiently generate ATP, the substance that our cells use for energy. Their mitochondrial respiration was increased while non-mitochondrial respiration was decreased. Their ability to respond to stress was also enhanced; both oxidative stress and starvation resulted in less cell death than their unmodified counterparts.

Enhancing uptake

The researchers then set their sights on ways that cells might be better encouraged to take up donor mitochondria into themselves. When a cell integrates foreign material, it is known as macropinocytosis, and the researchers wished to enhance this as much as was feasible.

What they discovered was very relevant to aging research as a whole. The suppression of the mTORC1 pathway was critical to the uptake of new mitochondria. Cells that had their mitochondria depleted activated the AMPK pathway, introducing the new mitochondria further activated it, and rapamycin, which suppresses mTORC1, was shown to activate AMPK further. Deprived of their energy sources, the cells were effectively undergoing caloric restriction. While the relationship is complicated, this shows a link between caloric restriction, deregulated nutrient sensing, and mitochondrial dysfunction.

Abstract

Mitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed. Mitochondrial disease patient-derived fibroblasts regained respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.

Conclusion

This cell culture research did not re-introduce the treated cells into a human being, so no claims can be made as to its effectiveness as an intervention. It only performed a preliminary investigation into methods for potentially introducing new mtDNA into existing, living cells.

It may be currently feasible to develop an intervention that uses injections of induced pluripotent stem cells (iPSCs) developed from mitochondrially replaced cells. An intervention that replaces mitochondria in situ, without the need to replace the cells themselves, is still beyond the horizon.

However, we look forward to further investigation on this subject, as an intervention that replaces damaged mitochondria with healthy counterparts may one day be an effective treatment or even an outright cure for mitochondrial dysfunction, one of the hallmarks of aging.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Elderly twins

Twin Study Shows That Diet and Exercise Lower Biological Age

Chinese scientists have performed a study on homozygous twins to determine how lifestyle factors – smoking, drinking, physical activity, and diet – affect biological age according to two biological age clocks. Their findings were a mixed bag, but they found evidence for eating lots of fruits and vegetables [1].

DNA methylation clocks

With age, our DNA gets “populated” with methylation marks – that is, methyl groups are added to nucleotides. These methylation marks control epigenetics: the way genes are expressed. DNA methylation clocks use this effect to measure biological age, a physical metric of an organism’s proximity to death, as opposed to chronological age. Other biological age clocks exist, such as ones that are based on blood markers or physical activity.

Although numerous correlations have been found between methylation clocks’ readings and various causes of mortality, the question of just how precise they are remains open. Reliable biological age clocks are desperately needed in longevity research, because if we want to develop anti-aging interventions, we must be able to rapidly measure their impact.

Results could be clearer

Several attempts have been made to link environmental and other external factors to DNA methylation (DNAm) age, with mixed results. For instance, while most studies show that heavy drinking accelerates DNAm aging, one study found no such connection [2]. A systematic review of 61 original studies showed no significant effect of smoking on DNAm age [3], while an American cohort study found that smoking significantly accelerates DNAm aging [4].

This does not mean that methylation clocks are useless. Rather, they are still in their infancy, and we are just beginning to uncover their strengths and limitations, with every new research paper adding to our understanding of their potential.

This new study is especially intriguing because it was done on homozygous twins – meaning the DNA they received from their parents is 100% identical. Working with homozygous twins enables scientists to disregard genetic differences, which play a major role in longevity. In this study, the researchers studied 173 pairs of identical twins of both sexes and various age groups.

Two clocks, four factors

The researchers chose four lifestyle parameters – smokers vs. non-smokers or former smokers; normal vs. heavy drinking; high vs. low physical activity levels, and, finally, consumption of fruits and vegetables (normal or higher vs. insufficient). A binary score was assigned to each parameter (smoker as 0, non-smoker as 1, etc.), and a combined score was calculated for every subject, with 4 being the maximum.

The researchers used two DNA methylation clocks in their study. One, developed by Steve Horvath back in 2013 [5], was the first multi-tissue epigenetic age clock that started it all. This groundbreaking invention is already beginning to show its age and has been surpassed in certain aspects and settings by newer clocks. The second clock, developed by Li et al. in 2018 [6], was originally tested mostly on Chinese subjects, although it demonstrated accuracy in Caucasian subjects as well. The researchers note that Li’s clock is especially well-suited for the Chinese population, from which they drew their subjects.

Quit smoking anyway

The study group’s ethnic composition might be the reason why Li’s clock showed clearer results. While Horvath’s clock failed to show clear correlation with any single factor, Li’s clock demonstrated inverse correlation between DNAm age and three factors: vegetable and fruit intake, physical activity, and the combined score. Horvath’s clock readings were just a tad lower for the healthiest group (an overall score of 4 points) but without reaching the level of statistical significance.

Higher intake of vegetables and fruits had the most significant correlation with DNAm age, while physical activity came close in the second place. The results were generally similar both across the whole group and for pairs of twins, which shows that lifestyle factors might shine through genetics when it comes to aging.

