Cracking the Methuselah code

David Galland
a few seconds ago
35 min read

The Quest to Cure Aging

Pretty much since the dawn of recorded history, humans have been fascinated by the idea of living far beyond normal lifespans.

The authors of the Bible tell us that Adam (the original) lived 920 years but was outdone by Methuselah—the grandfather of Noah—who was said to have lived 969 years.

John Appel

For reasons lost to the cosmos, over my career I have become acquainted with a cadre of individuals who have made their lives’ work the quest for something that rhymes with immortality.

These include Durk Pearson and Sandy Shaw, authors of the 1982 bestseller Life Extension: A Practical Scientific Approach, and Aubrey de Grey, President and Chief Science Officer for the Longevity Escape Velocity Foundation.

Through my acquaintance with her father, I spent a day squiring Laura Deming around a conference when she was still in her teens. In case the name is not familiar, at the age of 14 Laura was accepted into MIT and later founded The Longevity Fund with Peter Thiel.

To this day I continue to work with John Mauldin who, along with Dr. Mike Roizen of the Cleveland Clinic, author of The Great Age Reboot, regularly publishes research on aging.

And I am pleased to count as a friend and collaborator Chris Wood, Senior Editor of Transformative Age, a research publication dedicated to tracking the latest in life extension technologies. Chris provided a very knowledgeable backstop in creating this Deep Dive, which you’ve received in lieu of our usual Rational Optimist Diary.

Yet, until the point we decided to explore the most promising developments in extending life and health span for this Deep Dive, I have paid only passing attention to the topic.

Sure, I try to keep fit. And I pop off to the doctor for annual examinations. But that’s about it.

Consequently, it was with a mostly blank slate I began this report. Now, after more than a month doing some of the most intensive research I’ve ever done, I address you as a changed man.

It’s a change for the better.

If I manage to clearly communicate the key points of my research, you may also find yourself looking at your own health and life expectancy in a new, more hopeful light.

Durk & Sandy

I initially met Durk and Sandy as the result of a conference I used to help run. Ditto, Aubrey de Gray.

Like most people in the life extension field, Durk and Sandy were highly intelligent, with stellar academic credentials and a wide range of interests.

(In addition to his work on life extension, Durk found time to help design equipment for the Space Shuttle.)

In their heyday, their work and their message of hope got Durk and Sandy a lot of attention. They appeared on the Merv Griffin show more than 30 times.

I interacted with Durk and Sandy for the better part of a decade and can attest they were fully committed to the pursuit of human longevity. They were both extremely fit and followed a strict diet that included any number of compounds thought to reduce free radicals in the body and thus lessen the effects of aging.

Yet despite a lifetime of research and resolute adherence to anti-aging protocols, both Durk and Sandy died within the past few years, he at 81 and she at 78. That’s below the average life expectancy of a woman in the US.

But that was then, and this is now. Our understanding of what matters in extending health and lifespan has exponentially increased since the release of their book.

As you read this, I will have spent over a month trying to sort the proverbial wheat from the chaff on the topics of health span and lifespan expansion.

No small task, as the amount of unadulterated BS (bad science) one encounters whilst researching the topic is quite shocking.

A Tale of Two Parents

Perhaps influenced by Durk and Sandy in the 1980s, my father came to believe that following a calorie-restricted diet would all but guarantee he’d live to be 120 years old. Accordingly, he limited his intake to just 1,200 calories a day.

(After he died in his sleep at 79, I learned many of those 1,200 calories came in the form of candy bars. Sigh.)

In contrast, my mother, who has never followed a diet, is still going strong in her 100th year, living on her own and bopping all over town attending classes, visiting with friends and generally carrying on as if she were 30 years younger.

“Hey, mom. What one or two key things would you attribute to living so long?”

“Medical advances and seeing doctors who use them, plus accidentally eating the Mediterranean diet all my life and ending bad health habits, particularly smoking when I was 43. All of the above.”

To her list, I would add that she is constantly on the move.

Most people would also credit good genetics. Yet, according to leading scientists in the field of life extension, genetics are credited with just somewhere between 5% and 25% in how you age. Which means 75% to 95% of your health span is determined by your life choices and, perhaps, a bit of luck.

(The exception is that parents who live past 90 usually possess inheritable “super-aging” genes, making it far more likely their children will reach a similarly advanced age. Thanks, mom!)

Regardless, it’s scientifically accurate to say that by making smart lifestyle choices, monitoring key health-related data points, and generally being attentive and proactive to health issues, a long and healthy life is available to most of us.

That’s a hopeful thought, but one which still assumes we will all be folded back into the mantle within the normal range of human life.

That range is generally considered to come to a fairly hard stop around 120 years old, though the oldest person to have ever lived, Jeanne Louise Calment from France, was confirmed to have lived 122 years and 164 days.

This Deep Dive primarily aims to look at the potential for a paradigm shift in aging, blowing out the top of the current range so that, with proper maintenance, there need be no natural limit to how long we live.

Make no mistake: The scientists and researchers involved in the study of longevity believe to their cores that the fragility of old age followed by death is not inevitable.

Their research has become a serious endeavor, with top scientists armed with bushels of money and the latest science and technologies now racing to unlock the Methuselah code.

As you’ll read, in addition to the research initiatives underway at universities and government-financed labs, a literal Who’s Who of the world’s technology elite, perhaps hoping to avoid the fate of Steve Jobs, are heavily investing in longevity research.

The list includes Amazon’s Jeff Bezos, Peter Thiel (PayPal, Palantir), Sam Altman (OpenAI), Brian Armstrong (Coinbase), Patrick Collison (Stripe), Peter Diamandis (XPRIZE, Singularity University) and more.

Even Crown Prince Mohammed bin Salman has publicly committed to spending hundreds of millions of dollars annually on longevity research in Saudi Arabia.

Historical Context

When thinking about extending lifespan, it’s useful to understand why the average lifespan doubled over the last century.

The answer can be found by comparing the primary causes of death back then versus now:

So, what changed to extend the average lifespan? In a nutshell, medical researchers of the time solved the then prevailing causes of death.

