Can we actually reverse human aging?

XPRIZE has put $101 million behind that question, challenging scientists to demonstrate something far more meaningful than a younger biological-age score: measurable improvements in muscle function, cognition, and immune resilience.

In the first episode of The Rabbit Hole, I dig into the science behind the XPRIZE longevity competition and some of the approaches now being tested—from repurposed drugs and multimodal protocols to stem cells, gene therapy, extracellular vesicles derived from plants, and cellular reprogramming.

We explore why XPRIZE is shifting the conversation from biomarkers to actual human function, what the latest human data tells us, and the critical difference between longevity therapies you can access today and those that have actually been proven to work.

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AI Disclosure: Portions of this episode feature AI-generated voices used to turn my original reporting and research into a conversational format. The underlying research, sources, editorial direction, and final review are my own.

This podcast is for informational and educational purposes only and is not intended as medical advice. Always consult a qualified healthcare provider.

Welcome to the Optimized Woman, where we explore the future of longevity. I'm your host, Orshi McNaughton, and I bring you conversations with the pioneers advancing human performance and health optimization.

And I share what I discover as I explore this rapidly evolving field myself. Let's get into it. So what if you're only a few years away from actually being able to reverse human aging?

XPRIZE puts big prize money behind some of the world's hardest problems. To accelerate breakthroughs that might otherwise take decades.

A few years ago, they launched a 101 million dollar competition focused on human longevity out of 799 teams that entered the competition. Now the field is finally narrowing. And last week, 10 teams were selected for the next round of funding.

And some of what they are testing makes it feels like we are finally stepping into the future. So when I started looking into the research and some of the companies that are behind the science, I went down a serious rabbit hole.

And that gave me an idea for something new on the podcast. I recently started publishing my writing on Substack, where I have the opportunity to go much deeper into the longevity stories that I'm researching.

But rather than just recapping the articles so you hear on the podcast, I wanted to turn my writing into something more conversational and, and interesting to listen to. So I'm calling these shorter episodes the rabbit Hole. And I couldn't think of a better story to start with. So let's get into it.

You heard ori. I mean, $101 million. Yeah, that is. Well, it's just an astronomical number.

It really is. It's massive.

And it completely validates the electricity we're feeling right now around this X Prize healthspan competition. We are literally watching a global race to develop therapeutics that don't just, you know, slow down your aging.

They actually restore your muscle, your cognitive and your immune function by 10 to 20 years. And the kicker here, they have to do this in adults age 50 to 90. And after just one year of treatment,.

It is an incredibly ambitious target. And you know, as or she pointed out, what makes this so significant isn't just that massive prize money.

It's the absolute uncompromising standard of evidence that XPRIZE is demanding from these teams. Yeah, exactly like we are finally moving from this theme theoretical space of what if into really rigorous, randomized, controlled human trials.

So our mission for this deep dive is to basically take Orchi's reporting, dig into the actual XPRIZE data, and see exactly where longevity medicine is heading right now. A wildly optimistic future, but one that is actually tethered to some very strict scientific reality. Okay, let's unpack this.

To really understand why this competition is a watershed moment, we first have to look at how XPRIZE actually defines success, because it is a massive departure from what the current consumer wellness industry is pushing.

Oh, for sure. If you look at the longevity market today, I mean, it is completely saturated with what we call biological age tests.

Right.

You take a cheek swab or a blood test, and an algorithm looks at your DNA methylation.

Let's pause there for a second, because we hear that term a lot. What is DNA methylation like, practically speaking?

Right. So think of DNA methylation as these microscopic chemical tags sitting on top of your DNA.

Your.

You're born with a fixed genetic code, obviously, but as you age or experience stress or even change your diet, these chemical tags attach or detach, and that essentially turns certain genes on or off. So epigenetic clocks Read these tags to estimate how your cells are aging. The algorithm spits out a number and basically tells you, congratulations.

Chronologically, you're 55, but biologically, you're 45.

Which is incredibly satisfying for the consumer. Right. I mean, people are spending $300 online right now for these tests because everyone loves getting that validating result.

Oh, it feels fantastic. But, well, biologically speaking, those tests are just proxies. They are indirect measurements.

Right.

A biomarker or a favorable methylation pattern might suggest your cells are functioning well at a microscopic level. Sure, but it doesn't actually prove that your body can perform the way it did a decade ago.

And that's where the X prize completely changes the game.