Interestingly, smoking and drinking were not significantly associated with DNAm age in this study. Since we have a trove of data irrefutably proving the detrimental effects of smoking and drinking on our health, this seeming paradox will have to be addressed. Possible explanations are many: for instance, the notoriously low air quality in large Chinese cities might have obscured the effects of smoking. Bundling non-smokers and former smokers into one group might have also muddied the waters. Anyway, if you want to live longer, these results should not be taken as a license to smoke and drink at will.

Conclusion

Among this study’s limitations are its relatively small size and the fact that the lifestyle factors were only assigned a binary score. Yet, twin studies are always exciting because they enable us to see beyond genetic differences. The results of the study pose new questions about the general applicability of DNA methylation age clocks, and which clocks are better than others, but they also confirm the widespread notion that healthy diet and exercise are among the most effective anti-aging interventions available today.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Peng, H., Gao, W., Cao, W., Lv, J., Yu, C., Wu, T., … & Li, L. (2021). Combined healthy lifestyle score and risk of epigenetic aging: a discordant monozygotic twin study. Aging, 13.

[2] Horvath, S., Gurven, M., Levine, M. E., Trumble, B. C., Kaplan, H., Allayee, H., … & Assimes, T. L. (2016). An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome biology, 17(1), 1-23.

[3] Ryan, J., Wrigglesworth, J., Loong, J., Fransquet, P. D., & Woods, R. L. (2020). A systematic review and meta-analysis of environmental, lifestyle, and health factors associated with DNA methylation age. The Journals of Gerontology: Series A, 75(3), 481-494.

[4] Beach, S. R., Dogan, M. V., Lei, M. K., Cutrona, C. E., Gerrard, M., Gibbons, F. X., … & Philibert, R. A. (2015). Methylomic aging as a window onto the influence of lifestyle: tobacco and alcohol use alter the rate of biological aging. Journal of the American geriatrics society, 63(12), 2519-2525.

[5] Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome biology, 14(10), 1-20.

[6] Li, J., Zhu, X., Yu, K., Jiang, H., Zhang, Y., Wang, B., … & Wu, T. (2018). Exposure to polycyclic aromatic hydrocarbons and accelerated DNA methylation aging. Environmental health perspectives, 126(6), 067005.

Rejuvenation Roundup May

Rejuvenation Roundup May 2021

Another month passes, and more progress is made! As we kick off the beginning of summer, we have plenty of news to report regarding our upcoming conference and current campaign along with business news and the latest in rejuvenation research.

LEAF News

Summer is approaching, and we are happy to announce the fourth Ending Age-Related Diseases conference! On August 19-22, we will be meeting virtually to hear the latest developments from the leading experts in rejuvenation biotechnology research. During this four-day conference, you can exchange ideas with the best research teams working on the problem of aging, find new business partners, and spend time with like-minded people! Register today to take advantage of the Early Bird offer.

We thank our Platinum Sponsor NOVOS for fostering this scientific discussion on aging and rejuvenation!

Novos company logo

Aging Begins After a Rejuvenation Event in Early Life: This month, we have one of the authors, Dr. Vadim Gladyshev, joining us, and he will be talking us through new research showing that aging does not begin as early as we thought in humans; instead, it follows a “rejuvenation event” during embryogenesis.

Lifespan News

Lifespan News – NMN Human Trial: The effectiveness of NMN on prediabetic patients, the accomplishments of BioAge in 2021, an FDA-approved drug as a treatment for dry AMD, a negligibly senescent fish, and how the Chinese practice of qigong attenuates age-related cognitive decline.

Lifespan News – Rapamycin for Hearing Loss: Rapamycin to treat hearing loss in a mouse model, vibration to reduce senescent cell burden in rats, a drug that has shown scar-free healing in a mouse model, the scent of food affecting caloric restriction in nematodes, and Kizoo Technology’s €300 million investment in rejuvenation biotechnology.

Rejuvenation Roundup Podcast

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

Advocacy and Analysis

Developing a Science-Based Personal Longevity Strategy: Elena Milova advises people to perform careful self-monitoring when taking supplements and to use caution, patience, and self-discipline when devising a personal longevity strategy.

Elderly woman sleepingWhy Quality Sleep Should Be Part of Your Longevity Strategy: Quality sleep is one of the foundations of health, and a new study suggests that poor sleep quality is a major risk factor for developing Alzheimer’s disease and other dementias.

Crypto and Rejuvenation With Vitalik Buterin, Aubrey de Grey: VitaDAO, the world’s first decentralized intellectual property collective, hosted a discussion and AMA featuring Dr. Aubrey de Grey and Vitalik Buterin.

The Hallmarks of aging are the nine proposed reasons we age.Move Beyond the Hallmarks, Urges New Paper: David Gems of University College London and João Pedro de Magalhães of the University of Liverpool argue that the hallmarks should not be taken as the final word in aging because they don’t have sufficient explanatory power.

What is Glucosamine? A Summary of Glucosamine: This common supplement is a polysaccharide that naturally occurs in cartilaginous joint tissues and is involved in protein and lipid synthesis.