A shift from home births to hospitals, along with better hygiene in hospitals, helped to reduce birth-related mortalities, as well as among the general patient population. Eliminating so many early deaths caused the “average” for lifespans to leap upward.

Improving water quality and sanitation systems wiped out the prevalent killers of cholera, typhoid and various other diarrheal diseases, a leading cause of death for centuries.

Vast improvements in anesthetics and surgeries. As Dr. Roizen says in his book, The Great Age Reboot: “Surgery no longer requires four strong men holding you down at home for a procedure that could last only 10 minutes at most.”

The invention of antibiotics in 1925. Before antibiotics something as innocuous as a blister on your heel from playing tennis could kill you, as it did the 16-year-old son of US President Calvin Coolidge in 1924.

Likewise, the invention of vaccinations for killers such as smallpox (1796), diphtheria (1924), yellow fever (1930s) and polio (1955) effectively ended these endemic killers.

Learning how to prevent and treat malaria, including with new categories of drugs, continues to save millions of lives every year.

The evolution in imaging, starting with the X-ray and evolving to the high-resolution CT scan machines now found in most hospitals. These have greatly improved diagnostics and surgical accuracy.

New fertilizers and the development of disease-resistant grains, as well as better refrigeration and an increase in global trade. When I was a child in the 1960s, we were regularly told to clean our plates “because there were people starving in China”. Over recent decades, famines have effectively been eradicated.

You get the picture. Over the last couple of centuries resourceful individuals, armed with new tools and growing scientific understanding, set their teeth to solving the then prevailing causes of mass death.

Thanks to those individuals, (a) we now live considerably longer than in the past, and (b) today’s leading causes of death are increasingly age-related—particularly heart disease, cancer, strokes and dementia.

But the fight against the mass killers never rests, and so the world’s intellectual firepower has shifted its targets accordingly. Which is why, as you can see here, cancer deaths are down across the board in recent decades.

Likewise, a century of improvements in surgical procedures, drugs and treatments have led to remarkable progress in reducing death from the current leading cause of death, cardiovascular disease.

In my immediate circle of friends, three have had a cardiac ablation procedure for serious heart irregularities, and a fourth is on the waiting list to have the procedure. Worldwide, there are about 1.4 million cardiac ablation procedures every year, improving the quality of life and reducing the risk of heart attacks for millions of people.

Here’s a snapshot of the trend in human life expectancy. I see no reason for it not to continue.

All of which brings us to the key question, “At which point will aging itself be designated as the primary cause of death to be tackled by the scientific community?”

So, how close are scientists to being able to significantly extend the human lifespan? Say, by 10 or 20 years? More?

Cracking the Methuselah Code

“I believe that this is the decade that we fix those problems – that we are in the midst of a health span revolution – where converging exponential technologies such as AI, sensors, gene therapy, cellular medicine, and single-cell sequencing will help us understand why we age and add decades to our health span.“ Peter Diamandis

Though this report focuses mostly on the latest developments in lifespan extension, because of its relevance to the topic, I also spent too many hours to count studying what each of us might do to extend our personal health span: the period of time when we are healthy enough to enjoy our life.

After all, if a lack of attention to physical fitness coupled with excessive caloric intake has made you morbidly obese — a condition afflicting upwards of 9% of the US population — studies into the benefits of removing senescent cells in your body will provide little value.

Certainly not as much as going on a diet.

Fortunately, there is much each of us can do, starting immediately, to extend our health span to the point where we might actually benefit from the work researchers around the world are now doing to cure the disease of aging.

Most of which boils down to what the longevity community jokingly calls the “listen to your mother” approach: eat well, exercise regularly, sleep enough, avoid excess.

At some point, I’ll probably publish my findings on health span, but summing things up, maximizing your health span begins with a conscious decision to prioritize your health, rather than only thinking about it when something goes wrong.

Because once a problem arises, you’ve already crossed the line from ‘health care’ into ‘medical intervention.’

And with that gentle nudge to be more mindful of your lifestyle, let’s move on to an examination of how close scientists are to significantly extending maximum human lifespan.

While I wish I could provide a succinct answer to that question, it’s a complicated topic, and so we’ll have to walk slowly but steadily down the path to a rational conclusion.

Aubrey de Grey and LEV

Soon after delving into the topic of life extension, you’ll come across the term Longevity Escape Velocity (LEV), a term Aubrey de Grey coined. It sums up the goal so many researchers are working towards.

LEV is the point when a virtuous cycle is created where the human lifespan is extended far enough out that researchers have the added time needed to discover additional ways to extend lifespan even further.

The basic idea is that if your life expectancy is 80 years old and scientists extend that lifespan by five years, within those added five years, new breakthroughs will emerge to keep the continuum — and you — going. Perhaps indefinitely.

Given the massive amount of research underway — and the supercharged role AI now plays in the research — is it rational to hope that, within the next decade, the average human lifespan could be increased by five years?

Thus, giving researchers the time needed to extend lifespan another five or 10 years? Wash and repeat?

It may sound optimistic, even a bit irrational, but it’s certainly not out of the question.

Of course, we need to differentiate between “average” lifespan and “maximum” lifespan.

We’ll get into “maximum” lifespan shortly.

As for average lifespan, which in the United States is currently 75.8 years for men and 81.1 years for women, we might shift those data points forward by curing cancer.

To that end there are now hundreds, if not thousands of labs and biotech startups focused on doing just that, confident that success will bring extraordinary financial rewards.

Given the decades of serious research already behind us, and the accelerating power of AI, could cancer be effectively cured within the next five to 10 years — just as yellow fever was back in 1937?

I wouldn’t bet against it. Curing cancer, which globally kills close to 10 million people a year, could alone push average life expectancy out by two to three years, maybe longer.

As I was writing this, Nature published a new paper on promising research toward curing Alzheimer’s. If this — or any of the dozens of similar efforts now underway — proves successful in humans, that’s roughly 2 million deaths we can take off the global tally.

What about self-driving cars? Globally, there are about 600,000 deaths related to car accidents every year. Those numbers might drop by 95% with widespread adoption of self-driving cars. The dial shifts again.