Exactly. They are demanding proof of functional restoration. It's not about a younger number on a lab report.

It's about whether an older person can actually walk further or generate more lower body power.

Yeah, or process complex information faster.

Right. And demonstrate genuine immune resilience out in the real world.

I always think of it like an analogy.

It's the difference between rolling back the mileage on a car's odometer versus actually rebuilding the engine so it drives the way it did 10 years ago.

That is the perfect analogy.

You can change the number on the dashboard all you want, but if the transmission still slips when you hit the gas, you haven't actually fixed the car.

Exactly. You haven't fixed the car. And the threshold XPRIZE has set for that rebuilt engine is remarkably high.

They aren't just looking for, you know, a slight improvement in a group average.

Right. Averages can hide a lot.

They can be Deeply misleading.

A few people responding incredibly well to a drug can pull the mathematical average up, even if the vast majority of patients see absolutely zero benefit. So, to prevent that, XPRIZE uses rigorous customized thresholds.

Every single individual participant has a specific functional target they have to hit based on their own personal baseline.

Wow.

And if I'm reading the rules correctly, a team only wins if their treatment group exceeds the control group by at least 20 percentage points across all three of those domains. Muscle, cognition and immune function. All three?

Like, you can't just invent a drug that makes someone physically stronger but leaves their memory declining.

Right. That holistic requirement forces the industry to prove its claims in a way we've honestly never seen before.

But it also raises these fascinating questions about the biological domains themselves. Yeah, and Orshi brought up a really crucial point regarding women's health, specifically focusing on ovarian aging.

She did? She pointed out that ovarian aging profoundly affects endocrine signaling across the entire body.

I mean, it impacts muscle mass, brain function, metabolism, and the immune system.

Which leads to a massive structural question for the longevity field. Like, should ovarian function be considered its own distinct fourth domain of aging?

Oh, interesting.

Or is it actually a master upstream controller that dictates the decline of the other three domains we are measuring?

Right, because if a therapy aims to reverse functional Age by 20 years in a postmenopausal woman, can it truly achieve that without addressing the systemic endocrine shifts that are triggered by the loss of ovarian function?

Exactly. It just highlights how complex and deeply interconnected the human aging process really is.

So if the goal is completely rebuilding that human engine, how are the world's best scientists actually trying to pull it off? Let's look at the strategies revealed in the Xtrized Innovation Landscape Report.

Yeah, let's look at the data looking.

At the broader field. Of the 61 finals applicants, 62% propose what are called multimodal approaches.

Right, and multimodal simply means they are pulling several biological levers at once, rather than relying on a single pill or a single intervention. If you dig into the proposals, the most common foundational element is structured exercise. It actually appears in 36% of the applications.

So they're taking that baseline of exercise and layering it with a stack of repurposed drugs. We're seeing the usual suspects from the longevity world. Let's break down why they use them. They're using metformin and rapamycin, which basically.

Trick the body into cellular cleanup mode.

Rapamycin in particular inhibits a Specific protein pathway triggering a process called autophag, where your cells actively clear out their own damaged components.

Wow.

And then you add GLP1 agonists to fix metabolic signaling and manage weight plus NAD plus precursors to boost the actual energy production inside the mitochondria of the cells.

Exactly.

You layer all of that with various nutraceuticals and dietary changes. A prime example of this in the competition is a team called AgelessRx.

Yes, AgelessRVs is a great example. They're running a 14 month protocol that involves 12 different components.

12?

12.

It combines that structured resistance training with telehealth coaching and multiple prescription interventions, all carefully tracked and managed simultaneously.

I mean, the logic makes total sense to me. As the founder of Functional diagnostic Nutrition, Reed Davis, puts it, chronic dysfunction is metabolic chaos.

Aging isn't just one neat little broken gear.

No, not at all.

It is a system wide breakdown. So you hit it with everything you've got. But as Orshi highlighted, this creates a massive attribution problem for science.

Yeah, you've hit on the core dilemma in longevity research right there. Complexity versus isolation. Because if you change 10 variables at once, you might achieve an incredible outcome for the patient.

But you learn very little about which specific intervention actually deserves the credit.

Okay, wait, let me stop you there. I want to push back on this.

Sure.

If I take 12 pills, completely overhaul my diet, run on a treadmill three times a week, and I actually feel 10 years younger, isn't that just a massive win? Why does the scientific community care which specific pill did the heavy lifting?

It's a fair question.