Elderly Man on Pullup BarResilience as a New Measure of Biological Age: In a new paper published in Nature, a group of scientists led by Peter Fedichev explores human longevity through the concept of loss of resilience.

What is alpha-ketoglutarate? A Summary of AKG: Alpha-ketoglutarate (AKG) has long been a popular sports supplement, but interest in this molecule has now reached the aging research field due to its central role in metabolism.

Research Roundup

A long-eared, long-tailed mouseRapamycin Reduces Age-Related Hearing Loss in Mice: Researchers have found that rapamycin supplementation attenuates but not reverses age-related hearing loss in mice, even if the treatment starts later in life.

Vibration Reduces Cellular Senescence in the Bones of Rats: A new study published in the journal Aging has examined the effects of vibration on cellular senescence and osteoporosis. Low-magnitude vibration has been shown to be beneficial for bone growth.

Bigmouth Buffalo FishNo Sign of Aging in Long-Lived Bigmouth Buffalo Fish: Extremely long-lived bigmouth buffalo fish show no signs of a physiological decline with age, according to a new study.

People Living 105+ Years Appear to Repair DNA Better: A new study has shown that people who live for over 105 years typically have a genetic makeup that allows better repair of DNA damage.

Dividing cellsHarnessing the Unaging Germline: A team of researchers, including Michael West of AgeX Therapeutics, has authored a review paper that posits a fundamental difference between “immortal” germline cells and “mortal” somatic cells.

Gene Therapy Improves the Brains of Mice With Alzheimer’s: Scientists have successfully improved learning and memory, as well as neuronal morphology, in Alzheimer’s-prone mice with the help of a gene therapy that upregulates a vital protein.

Spinal degradationDHE Reduces Inflammation, Senescence in Intervertebral Discs: Recent research out of Frontiers in Pharmacology has shown that a natural herbal compound reduces senescence and intervertebral disc degeneration in mice.

Intermittent Fasting During Ramadan Alters Gut Bacteria: Intermittent fasting changes the composition of the gut microbiome, according to new research. An increase in Lachnospiraceae bacteria may explain some of the health benefits linked with dietary restriction.

Research mouseSIRT6 Linked to Slower Aging in Mice: A study published in Aging has shown that the sirtuin SIRT6 has positive effects on multiple hallmarks of aging in the hearts of mice.

Nicotinamide Riboside Rejuvenates Blood Stem Cells in Mice: Researchers have reversed the age-related decline in the function of hematopoietic stem cells (HSCs) in older mice using nicotinamide riboside.

Respiratory tract infectionHuman Trials of mTOR Inhibitors for Immune Aging: A new study published in The Lancet shows the results of Phase 2a and Phase 3 clinical trials for the effectiveness of mTOR inhibition on bolstering the aging immune system against respiratory illnesses.

OSKM in Early Life Increases Lifespan in Mice: An article preprint published on bioRxiv shows that a single OSKM treatment in early life provides lifelong benefits in mice.

OverworkOverwork Linked to Heart Disease and Stroke: In the largest study of its kind to date, researchers have revealed that a considerable part of all deaths from ischemic heart disease and stroke worldwide is caused by working long hours.

Cytosolic dsDNA as a Marker of Senescence: Senescent cells are surprisingly hard to identify, but a recent publication in Tissue and Cell makes the case for using cytoplasmic DNA as a marker of senescence.

RNA strandLong Non-Coding RNAs as an Alternative to Senolytics: New research has identified a set of long noncoding RNAs involved in inflammaging and the senescence-associated secretory phenotype (SASP). These RNAs are conserved across a range of species, including humans.

Heavy Alcohol Use Linked to Greater Epigenetic Age in Women: A study funded by the National Institutes of Health has found that excessive alcohol consumption increases the epigenetic age of non-Hispanic White women according to the GrimAge epigenetic clock.

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle: This preprint shows that long-term CR and rapamycin-treated geriatric mice display distinct skeletal muscle gene expression profiles despite both conferring benefits to aging skeletal muscle.

Epigenetic predictors of maximum lifespan and other life history traits in mammals: In this preprint, methylation-based models accurately predict maximum lifespan using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species.

Rapamycin activates mitophagy and alleviates cognitive and synaptic plasticity deficits in a mouse model of Alzheimer’s disease: Rapamycin enhances learning and memory viability, synaptic plasticity, and the expression of synapse related proteins in APP/PS1 mice.

An aged immune system drives senescence and ageing of solid organs: An aged, senescent immune system has a causal role in driving systemic aging and therefore represents a key therapeutic target to extend healthy aging.

Restoration of energy homeostasis by SIRT6 extends healthy lifespan: SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.

Safety and tolerability of chronic intranasal oxytocin in older men: results from a randomized controlled trial: Chronic intranasal oxytocin appears safe and well-tolerated in generally healthy older men. These findings provide support for continued human research on potential benefits of chronic oxytocin in older adult populations.