Those are just a few of the ways average lifespan could be extended, allowing more of us to live healthier, longer.

As far as extending maximum lifespan, achieving LEV so that people regularly live to 120 years old or longer, Aubrey believes that with the proper level of funding, humanity can achieve LEV by the end of the 2030s.

But Aubrey’s work goes far beyond simply conceptualizing LEV: It was his SENS research (Strategies for Engineered Negligible Senescence), published in 2002, which laid the foundation for much, if not most, of the important work going on finding a cure for aging at the cellular level.

According to Aubrey, aging isn’t mysterious or unstoppable. It’s simply the gradual accumulation of specific types of cellular and molecular damage that the body fails to repair over time. If we can periodically identify, repair, or remove that damage, we can restore youthful function indefinitely.

De Grey classifies the root causes of aging into seven repairable categories, each with proposed interventions:

Cell loss and atrophy: Some cells die and aren’t replaced. Proposed fix: stem cell therapies to replenish lost cells.
Senescent cells: “Zombie” cells that stop dividing but don’t die, releasing toxic signals and causing many of the classic signs of aging. Proposed fix: drugs designed to find and destroy damaged cells, called senolytic drugs.
Mitochondrial mutations: Damage to mitochondrial DNA impairs energy production. Proposed fix: Move essential mitochondrial genes to the cell nucleus (a process he calls “allotropic expression”).
Extracellular crosslinks: Proteins like collagen get “gummed up,” stiffening tissues (e.g., arteries, skin). Proposed fix: Develop enzymes to break crosslinks.
Extracellular aggregates: Junk proteins accumulate outside cells (e.g., amyloid plaques in Alzheimer’s). Proposed fix: vaccines or immune therapies to clear them.
Intracellular aggregates: Junk builds up inside cells (like lipofuscin). Proposed fix: Engineer enzymes or nanomachines to digest the waste.
Cancer-causing mutations: Over time, cells accumulate DNA damage that can lead to cancer-causing mutations. Proposed fix: Limit the uncontrolled cell growth that leads to tumors by keeping telomerase — the enzyme that lets cells divide indefinitely — tightly regulated, while using healthy stem cells to renew tissues when needed.

De Grey’s central claim is that aging can be indefinitely postponed by periodically repairing these types of damage — much like maintaining a classic car. When repair technologies advance faster than we age, presto, we have LEV.

A 2013 paper published in the prestigious journal Cell called “The Hallmarks of Aging” builds on the work done by De Grey, identifying nine major “hallmarks” — molecular, cellular, systemic, and emergent processes that drive aging.

Three more “hallmarks” were added in 2023, increasing the total to 12. By addressing these hallmarks, we can potentially slow, stop, or even reverse biological aging. There’s overlap among these 12 hallmarks and De Grey’s list, but the 12 hallmarks cover a broader and more systemically inclusive set of issues, which also better captures the interconnectedness of these driving forces.

Which neatly brings us to what most researchers would acknowledge as the biggest breakthrough to date in the fight against aging at the cellular level.

Dr. Shinya Yamanaka’s Four Factors

In 2006, Dr. Shinya Yamanaka, an orthopedic surgeon from Osaka, Japan, discovered that it was possible to reset an ordinary adult cell back to its embryonic beginnings, called induced pluripotent stem cells (iPSCs).

Pluripotent stem cells are the foundation of regenerative medicine, offering the possibility not just to slow aging, but to turn old cells “young” again, repairing the damage aging leaves behind.

By reprogramming skin or blood cells into stem cells capable of becoming virtually any tissue in the body, Yamanaka eliminated the need to destroy embryos for research and sparked a new wave of interest in regenerative medicine. His research won him the Nobel Prize in Physiology or Medicine in 2012.

Yamanaka’s process involves infusing a harmless virus with four special proteins (Oct4, Sox2, Klf4 and c-Myc) that are collectively referred to as either OSKM or the Yamanaka Factors.

The virus with the Yamanaka Factors is able to enter the targeted cells, activating them to “reset” to pluripotent stem cells.

While near miraculous, there are “complications” with the Yamanaka factors.

To give just one example, if enough specialized heart cells reset to “blank slate” stem cells, they’ll no longer provide the core function of keeping the heart beating and, THUD, game over.

By their very nature, stem cells steadily reproduce — just as cancer cells do — so the process can quickly lead to tumor formation. Especially as one of the Yamanaka transcription factors, c-Myc, is a known carcinogen.

So, we have this amazing technology which can literally de-age cells, but we have two serious hurdles — cellular dedifferentiation and uncontrolled growth or malignancy — holding it back.

Of course, scientists are nothing if not eager beavers, ready to chew through problems like soft pine, and so the race to solve the issues with the Yamanaka factors has been well joined.

Here are just a few of the well-financed standouts now working to solve those problems.

Altos Labs

Zuckerberg’s META has been much in the news lately for trying to advance the company’s AI ambitions by spending huge amounts of money to attract top talent away from Microsoft, OpenAI and others.

It is somewhat useful to view Altos Labs, the $3 billion startup financed in part by Amazon’s Jeff Bezos, in a similar light.

In its quest for LEV, the company has recruited some of the world’s top scientists, including Dr. Yamanaka himself.

Another member of the team is AI pioneer Dr. Thore Graepel, co-inventor of AlphaGo, the AI program that fired the starting gun for widespread AI adoption by outplaying the world’s leading Go players.

As an amateur Go player myself, I can tell you, this was no small feat. A chess player might face about three dozen possible moves at any turn. In Go, that number can exceed two hundred, creating an almost unimaginable range of possible board positions — more than the number of atoms in the observable universe (that’s a true statement, I checked).

The fact that Altos recruited Thore Graepel, one of the minds behind DeepMind’s AlphaGo, indicates just how serious they are.

The lead on the Altos team is Juan Carlos Belmonte, formerly with the Salk Institute. He’s a pioneer in what is called “cyclic OSKM expression”, a promising approach to solving the Yamanaka problems, though we won’t know until human trials are successfully concluded.