Because if aging really is metabolic chaos, why are the top extra eyes judges suddenly rewarding single targeted therapies?

When we look at the 10 milestone two awardees, the teams that just won a million dollars each, seven out of those 10 teams built their entries around a single therapy, a monotherapy. Why reward a single bullet for a systemic war?

It all comes down to scaling and patient burden.

Ah.

A daily 12 step protocol requires sustained behavioral change. You're asking a patient to take multiple prescriptions, alter their diet, engage in resistance training, and meet with health coaches.

Yeah, that is a lot.

The friction there is enormous. And from a public health perspective, honestly, most people simply won't do it.

But a single targeted biological intervention, say a one time gene therapy, or an infrequent stem cell infusion, well, that has a remarkably low patient burden.

So it's about what the average person will actually stick to in the real world, combined with what the FDA can actually regulate.

Precisely. If you can achieve systemic rejuvenation through a single upstream biological target.

The intervention is infinitely more scalable, testable, and accessible. Proving that a single therapy can restore muscle, cognition and immune function all at once is scientifically daunting.

I feel like. Yeah. So there is a South Korean team run by PRG Science and Technology.

They are testing a small molecule called progeranin, and their target is a protein called progerin.

Right.

So progerin is the abnormal, toxic protein responsible for Hutchinson Gilford progeria syndrome.

Okay.

This is a devastating, incredibly rare genetic disorder where children experience dramatically accelerated aging. They often pass away from cardiovascular disease in their early teens.

Here's where it gets really interesting. Are we seriously saying that studying a rare, tragic pediatric disease might hold the master key to unlocking normal adult aging?

That is the bold hypothesis this team is testing.

Wow.

Their research suggests that this toxic progerane protein doesn't just exist in children with this rare syndrome. It also slowly accumulates in the tissues of normally aging adults. In our arteries, our muscles, our adipose tissue. Yeah.

It acts like cellular trash that our bodies simply forget how to clear out over time.

So their drug, progernin is basically a targeted search and destroy chemical designed to hunt down this specific protein and degrade it.

Exactly.

One pill, one target. If it works, it clears out the cellular trash, causing the tissue to age, which makes the potential payoff massive.

If that mechanism translates to human adults, the treatment burden is basically zero.

It is. But as Orshi noted, relying on a single molecule to fix systemic aging is an enormous scientific if.

Right. Okay, so progeridin acts like a cellular garbage disposal to clear out the toxic junk.

But once the trash is gone, how do you actually rebuild the tissue that was already damaged?

And that brings us to what the team Longiveron is doing with cell therapy.

Yes, they are bringing some of the most concrete human data to the table. They have an investigational therapy called loramestrosil.

Right. Which is a mesenchymal stem cell product. And when we say stem cells, people often think of the controversies from 20 years ago.

Oh, for sure.

But these are different. Mesenchymal stem cells are essentially the body's natural repair contractors.

They are multipotent cells derived from the bone marrow of young, healthy adult donors.

Okay, so how do they work?

The idea is that these young cells naturally seek out inflammation.

When infused into an older patient, they secrete proteins and exosomes that act on the older, damaged tissues, orchestrating a massive repair response.

And they aren't just working. In theory, or in mice.

They actually published a randomized placebo controlled phase 2b trial in the journal Cell Stem Cell, focusing on frail older adults. The primary endpoint was a six minute walk test, which is exactly the kind of functional real world metric XPI demands.

And the results were striking. At nine months, the patients who received the young stem cells could walk 63.4 meters further than the placebo group in that six minute window.

Wait, 63 meters? That's essentially the length of an entire ice hockey rink. It's huge for a frail adult who might struggle just to get to the mailbox and back.

We aren't just talking about a statistical bump on a chart. So if stem cells are the repair contractors, how do we get the body to do this without needing an IV drip of someone else's cells?

Right, let's look at Mini Circle. Or she is actually doing a self experiment with their follistatin gene therapy right now.

But for the X prize, Mini Circle is using a non viral plasmid gene therapy that combines follistatin and Clotho.

Let's break down how that actually works inside the body.

Instead of giving a patient a pill every day or repeatedly injecting a protein, Mini Circle is delivering temporary genetic instructions directly into the patient's existing cells. They use a circular piece of DNA called a plasmid.

Wait, so it's not a virus? Because usually when we hear about gene therapy, it involves a modified virus delivering the genetic payload which, you know, carries a lot of risk.

Yeah, totally. Think of the plasmid as a biological flash drive you plug directly into the cell.