Intranasal Oxytocin Improves Lean Muscle Mass and Lowers LDL Cholesterol in Older Adults with Sarcopenic Obesity: This proof-of-concept study indicates that oxytocin may be useful for the treatment of sarcopenic obesity in older adults.

Invariant natural killer T cells coordinate removal of senescent cells: These results uncover a senolytic capacity of tissue-resident iNKT cells and pave the way for anti-senescence therapies that target these cells and their mechanism of activation.

KDM4 orchestrates epigenomic remodeling of senescent cells and potentiates the senescence-associated secretory phenotype: KDM4 targeting presents a new therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies, including cancer.

In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche: Expressing OSKM in myofibers regulates the expression of genes important for the stem cell microenvironment.

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes: The combination of epigenetic aging and a common precursor state for blood cancer may be used to identify a population at high risk for adverse outcomes.

Taxonomic signatures of cause-specific mortality risk in human gut microbiome: This study helps to establish the basis for examining long-term associations between human gut microbiome composition, incident outcomes, and general health status.

Generation of somatic mitochondrial DNA-replaced cells for mitochondrial dysfunction treatment: Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.

Induced pluripotent stem cell-derived mesenchymal stem cells deliver exogenous miR-105-5p via small extracellular vesicles: These findings indicate that these induced pluripotent cells are a promising candidate for obtaining small extracellular vesicles on a large scale.

Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway: This may pave the way to a promising therapeutic treatment to ameliorate vascular calcification in CKD.

Time-restricted eating and concurrent exercise training reduces fat mass and increases lean mass in overweight and obese adults: This study supports the use of time-restricted eating and concurrent exercise training as a short-term dietary strategy.

Joint association between accelerometry-measured physical activity, sedentary behavior and all-cause mortality: The strongest association is with time spent in moderate to vigorous physical activity, but it is modified by the balance of time spent in light physical activity relative to sedentary behavior.

Light-Intensity Physical Activity and Life Expectancy: National Health and Nutrition Survey: Physical activity promotion efforts may capitalize on emerging evidence on light-intensity physical activity, particularly among the most inactive groups.

Extreme lifespan extension in tapeworm-infected ant workers: This study demonstrates an extreme lifespan extension in a social host following tapeworm infection, which appears to enable host workers to retain traits typical for young workers.

News Nuggets

EyeAdverum Biotechnologies Explains Phase 2 Trial of ADVM-022: After a patient lost vision in an eye treated with ADVM-022, Adverum Biotechnologies has unveiled the details of its Phase 2 trial of this gene therapy for diabetic macular edema.

Kizoo Technology Pledges €300 Million to Rejuvenation: Michael Greve, founder of Forever Healthy and Kizoo, has committed over $360 million to support the development of rejuvenation biotechnology startups.

Deep LongevityDeep Longevity Partners With LifeHub & LifeClinic: Deep Longevity has added LifeHub and LifeClinic to its network of longevity-focused companies. This company plans to use multiple AI-based biological aging clocks to test a variety of longevity interventions.

Elevant’s Leaders Introduce Elevant Prime: Elevant launched its first product, Prime, in January 2021. Prime is a daily NMN supplement featuring a unique form of cGMP-manufactured NMN called NMN-C.

Oisin LogoOisín Announces $5 Million in New Seed Funding: Oisín Biotechnologies, a well-known developer of senolytics, drugs that destroy harmful senescent cells, has announced that it has more than doubled its total funding through an oversubscribed round.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Elderly woman drinking alcohol

Heavy Alcohol Use Linked to Greater Epigenetic Age in Women

A study funded by the National Institutes of Health has found that excessive alcohol consumption increases the epigenetic age of non-Hispanic White women according to the GrimAge epigenetic clock.

A large study with a few conclusive results

This study, the first of its kind to show a relationship between alcohol use and epigenetic age, consisted of 2,316 women with a median age of 55.3 years. It used four epigenetic clocks: Hannum, Horvath, PhenoAge, and GrimAge, a recently developed clock that has been vaunted for its accuracy. The difference between a person’s chronological age and epigenetic age is known as acceleration: the “Accel” of each clock. 

While neither recent alcohol consumption nor a history of binge drinking were shown to have any epigenetic effects, according to GrimAgeAccel, an additional 135 alcoholic drinks per year over a lifetime were responsible for an average of four additional months of epigenetic aging when other lifestyle and economic factors, such as exercise, education, BMI, waist-to-hip ratio, and smoking, were controlled for.

However, these conclusive results actually came from the highest quintile of drinkers. All of the other quintiles, even with GrimAgeAccel, had inconclusive results; even women who drank a lifetime average of slightly less than one alcoholic drink every other day were not shown to experience any additional epigenetic aging. The highest quintile of drinkers drank an average of 327 drinks a year, and when their measurements were controlled for other factors, they were shown to have an average GrimAgeAccel of approximately nine months over people in the first quintile, who only drank an average of 7 drinks a year.