Altos uses two- or three-day ‘pulses’ of the OSKM factors, applying them just long enough to roll back some of the cellular damage and rebuild a healthy buffer of resilience against further damage. The intervention then naturally degrades, without triggering dedifferentiation or tumors.

The Altos team has successfully reversed aging in mice by about 30%, without the cells losing their identity and without causing cancer.

If Altos’ approach succeeds in moving into human trials and gaining FDA approval, in the future you might go into a clinic for a tune-up every few years, partially resetting your cellular age, therefore maintaining a lower biological age.

Of course, mice aren’t humans, and so there is much left to do before we get to human trials. Fortunately, Altos has the talent and the funding to keep the ball moving forward.

Life Biosciences

One of the more interesting anti-aging research groups, Life Biosciences, is taking a novel approach to rejuvenating cells, dropping the known carcinogen — c-Myc — from the Yamanaka Factors, leaving just OSK.

I’ll admit to initially being a bit wary about including Life Biosciences in this report — mainly because of its controversial co-founder, Dr. David Sinclair, a tenured professor at Harvard Medical School. I won’t rehash all the details here, but a quick Google search will turn up plenty of unflattering commentary about him.

Even so, as I dug deeper into Sinclair’s work, I found a more nuanced picture. He may be an unhesitant self-promoter, but he’s also a genuinely capable biologist with over 450 peer-reviewed papers to his name. It was his research on epigenetic reprogramming that inspired the creation of Life Biosciences.

Life Biosciences and its collaborators have shown in animal testing that partial cellular reprogramming, using just the OSK factors, can safely reset biological age.

The company calls this process Partial Epigenetic Reprogramming (PER). In preclinical studies, OSK expression has been used to restore vision in mice with glaucoma and even to repair optic nerve damage in non-human primates — exciting early results that suggest cells can be safely rejuvenated without losing their identity.

Unlike the natural pulsing approach used by Altos Labs, Life Biosciences’ method relies on using a common antibiotic to switch on the OSK genes. Once the antibiotic is administered, the reprogramming genes activate and the rejuvenation process begins; when the antibiotic is stopped, the genes switch off, halting the process.

We may soon have an answer to whether PER’s success in mice and monkeys will translate to humans, as Life Biosciences is planning a human trial early in 2026 (postponed from 2025). The trial will involve injecting participants with the OSK factors in an attempt to repair glaucoma as well as a form of sudden-onset blindness in humans.

If the human trial goes forward and is a success, it will likely unleash a tremendous new wave of research funding and move humanity one step closer to being able to turn back the aging clock.

Retro Biosciences

Retro Biosciences, backed by OpenAI’s Sam Altman with a $180 million investment, is on a mission to add at least 10 healthy years to the maximum human lifespan.

The company focuses on fixing three core “bugs” that drive aging: toxic molecules that accumulate in our blood, genetic “error messages” in our DNA and the slowdown of our cells’ internal cleanup systems.

One of Retro’s earliest programs targets pro-aging factors — inflammatory proteins and waste products that build up in the blood and accelerate aging. Research has shown that blood chemistry powerfully influences aging.

In 2005, in a somewhat macabre experiment, scientists physically connected the circulatory systems of old and young mice. The old mice grew more youthful, while the young ones aged faster.

Later studies revealed it wasn’t “young blood” doing the magic — it was simply the removal of old blood factors. Replacing half the plasma in old mice with saline similarly rejuvenated their muscles, livers and brains.

Retro aims to turn this discovery into a practical therapy. Instead of hospital-based plasma exchange treatments (which require several clinical sessions a year) or donating blood (which can have a similar effect), Retro is developing a drug that mimics the same rejuvenating “flush” without machines or transfusions. This program has already passed proof of concept and is in the preclinical stage.

Retro has another program that follows a similar path to that of Life Biosciences by using the OSK gene therapy to gently “reboot” aging cells. In one study, the company was able to significantly extend the lifespans of elderly mice by 18 weeks, versus 9 weeks for the control group.

Restarting the Body’s Cleanup Crew

Retro’s most advanced effort is a drug called RTR-242, designed to boost autophagy — the body’s natural cellular cleanup and recycling process. Think of autophagy as a team of biological janitors that remove broken proteins and damaged cell parts. With age, that crew slows down, leading to a toxic buildup that contributes to neurodegenerative diseases like Alzheimer’s.

RTR-242 is engineered to restart that cleanup system. Phase 1 human trials are expected to begin later this year, focusing first on early Alzheimer’s patients.

AI Accelerator

Retro isn’t just a biology company — it’s also an AI company. Thanks to its connection to Sam Altman, founder of OpenAI, Retro has collaborated with the AI giant to build a new AI model that dramatically speeds up its longevity research, particularly its cellular reprogramming program — reportedly making it 50 times more efficient while reducing safety risks.

The relationship with OpenAI and the integration of cutting-edge AI with biotechnology give Retro a real chance at grabbing the golden ring.

Retro is now reportedly raising around $1 billion to expand its pipeline, which also includes research into clearing “zombie” senescent cells and other advanced aging mechanisms.

New Limit

As with many leading contenders in the race toward LEV, New Limit enjoys the backing and even active involvement of major tech investors. The company was co-founded by Coinbase’s Brian Armstrong and longevity scientist Blake Byers. Among its financial backers are Peter Thiel and Eric Schmidt, the former CEO and chairman of Google.

The company is similar to Altos Labs and others focused on reprogramming cells to make them young again without losing their identity and purpose.

New Limit’s goal is to find a safer combination of transcription factors (TF) than the four Yamanaka factors.

The company’s key differentiator is that it’s built a super-fast, high-tech system that can test huge numbers of these combinations at once.

Basically, it runs tons of tiny experiments at once on individual cells, watches the effects, then uses AI to predict which TF combos are most likely to make cells act young without messing up their identity. Then they quickly test those best guesses in the lab. So it’s compressing decades of work into days. Something that simply wouldn't be possible without AI.