Study results on alcohol and epigenetic age

The only other conclusive results from this study came from the Hannum clock, which reported that current drinkers were physically a year older than their never-drinking counterparts, and additional GrimAge results showing that former drinkers were a year older than their never-drinking counterparts. However, women who never drank alcohol only constituted 3% of this study’s participants, and they may have also been engaged in other healthy behaviors that reduce their epigenetic age.

Abstract

Epigenetic age acceleration is considered a measure of biological aging based on genome-wide patterns of DNA methylation. Although age acceleration has been associated with incidence of diseases and death, less is known about how it is related to lifestyle behaviors. Among 2,316 women, we evaluate associations between self-reported alcohol consumption and various metrics of epigenetic age acceleration. Recent average alcohol consumption was defined as the mean number of drinks consumed per week within the past year; lifetime average consumption was estimated as the mean number of drinks per year drinking. Whole blood genome-wide DNA methylation was measured with HumanMethylation450 BeadChips and used to assess four epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge) and their corresponding metrics of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, GrimAgeAccel). Although alcohol consumption showed little association with most age acceleration metrics, both lifetime and recent average consumption measures were positively associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.30 years, 95% CI: 0.11, 0.48, p=0.002; recent, per additional 5 drinks/week: β=0.19 years, 95% CI: 0.01, 0.37, p=0.04). In a mutually adjusted model, only average lifetime alcohol consumption remained associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: β=0.27 years, 95% CI: 0.04, 0.50, p=0.02; recent, per 5 additional drinks/week: β=0.05 years, 95% CI: -0.16, 0.26, p=0.64). Although alcohol use does not appear to be strongly associated with biological age measured by most epigenetic clocks, lifetime average consumption is associated with higher biological age assessed by the GrimAge epigenetic clock.

Conclusion

This study showed conclusive results in only a few areas, and its lack of results in other areas can be taken to support the idea that moderate alcohol use does not significantly affect epigenetic aging. Additionally, while this study controlled for many factors, it is conceivable that the heaviest alcohol drinkers were also engaged in other negative behaviors that had effects on epigenetic age.

However, this study was specifically on the effects of alcohol use on epigenetics and not any other biomarker, and it obviously does not invalidate the fact that alcoholism often leads to serious psychological and physical problems that can drastically shorten lifespan. It also does not have anything to do with the catastrophic and frequently fatal consequences of inebriation under adverse circumstances (such as drunk driving).

Therefore, while light and moderate drinkers are unlikely to be noticeably epigenetically aging themselves through their alcohol consumption, they must always keep in mind that many things that are not directly related to aging can still put an abrupt halt to their quest for longevity.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
AKG may be a useful supplement for slowing down aging.

What is alpha-ketoglutarate? A Summary of AKG

Alpha-ketoglutarate (AKG) has long been a popular sports supplement and is often used in the bodybuilding world, but interest in this molecule has now reached the aging research field due to its central role in metabolism.

What is alpha-ketoglutarate?

AKG is a naturally occurring endogenous intermediary metabolite and part of the Krebs cycle, which means that our own bodies create it. The supplement industry also produces a synthetic version which is chemically identical to naturally produced AKG.

History of alpha-ketoglutarate

Alpha-ketoglutarate (AKG) was discovered in 1937 by Hans Adolf Krebs and William Arthur Johnson at the University of Sheffield, with Krebs going on to receive the Nobel Prize for Physiology or Medicine in 1953. The discovery of AKG was part of the overall identification of the citric acid cycle, which is commonly known as the Krebs cycle due to its discoverer.

Collectively, the Krebs cycle is a series of chemical reactions that is used to generate energy via the oxidation of acetate, which is derived from carbohydrates, fats, and proteins, into carbon dioxide.

What does AKG do?

AKG is a molecule involved in a number of metabolic and cellular pathways. It works as an energy donor, a precursor in amino acid production, and a cellular signalling molecule, and it is a regulator of epigenetic processes. It is a critical molecule in the Krebs cycle and regulates the overall speed of the citric acid cycle of an organism. It works in various pathways in the body, to help build muscle, and to help heal wounds, this is one reason it has become popular in the bodybuilding community.

Sometimes healthcare providers administer alpha-ketoglutarate intravenously for preventing injury to the heart resulting from blood flow issues during heart surgery and for preventing muscle loss following surgery or trauma.

AKG also acts as a nitrogen scavenger and can prevent nitrogen overload and prevent the build-up of excessive ammonia. It is also a key source of glutamate and glutamine, which stimulates protein synthesis and inhibits protein degradation in the muscles.

Additionally, it regulates the ten-eleven translocation (TET) enzymes, which are involved in DNA demethylation and the Jumonji C domain containing lysine demethylases, which are the major histone demethylases. In this way, it is an important player in gene regulation and expression.

Can AKG slow aging?

There is evidence that AKG can influence aging, and a number of studies suggest that this is the case. A 2014 study showed that AKG extends the lifespan of adult C. elegans by roughly 50% by inhibiting ATP synthase and the target of rapamycin (TOR) [1].

During this study, it was found that AKG not only increased lifespan but also delayed certain age-related phenotypes, such as the loss of rapid coordinated body movement commonly seen in aged C. elegans. In order to understand how AKG influences aging, we will describe the mechanism by which AKG inhibits ATP synthase and TOR to extend lifespan in C. elegans and likely other species as well.

ATP synthase

Mitochondrial ATP synthase is a ubiquitous enzyme involved in the energy metabolism of most living cells. ATP is a membrane-bound enzyme that acts as an energy carrier facilitating cellular energy metabolism. The 2014 study showed that in order to increase lifespan in C. elegans, AKG needs ATP synthase subunit β and is dependent on downstream TOR.

The researchers found that ATP synthase subunit β is a binding protein of AKG. They discovered that AKG inhibits ATP synthase, which leads to a reduction of available ATP, decreased oxygen consumption, and an increase of autophagy in the cells of both C. elegans and mammals.

The direct binding of ATP-2 by AKG, the associated inhibition of enzymes, the reduction of ATP levels, reduction of oxygen consumption, and increased lifespan were almost the same as when ATP synthase 2 (ATP-2) is directly, genetically knocked out. From these findings, the researchers concluded that AKG likely increases lifespan by targeting ATP-2.

Essentially, what is happening here is that mitochondrial function is being somewhat suppressed, in particular the electron transport chain, and it is that partial suppression that is responsible for increased lifespans in C. elegans.

The key is to reduce mitochondrial function just enough without going too far and it becoming detrimental. So, the old saying “live fast, die young” is absolutely correct, only in this case, the worms are living slow and dying old thanks to ATP suppression.

Alpha-ketoglutarate and the target of rapamycin (TOR)

TOR is part of a group of serine/threonine kinases from the phosphatidylinositol kinase-related kinase (PIKK) family. It is a conserved pathway, meaning that it is common to multiple species, including C. elegans, mice, and humans, and its job is to regulate growth and metabolism. In mammals is it is called mammalian target of rapamycin or mTOR.

There have been various studies showing that the inhibition of TOR can influence aging in multiple species, including slowing aging in yeast [2], slowing down aging in C. elegans [3], slowing aging in fruit flies [4], and regulates lifespan in mice [5].

AKG does not directly interact with TOR, though it does influence it, mainly via the inhibition of ATP synthase. AKG depends at least partially on activated protein kinase (AMPK) and Forkhead box ‘Other’ (FoxO) proteins to influence longevity.

AMPK is a conserved cellular energy sensor found in multiple species, including humans. When the AMP/ATP ratio is too high, AMPK is activated, which inhibits TOR signaling by activating phosphorylation of the TOR suppressor TSC2. This process allows the cell to adjust its metabolism and balance its energy status effectively.

FoxO is a subgroup of the Forkhead transcription factor family and plays a critical role in regulating the impact of insulin and growth factors on a wide range of functions, including cell proliferation, cellular metabolism, and apoptosis. A study showed that in order to increase lifespan via the reduction of TOR signaling, the FoxO transcription factor PHA-4 is required [6].

Alpha-ketoglutarate and autophagy

Finally, autophagy, which is activated by caloric restriction and also the direct inhibition of TOR, is increased significantly in C. elegans given additional AKG. This means that AKG and TOR inhibition are increasing lifespan either via the same pathway or through independent/parallel pathways and mechanisms that ultimately converge on the same downstream target.

Further support for this has been shown in studies with starving yeast and bacteria [7] and in humans post-exercise [8], where AKG levels are shown to be elevated. This increase is believed to be a starvation response, in this case anaplerotic gluconeogenesis, which activates glutamate-associated transaminases in the liver to generate carbon derived from amino acid catabolism.

This is consistent with the findings of the 2014 C. elegans study [1], which showed that AKG levels are elevated in starving worms but that AKG did not increase the lifespan of calorically restricted animals. This suggests that AKG is a key metabolite and player in the regulation of lifespan via starvation and caloric restriction. It also suggests that AKG is a molecular link between cellular energy generation and dietary restriction in the context of lifespan regulation.

Finally, it means that AKG is a potential target for the delay of aging and the treatment of age-related diseases.

Building on these findings, recently, Dr. Brian Kennedy has published a new mouse study with AKG and demonstrated its potential to extend healthspan and lifespan [9]. Dr. Kennedy also gave a talk at our EARD 2020 conference about his work with AKG and its potential implications for the treatment of aging and age-related diseases.

Alpha-ketoglutarate side effects

No significant side effects caused by alpha-ketoglutarate have been reported in humans but as with any supplement, if you do experience any adverse effects you should cease taking it immediately and consult your doctor.

Disclaimer

This article is only a very brief summary. It is not intended as an exhaustive guide and is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor, and all discussion here is for scientific interest.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., … & Hu, E. (2014). The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature, 510(7505), 397-401.

[2] Kaeberlein, M., Burtner, C. R., & Kennedy, B. K. (2007). Recent developments in yeast aging. PLoS Genet, 3(5), e84.