Perhaps instead of OSKM, or just OSK, there is another combination of even more effective transcription factors waiting to be discovered? That’s New Limit’s goal.

Cambrian Biopharma

Cambrian Biopharma is taking a “hub and spokes” approach to longevity medicine, coordinating a network of biotech companies, each targeting a different hallmark of aging.

Its business model allows shared legal, financial and scientific resources across a number of companies, consisting of 15 active drug programs — boosting efficiency and dramatically increasing the odds of breakthrough success.

Initially the company is advancing therapies targeting specific diseases such as diabetes and heart disease, with the goal of later repurposing them for preventive, health-span-extending uses once regulators catch up.

Pipeline highlights include:

Amplifier Therapeutics: Developing an “exercise in a pill” therapy designed to mimic the cellular and metabolic effects of physical activity. Currently in Phase 1b trials, its compounds aim to activate key molecular pathways involved in muscle strength, endurance and metabolic health — offering potential benefits for patients unable to exercise due to age or illness.
Tornado Therapeutics: Developing improved versions of rapamycin, a drug derived from a bacterium first discovered in soil on Easter Island. Rapamycin has been shown to slow aging and extend lifespan in animals, but it can cause unwanted side effects. Tornado’s next-generation versions aim to capture the same anti-aging and health benefits while making the drug safer and more targeted in how it works inside the body.
Isterian Biotech: Focused on reversing tissue stiffening and fibrosis, two key drivers of organ failure and aging. Its drug candidates aim to restore elasticity and proper cellular function in tissues such as the heart, lungs and liver — offering hope for treating chronic fibrotic diseases currently lacking effective therapies.
Oviva Therapeutics: Dedicated to extending female reproductive and overall health by preserving ovarian function. Because the ovaries are among the first organs to decline with age, Oviva’s therapies aim not only to lengthen fertility but also to sustain hormonal balance, bone strength and metabolic vitality as women age.
Vita Therapeutics: Developing regenerative stem-cell therapies to rebuild and strengthen muscle tissue lost to disease, injury or aging. By combining advanced cell engineering with targeted delivery, the company seeks to restore muscle function in conditions such as muscular dystrophy and age-related muscle wasting.

Backed by $200 million and billionaire Christian Angermayer, Cambrian’s innovative structure gives it the scale of Big Pharma with the agility of a startup.

Juvenescence

Juvenescence, founded by longevity investor Jim Mellon, is tackling aging from two angles: developing its own drugs and investing in a portfolio of cutting-edge biotech startups.

Like Cambrian, its science focuses on the hallmarks of aging — cellular and molecular breakdowns that cause multiple diseases at once.

The company plans to have five in-house therapies in human trials by year-end, targeting fibrosis, muscle wasting, rheumatoid arthritis, heart failure and Alzheimer’s. Its investments span seven pioneering ventures, including:

LyGenesis: Developing a breakthrough platform that uses lymph nodes as bioreactors to grow functioning replacement organs — such as livers, thymuses and pancreases — inside the patient’s own body. The approach could eliminate the need for traditional organ transplants and the long waitlists that accompany them.
Morphoceuticals: Harnessing the body’s natural bioelectric signaling to guide tissue repair and regeneration. By “reprogramming” these cellular electrical patterns, the company aims to regrow limbs, repair spinal cords and heal damaged organs in ways once thought impossible.
Chrysea: Creating nutritional compounds that activate autophagy, the body’s process of cellular renewal and cleanup. Its supplements are designed to help maintain cellular health and longevity by clearing damaged proteins and cellular waste linked to aging and disease.
Relation Therapeutics: Building an AI-powered platform to uncover hidden relationships between genes, diseases, and treatments. By applying advanced machine learning to biological data, the company hopes to accelerate drug discovery and design more precisely targeted therapies.

Like most of the companies in the space, AI plays an increasingly important role in everything Juvenescence does. The company’s acquisition of Ro5, a pioneering drug discovery platform built around machine learning and AI, has supercharged its drug-design process to help identify targets, design molecules and optimize trials faster and cheaper than traditional pharma.

Of course, epigenetic reprogramming and the development of new drugs are far from the only lines of research ongoing to combat aging.

Replace Rather than Repair

Some of the biggest names in longevity and regenerative medicine recently wrote a paper entitled “Replacement as an aging intervention”.

The thesis of their paper is simplicity itself. Namely, while the multitude of research teams are hard at work trying to solve aging at the cellular level, modern medicine already has most of the tools needed to do a really good job replacing failing human parts.

Joint replacement has become commonplace, and advances in everything from prostheses to brain-computer interfaces are being made every day.

Now imagine the impact on lifespan if scientists succeed in 3D printing organs using cells from the recipient, reducing or eliminating the chances of organ rejection.

I have a friend who received a heart transplant over 10 years ago. Against all odds, he’s still alive, though his quality of life is far from where he’d like. Due in no small part to the quantity of drugs he’s required to take to stop organ rejection.

Liver failing? Print a new one. You get the idea.

I won’t go deep on this line of research, but the problems with organ replacements are well-known and therefore well-studied. In the not-too-distant future, replacement, probably in conjunction with repairs at the cellular level, could prove a game-changer, and so it is something to keep an eye on.

Has the First Longevity Drug Already Been Invented?

By now pretty much everyone is familiar with GLP-1 drugs, in particular Ozempic, Wegovy and Mounjaro.

Originally designed for diabetes, GLP-1 drugs have emerged as a breakthrough in longevity medicine. These peptides are being shown to solve a wide range of health issues before they become medical problems.

In a massive trial of 17,000 patients, semaglutide reduced major cardiovascular events by 37% within three months, halved deaths from heart disease within six months, and cut hospitalizations for heart failure by 59%.

Importantly, these benefits appeared before significant weight loss, suggesting direct protection of the heart and blood vessels.

Brain health benefits are equally striking. A study of 1.7 million patients found those taking semaglutide had a 40% to 67% lower risk of dementia compared with other diabetes drugs, prompting trials to see if GLP-1s can preserve memory and cognition.

These drugs also protect the kidneys and reverse damage in fatty liver disease (MASH). Studies in the New England Journal of Medicine show semaglutide and tirzepatide reduce liver fat, inflammation and even fibrosis — once thought irreversible. The FDA has now approved semaglutide for treating advanced MASH.

If as suggested by these studies, GLP-1 drugs improve cardiovascular, brain, liver, and kidney health simultaneously, they may represent the first true whole-body longevity therapy.

The big drawback to these drugs is that they require you to self-inject them, not something most people like the thought of. The reason they need to be injected is that Peptides get destroyed by stomach acids and enzymes if they are swallowed.

That will likely change within the next year or two, as Eli Lilly (LLY) is hard at work on a new drug, Orforglipron, a GLP-1 receptor agonist like semaglutide and tirzepatide. Because it’s a small molecule, not a peptide, it can be delivered in a pill form, not an injection.

This, from Chris Wood writing in Transformative Age:

Most importantly, Orforglipron works. In large Phase 3 trials it delivered weight loss and health improvements on par with the injectable GLP-1 drugs.

In Lilly’s pivotal obesity trial, patients on the highest dose lost 12.4% of their body weight on average. 60% of these patients lost at least 10% of their weight, and 20% lost at least 20% of their weight. These are life-changing numbers.

And it’s not just weight. Patients on Orforglipron saw wide-ranging health benefits, including a striking drop in inflammation measures.

Just as important, Orforglipron’s safety and side effects were similar to other GLP-1s. There were no signs of serious liver injury, which was a concern with a different oral GLP-1 candidate that Pfizer ultimately discontinued.

And this:

Today, injectable GLP-1s—as amazing as they are—reach only a tiny fraction of the people who could benefit. In the US, only an estimated 2% of the more than 100 million adults with obesity are on GLP-1 therapy, largely because of cost and logistical barriers. In many countries, these drugs aren’t available at all or are too expensive for widespread use.

Orforglipron has the potential to change that landscape.

In the coming years, this could become the world’s most successful drug, pushing human health and lifespan forward into the future.

Expect it to be joined by others, which will collectively keep the upward trend in health span and lifespan intact.

Experimental = Unproven

Given the quantity of astounding claims made about this or that longevity breakthrough, I thought including a cautionary tale to be appropriate.

At this year’s Revolution Against Aging and Death Festival in Las Vegas — known in the longevity world as RAADfest — two attendees landed in intensive care after receiving unapproved peptide injections at a booth run by a so-called “age-reversal” doctor.

The injections, administered on-site by a California physician without a Nevada license, led to severe illness requiring ventilators to keep the women alive.

I know a lot of people who pay what may be an unhealthy level of attention to their health, jumping from fad to fad, in the hope of living longer and stronger. The fact that people were lining up to get injected with an unproven drug in an exhibitor’s booth at a conference speaks volumes.

For many, the FDA and “Big Pharma” are seen as the enemy, stifling otherwise effective supplements or interventions to prevent them from cutting into profit margins should their effectiveness become widely known.

I have even heard the charge that Big Pharma companies regularly buy effective but inexpensive drugs and shelve them to retain the market for their more expensive products.

In London, Aubrey de Grey and I discussed this line of skepticism, and he was clear in his experience-based opinion that this is simply not happening.

He generally respects the FDA and doesn’t view Big Pharma as the bad guys.

Once again, there is nuance. The cost of taking a drug through the FDA safety and efficacy protocols can run into hundreds of millions of dollars, even a billion or more, and take upwards of 10 years.

Logically, then, pharmaceutical companies prioritize drugs that (a) they think can make it all the way through the process, and (b) once through, will have a big enough addressable market to offset the costs and resources involved and still turn a profit. Hopefully for many years.

The FDA has no vested interest in suppressing effective drugs or supplements, period.

As for supplements, there’s an interesting program run by the National Institute on Aging (NIA) called the Interventions Testing Program (ITP).

Established in 2003, the ITP’s mission is to rigorously evaluate compounds, supplements and dietary interventions that might extend lifespan and improve health span. Each year, scientists from universities and research institutions worldwide are invited to submit proposals for interventions to be tested.

What makes the ITP unique is that the studies are conducted simultaneously at three independent laboratories: The Jackson Laboratory (Maine), the University of Michigan and the University of Texas Health Science Center at San Antonio. This replication across sites eliminates many sources of bias and ensures reproducibility.

Dozens of interventions have been tested, mainly on mice, with the results published openly, whether positive or negative, helping the broader scientific community identify genuine aging interventions from overhyped claims.

Has your favorite supplement been tested? Here’s the link to the results of all the ITP findings.

Let me stress again that if there was ever an area where skepticism is called for, it’s when coming across ebullient health and longevity claims. Before you adopt any new supplement or regimen, do your research.

To that end, I’ll provide some useful resources at the end of this report.

Conclusion: It’s All Happening Now

At a recent industry conference in Copenhagen, senior scientists from Eli Lilly (LLY) and Novo Nordisk (NVO) described GLP-1s, which have heretofore been discussed almost exclusively as treatments for diabetes and obesity, as longevity drugs.

And they repeated that claim on stage multiple times throughout the conference.

That is a seismic shift in attitude from “Big Pharma” which until recently viewed longevity-related research mostly as belonging in the realm of quacks and charlatans.

It’s hard to overstate the importance of this shift in mindset.

Consider: While the total annual budget of the US government’s National Institute of Health is about $50 billion, the bulk of that budget is spent researching specific diseases like cancer and Alzheimer's. Meanwhile, the study of aging, the root cause of most of today’s leading causes of death, receives less than $1 billion.

As the race for LEV gathers steam and new successes are reported, the odds grow that governments around the world will shift their health funding priorities toward longevity.

With the proper level of funding, will one of the research teams now working on breaking the Methuselah code find success in the foreseeable future? Aided by AI, I think the odds of it happening within Aubrey de Grey’s time frame of the end of the 2030s are possible.

When you have time, find a quiet spot and think through the consequences of that breakthrough for you and your family. Are you prepared to live in good health to the ripe old age of 110 or beyond?

It changes pretty much everything. Much to ponder, personally and for society writ large.