[3] Hansen, M., Taubert, S., Crawford, D., Libina, N., Lee, S. J., & Kenyon, C. (2007). Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging cell, 6(1), 95-110.

[4] Luong, N., Davies, C. R., Wessells, R. J., Graham, S. M., King, M. T., Veech, R., … & Oldham, S. M. (2006). Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell metabolism, 4(2), 133-142.

[5] Selman, C., Tullet, J. M., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., … & Woods, A. (2009). Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science, 326(5949), 140-144.

[6] Sheaffer, K. L., Updike, D. L., & Mango, S. E. (2008). The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Current Biology, 18(18), 1355-1364.

[7] Brauer, M. J., Yuan, J., Bennett, B. D., Lu, W., Kimball, E., Botstein, D., & Rabinowitz, J. D. (2006). Conservation of the metabolomic response to starvation across two divergent microbes. Proceedings of the National Academy of Sciences, 103(51), 19302-19307.

[8] Brugnara, L., Vinaixa, M., Murillo, S., Samino, S., Rodriguez, M. A., Beltran, A., … & Novials, A. (2012). Metabolomics approach for analyzing the effects of exercise in subjects with type 1 diabetes mellitus. PloS one, 7(7), e40600.

[9] Shahmirzadi, A. A., Edgar, D., Liao, C. Y., Hsu, Y. M., Lucanic, M., Shahmirzadi, A. A., … & Kuehnemann, C. (2020). Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metabolism, 32(3), 447-456.

Elderly Man on Pullup Bar

Resilience as a New Measure of Biological Age

In a new paper published in Nature, a group of scientists led by Peter Fedichev explores human longevity through the concept of loss of resilience, by which the researchers mean the gradual age-related expansion of time that the body needs to recover from stress, such as illness. According to the findings, this progressive loss of resilience might be the factor that puts a cap on human lifespan [1].

Is there a maximum lifespan?

Our scientific knowledge seems to confirm that most species have maximum lifespans, which usually correlates with certain parameters such as body weight, except for a small number of extremely long-lived species. This includes us as humans: despite the immense scientific achievements that led to a drastic increase in life expectancy in just a few decades, humans are still unable to break the age barrier of 120-ish years. Medical interventions and a healthy lifestyle can fight off age-related diseases for quite some time, but even the healthiest individual eventually succumbs to a short period of extreme frailty and illness followed by death – an effect called “compressed morbidity” [2]. Scientists are divided on the question of whether any existing or future technology can overcome this sad predicament.

Variance is the key

In this paper, the researchers introduce an index called DOSI (dynamic state organism index). At the heart of DOSI is a biological age clock based on CBC (complete blood count). CBC is a routinely performed blood test, which means CBC records are plentiful, and they provide a trove of data. This is a plus, even if a CBC-based clock may not be as precise as some other biological age clocks that use more esoteric markers, such as DNA methylation.

DOSI’s most important feature is that its dynamics over time are intended to measure resilience – the metric of how fast the body overcomes various types of stress and returns to homeostasis.

The data shows that with age, DOSI variance increases (meaning the body gets more affected by stress) while the ability to return to the age-adjusted baseline representative of a healthy organism dwindles, until such return is no longer possible. Extrapolation of this data hints at a maximum lifespan: the baseline and DOSI are expected to irreversibly diverge at the age of 120-150 years.

This theoretical prediction might explain the common experience of aging, as well as the phenomenon of compressed morbidity and extreme frailty near life’s end. We all know that with age, it gets harder to recover from such types of stress as illness, physical exertion, lack of sleep, or alcohol consumption. Near the end of life, any disease or trauma strikes harder than before, and recovery becomes less and less possible; this is how the age-related decline in resilience manifests itself. Dr. Fedichev explains it as follows:

We are a quite long-lived species, and so, our body is more or less dynamically stable for the most of our lifespan. Stress factors and shocks are absorbed, and the organism’s state recovers its homeostatic position within a few weeks in healthy individuals in mid-life. As we age and get sick, resilience is reduced. Fluctuations of the organism’s state increase in magnitude in such a way that the probability of losing the dynamic stability increases exponentially. Recovery rate increases with age and eventually runs away at around 120+ no matter how you measure it. Low resilience and increased variance can be an early sign of an upcoming period of extreme frailty.

DOSI can be used to interpret dynamic changes in various biological age clocks. According to Fedichev, the high variance we see in many biological age clocks is due to the fact that their readings are heavily affected by the current fleeting state of the organism. When stressed, the organism looks much less healthy in many aspects, which can be interpreted by biological clocks as premature aging. However, the same organism can give a very different reading upon recovery. If this is the case, biological age is better derived not from a single reading of any particular set of biological parameters but from a longitudinal analysis of the organism’s ability to recover.

The fact that a high sampling rate is crucial for calculating resilience is the reason the researchers chose CBC for their model in the first place. CBC is so ubiquitous that the data set they used, which was collected from a Russian clinic, contained numerous measurements for each individual.

Understanding resilience from exercise

According to Fedichev, since the states of various components of living systems are highly correlated with each other, especially at the point of catastrophic failure (i.e, death), any variable associated with all-cause mortality could be used to estimate DOSI, including physical activity.