Summarizing what I have personally taken away from being immersed in the research for over a month:

There is much each of us can do to improve our health span. I’m now far more mindful about my health. I wear a monitoring device to track key health metrics and have adopted a schedule that includes regular exercise, diet and some supplements. When a pill such as Orforglipron becomes available, I will almost certainly take a low-dose form of it.
Hundreds of serious scientists are hard at work on tools to anticipate health issues before they occur, detect diseases early and — eventually — cure aging itself. With adequate funding and the steadily advancing application of AI across the sciences, we will see regular breakthroughs going forward.

Just as improved sanitation and the invention of specialized drugs and antibiotics eliminated a wide array of causes of death in the past… epigenetic reprogramming, CRISPR, and a host of new drugs, proteins and peptides discovered with the help of AI will allow each of us to live longer and healthier, while dramatically reducing deaths from the current ‘leaderboard’, most of which are age-related.

There’s a good chance that new drugs and treatments have already shifted the average life and health span out another five or even 10 years. Today’s children are pretty much certain to live to 100 and, with LEV, well beyond.

What do you think about expanding lifespan? As always, I enjoy hearing from readers.

What topics would you like to see us cover in future Deep Dives?

Drop me a note at Galland@rationaloptimistsociety.com.

And, if you find this Deep Dive of value, please forward it to your friends, family members and associates with a recommendation that they join our growing membership and help spread the good news about today’s world. They can use this link to sign up.

Be sure to take a look at the Resources and Addendum just below. They should be of use.

Until next time…

David Galland

For the Rational Optimist Society

Resources and Addendum

As I wrote this report, I became increasingly aware of the tremendous amount of press coverage dedicated to “breakthroughs” in health and longevity.

To help you separate facts from reality, here are a few sources to bookmark. A couple of them allow you to search for double-blind peer-reviewed studies on everything from drugs to supplements, and even interventions like the impact of sleep on health:

The FDA site, searchable.
The Interventions Studies Website, referenced above.
For a credible source of searchable research, check out PubMed.
For a solid overview of the longevity movement, as well as an extensive list of wellness clinics around the world, download the Longevity Metatrend Report from Peter Diamandis here.
PNAS.Org. Another generally unbiased source for searching and reading the latest research on a variety of biological research.
A commonsense checklist of questions you should ask before trying unconventional aging treatments.

Influencers

There is an army of health “influencers” promoting their content and their products online. Be skeptical, very skeptical. Here are a few, all of whom are medical professionals, who I have found to offer credible research, backed up with hard science:

Dr. Peter Attia
Dr. Andrew Huberman, neuroscientist
Dr. Mark Hyman
Dr. Matthew Kaeberlein
Dr. Rhonda Patrick
Dr. Brad Stanfield

While they may offer a wellness program, or even promote a supplement, they are very moderate and forthright in their offerings, in stark contrast to the aggressive pill pushers you’ll encounter at every turn when looking for solid health advice.

Which Journal?

A recent article in ZeroHedge highlighted the growing scandal over scientific “paper mills.” You can read it here.

Simply put, academic publishing operates like a hierarchy — a pyramid with highly respected, rigorously managed journals at the top, and a multitude of lesser ones below. Among the latter are journals that turn a blind eye to “paper mills,” which churn out sketchy research papers and sell co-author or even lead-author credits to aspiring academics eager to pad their résumés.

I mention this because if in your own research you come across an exuberant headline linked to an obscure journal, be skeptical. When truly groundbreaking research is uncovered, it will be published in one of the publications at the top tier, which include these:

Nature (UK) — Possibly the most prestigious multidisciplinary science journal in the world.
Science (AAAS, US) — The American counterpart to Nature; publishes groundbreaking work across disciplines.
Cell (Elsevier, US) — Premier life sciences and biomedical journal.
The Lancet (Elsevier, UK) — One of the world’s top medical journals.
New England Journal of Medicine (NEJM) — Preeminent in clinical and medical research.
JAMA (Journal of the American Medical Association) — Another top-tier general medical journal.
PNAS (Proceedings of the National Academy of Sciences) — Elite multidisciplinary US-based journal.
BMJ (British Medical Journal) — Highly respected, especially for clinical medicine and public health.

Of course, that doesn’t mean that papers published in the premier journals should be taken as the gospel truth, but the odds are improved.

Research institutes, labs & programs

To give you a sense of the financial and intellectual firepower now being applied to longevity and health span, the following is a partial list of foundations, companies, universities and government research organizations focusing on the topics.

Academic & Research Institutions:

Albert Einstein College of Medicine (US) — Institute for Aging Research; Nathan Shock Center; human longevity genetics (Barzilai).
Babraham Institute (UK) — Epigenetics and healthy aging programs.
Brown University (US) — Center on the Biology of Aging; unifies aging biology across labs; senescence and neurodegeneration.
Buck Institute for Research on Aging (US) — Independent institute focused solely on the biology of aging.
Calico Life Sciences (Alphabet) — Fundamental biology of aging and drug discovery; multi-year collaboration with the Broad Institute.
CUHK Jockey Club Institute of Ageing (Hong Kong) — Healthy aging research and policy translation.
Harvard Medical School (US) — Paul F. Glenn Center for Biology of Aging Research; genetics and epigenetics of aging; therapeutic interventions.
Max Planck Institute for Biology of Ageing (Germany) — Basic mechanisms of aging; part of the Cologne life-science cluster.
Mayo Clinic (US) — Robert & Arlene Kogod Center on Aging; geroscience across clinics and labs.
MIT AgeLab (US) — Aging, behavior, caregiving, mobility, and longevity planning.
Newcastle University (UK) — Aging & Health / NIHR BRC; the only UK BRC dedicated to aging and multiple long-term conditions.
Northwestern University (US) — Potocsnak Longevity Institute & Human Longevity Lab; measures biological age and conducts human trials of interventions.
NUS Medicine (Singapore) — Healthy Longevity; research themes to add healthy years of life.
NUS/NUHS Singapore — Center for Healthy Longevity; biomarkers and clinical testing of aging-slowing interventions.
Okinawa Research Center for Longevity Science (Japan) — Centenarian studies and determinants of exceptional longevity.
Oxford Institute of Population Ageing (UK) — Demographic and health implications of population ageing; global networks.
Stanford Center on Longevity (US) — Multi-disciplinary longevity initiatives (“New Map of Life”).
UCL Institute of Healthy Ageing (UK) — Cellular mechanisms of ageing; model-organism to human biology.
University of Southern California (USC) Leonard Davis School (US) — Longevity Institute; translational aging research and geroscience leadership.
University of Washington (US) — Healthy Aging & Longevity Research Institute / HALO; home to a Nathan Shock Center; basic mechanisms of aging.
Yale University (US) — Center for Research on Aging (Y-Age) & Program on Aging; molecular aging and Pepper Center clinical research.