This led Fedichev’s company, Gero, to attempt to detect resilience using data collected by wearable fitness devices. In another paper, the researchers describe a model that derives resilience measurements from the dynamics of physical activity or a lack of it [3]. For instance, if you begin to exercise less, and the periods between bouts of exercise widen, Gero’s app, which is already available for download, might interpret it as a decline in your resilience potential.

Even if data from wearable devices might not be a very good indicator of biological age, frequent measurements might be able to compensate for this disadvantage. “Due to the ubiquity of wearable trackers”, explains Fedichev, “physical activity data is available for multitudes of users over long periods of time in quantities sufficient to compute resilience”.

We have asked Dr. Fedichev a few questions about his work.

How does this benefit people, what does it tell them about their biological age, and how will they be able to adjust their lifestyle in order to age slower?

Right now, we report resilience as a purely informative feature. We plan to test if resilience can be associated with lifestyle choices, supplements, or drugs in our further studies.

How is your app different from other lifestyle apps?

Resilience is not something other lifestyle apps can measure. I think most people who tried tracking weight, sleep duration, or the number of steps taken daily know how difficult it can be to distinguish an emerging trend from a temporary fluctuation.

“Am I just a bit tired, or is this aging knocking at my door?” I guess this is an important distinction.

Yes, personally, I have always felt that measuring the rate of recovery would be an extremely useful feature that today’s health apps lack.

How would you describe the major takeaway from your study?

As resilience is being lost with age, the magnitude of fluctuations in biological age becomes too big at the chronological age of around 120+. This means that any intervention aimed solely at already existing health conditions, that is, any attempt to fix the current state, would at some point quickly become insufficient.

Even the best interventions of this kind could only compress morbidity. Meanwhile, quality of life will continue to dwindle due to diminishing resilience, increasing fluctuations in the organism’s state, and loss of coherence between its organs and subsystems.

On the positive side, we may speculate that yet-to-be-discovered interventions aimed specifically at the loss of resilience, rather than at specific health conditions, might have a major effect on lifespan. Hence, this should be the future of anti-aging therapeutics.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Pyrkov, T. V., Avchaciov, K., Tarkhov, A. E., Menshikov, L. I., Gudkov, A. V., & Fedichev, P. O. (2019). Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts ultimate limit of human lifespan. bioRxiv, 618876.

[2] Fnnzs, J. F. (1980). Aging, natural death, and the compression of morbidity. The New England journal of medicine, 303(3), 130-250.

[3] Pyrkov, T. V., Sokolov, I. S., & Fedichev, P. O. (2021). Deep longitudinal phenotyping of wearable sensor data reveals independent markers of longevity, stress, and resilience. Aging (Albany NY), 13(6), 7900.

PEARL AMA

Ask the PEARL Team Anything!

Today, we want to announce we are doing an AMA on Reddit Futurology! The Ask Me Anything thread will be open May 28 and 29 for pre-questions, and on May 30 and 31, the PEARL team will be answering questions.

This is your opportunity to ask questions about the project, which aims to launch human longevity trials with rapamycin.

Ok, but what is rapamycin?

Rapamycin was originally discovered as an antifungal metabolite created by Streptomyces hygroscopicus bacteria isolated from a soil sample taken from Easter Island (Rapa Nui).

Rapamycin is perhaps known best for its use as an immunosuppressant but has also been shown to extend the lifespan of multiple species in studies. It reliably increases lifespan in mice and with far better data than metformin, another frequently touted longevity drug.

Forget live fast, die young. Do the opposite!

Rapamycin appears to slow down metabolism in such a way that it increases lifespan, so unlike the popular phrase, it’s better to live slow, die old! It is thought to increase lifespan due to its influence on the mammalian target of rapamycin (mTOR), an important regulatory pathway for metabolism.

While rapamycin appears to trigger some of the same mTOR pathways associated with caloric restriction (CR), it is not simply a mimetic and has distinct targets in addition to the ones shared by CR.

While the data showing that it can reliably increase lifespan in various species has been published, the lack of human data focused on aging and longevity is lacking. This is where PEARL comes in, as this project seeks to launch meaningful human trials to see if the effects seen in other species translate to people.

Reducing the costs of human trials for longevity

Due to the nature of the PEARL project, particularly its crowdfunded aspects, it is possible to reduce the costs to make a rapamycin trial viable and within reach of our community. PEARL has already smashed its initial fundraising goal of $75,000 and is now into its stretch goals, which expand the scope of the project.

Public funding sources have shown little interest so far in investigating longevity interventions, so we can expect more projects like this to become the norm in the future, as our own community supports the drive to end age-related diseases. If we want the data showing that these things can work, then it seems that we as a community must fuel that progress with initiatives like PEARL.

Join us today for the AMA, and ask the PEARL team anything! We would like to thank the moderators over at Futurology, a subreddit devoted to the field of future studies and speculation about the development of humanity, technology, and civilization.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.