Private Biotech & Corporate Research:

Aeovian Therapeutics — Selective mTORC1 inhibitors for age-related diseases.
Altos Labs — Cell reprogramming/rejuvenation biotech financed by Jeff Bezos, with sites in the US, UK, and Japan.
BioAge Labs — Uses longitudinal human cohorts + proteomics/ML to find aging pathways; clinical pipeline.
Cambrian Biopharma — “Company-builder” developing geroscience drugs across multiple subsidiaries.
Elevian — Regenerative therapeutics inspired by GDF11 biology; cardiometabolic and neurology focus.
Gordian Biotechnology — In-vivo pooled screens in aged animals to discover therapeutics.
Insilico Medicine — AI-driven target ID and small-molecule discovery; aging indications among focus areas.
Juvenescence — Longevity biotech investment/development platform with multiple programs.
Life Biosciences — Dr. David Sinclair’s company focusing on epigenetic reprogramming.
Loyal — Longevity drugs for companion dogs; large-breed healthspan focus.
NewLimit — Epigenetic reprogramming and cell-state control for rejuvenation.
Rejuvenate Biomed — AI-driven drug discovery platform with a pipeline of combination drugs targeting neuromuscular, musculoskeletal, metabolic, cardiovascular, nephrological, and neurodegenerative diseases.
Centenara Labs (previously “Rejuveron Life Sciences”) — Company-builder backing therapeutics for healthy aging.
Retro Biosciences — Cellular rejuvenation (reprogramming, autophagy, plasma-related programs).
Rubedo Life Sciences — Targeted small molecules (e.g., senolytics) via Onco-FAP-like chemistries.
Turn Biotechnologies (Turn.Bio) — mRNA-enabled epigenetic reprogramming (ERA™) for tissue rejuvenation.

Government, National Centers & Networks:

Nathan Shock Centers (US) — NIA-funded centers of excellence in basic biology of aging (e.g., Einstein; UW/HALO).
US National Institute on Aging (NIA) — Intramural Research Program; seven core labs and Translational Gerontology Branch.

Societies, Alliances & Professional Bodies:

Alliance for Aging Research (US) — Policy and education advocacy for aging research.
American Aging Association (AGE) (US) — Biogerontology society.
American Federation for Aging Research (AFAR) (US) — Funds aging-biology research and training.
European Geriatric Medicine Society (EuGMS) — Pan-European clinical and academic society in geriatrics.
International Longevity Alliance (Global) — Umbrella advocacy network for longevity science and policy.

Philanthropy, Funders & Prizes:

Glenn Foundation for Medical Research / Glenn Centers — Multi-site basic aging-biology centers (e.g., Harvard).
Hevolution Foundation (Global/Saudi) — Grants, investments, HF-GRO program; backer of XPRIZE Healthspan.
Lifespan Research Institute (LEAF + SENS merger) — Research, education, investor network; publishes Rejuvenation Roadmap.
Longevity Escape Velocity Foundation (LEV Foundation) — Funds and executes rejuvenation research; hosts LEV events.
Methuselah Foundation — Early-stage funding and prizes for rejuvenation biotech and tissue engineering.

SOURCES:

Science article on studies by Life Biosciences and Retro Labs on applying OSK factors to elderly mice.

https://www.science.org/content/article/two-research-teams-reverse-signs-aging-mice

Semaglutide and Cardiovascular Outcomes in Obesity (SELECT trial, NEJM) — In more than 17,000 adults with obesity but no diabetes, weekly semaglutide lowered the risk of heart attack, stroke, or cardiovascular death by 20 – 37% within months of starting therapy.

https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

Associations of Semaglutide with Alzheimer’s Disease-Related Dementia (Journal of Alzheimer’s Disease) — A real-world analysis of 1.7 million patient records showing that people with type 2 diabetes taking semaglutide were 40 – 67% less likely to develop dementia than those on other diabetes drugs.

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14313

Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis (NEJM) — A Phase 3 trial demonstrating that tirzepatide, a dual GLP-1/GIP drug, markedly reduced liver fat, inflammation, and scarring in patients with advanced fatty-liver disease (MASH).

https://www.nejm.org/doi/full/10.1056/NEJMoa2401943

Phase 3 Trial of Semaglutide in MASH (ESSENCE trial, NEJM / PubMed) — Confirmed that semaglutide significantly improved liver health and reduced fibrosis, leading to its FDA approval for treating moderate-to-advanced MASH.

https://pubmed.ncbi.nlm.nih.gov/40305708/

JAMA Paper on results of a large study in Finland on the effects of regular sauna baths on cardiovascular and brain health.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2130724

ZeroHedge Article on “Paper Mills”, factories churning out fake scientific papers.

https://www.zerohedge.com/political/paper-chase-global-industry-fuels-scientific-fraud-us

Regarding Jeff Bezos funding of Altos Labs:

https://www.thetimes.com/article/6e8f2d55-80c6-481d-9578-3804432bf6a0

Research in Nature on possible cure for Alzheimer’s. https://www.nature.com/articles/s41392-025-02426-1

Meta analysis on psyllium husk.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11155034/

Resveratrol does not mimic positive effects of caloric restriction (and may cause brain damage later in life.

https://www.nature.com/articles/s42003-024-07387-9