This flash drive tells the patient's own cells to manufacture two specific things. First, Follistatin, which actively promotes muscle growth and combats frailty.

Okay.

And second, Clotho, which is a protein heavily associated with longevity, kidney protection and brain health.

It's a one time administration that is the ultimate low burden model.

Oh, absolutely. And speaking of high potential and high uncertainty, we have to talk about the teams utilizing extracellular vesicles or EVs.

Yes, extracellular vesicles are fascinating. Think of them as microscopic biological shipping bubbles that cells naturally release to communicate with each other.

Right.

They carry proteins, lipids and genetic information from one part of the body to another. Gotalab out of Japan is engineering these shipping bubbles to deliver regenerative cargo directly into aging tissues.

Which is brilliant.

But the team that really blew my mind is called Time Traveler.

They screened over 140 different edible plants to find the best anti inflammatory properties and their therapy Uses extracellular vesicles derived from. Wait for it. Parsley.

I know it sounds like pure science fiction, right? But plant derived EVs are actually a very active and legitimate area of research.

Scientists are exploring if the biological shipping bubbles from a plant can effectively cross over, survive the human digestive tract or bloodstream, and deliver rejuvenating anti inflammatory information to human cells.

Wait, pause.

Parsley.

Like the garnish sitting next to my pasta?

Yes, exactly. That parsley.

You're telling me scientists are trying to use plant shipping bubbles to fundamentally talk to human biology? That is wild.

It's incredible science, but okay.

Seeing a hockey rink's worth of walking improvement or gene therapies or parsley bubbles in action is thrilling.

We need to do a reality check here.

Yeah, we do.

When does this future actually arrive for you? The listener? Because Orshi highlights a massive gap between what is available to buy today and what is actually proven to work.

It is the single most critical distinction consumers need to make in the longevity space today. Availability and evidence are moving on completely different timelines.

Definitely you can go online right now and access pieces of the longevity frontier.

AgelessRx operates a massive telehealth platform where you can get prescriptions for things like metformin or NAD plus precursors shipped straight to your door.

Right.

Mini Circle's Follistatin therapy is currently available through through international clinics outside the U.S. but longeviron stem cell therapy, which actually has published randomized human data, is still strictly investigational in the United States. And this is where consumers need to be incredibly cautious. Being purchasable is not the same as being proven.

That is such a good point.

You can buy a lot of things today, but nobody is definitively proven that their intervention can restore 10 years of human function across multiple bodily systems simultaneously.

And that's why the xdri's timeline is so important. They aren't hand handing out the $81 million grand prize tomorrow.

Wow.

They have to generate the hard, undeniable clinical evidence needed to literally redefine human aging before they see a dime of that grand prize.

But there is a massive wave of optimism in the data Xdrise just released. The field is maturing incredibly fast.

When the competition started in the qualifying rounds, only 46.9% of the teams had actual human clinical evidence. Most were just showing lab results in petri dishes or testing on mice. Yeah, but by the finals, that number jumped to 93.4%.

That jump is staggering. It means we are rapidly moving out of the laboratory and into real human beings.

Yeah.

And if we connect this to the bigger picture, even if you cannot Access a proven FDA approved 10 year age reversal pill today, the XBIZ has forever changed the standard.

They've drawn a permanent line in the sand.

From now on, when a wellness clinic or a supplement company claims to reverse aging, the consumer should demand functional proof.

Exactly.

Don't show me a proxy biomarker. Show me the data where a patient walked further thought clearer and fought off illness better.

The standard we should demand from longevity claims going forward has been permanently elevated.

Bringing this all together. The future of healthy aging isn't about chasing a younger number on a blood test.

It is highly functional, it is deeply rigorous, and it is driven by clinical trials that measure how we actually live, move and think in the real world.

It's a fundamental shift from merely extending the lifespan to maximizing the health span.

And as these clinical trials gather momentum, the implications are just staggering. Which brings to mind a recent development outside of the X prize, but completely in the same vein of this functional revolution.

Life Biosciences, a company co founded by Harvard geneticist David Sinclair, recently dosed its first human in a clinical trial for a therapy called ER100.

This is a fascinating trial.

They are using controlled expression of three specific Yamanaka factors, Oct4, Sox2 and KLF4, to target damaged retinal ganglion cells in the human eye.

And their goal isn't just to stop the damage from getting worse. They are trying to reset the epigenetic patterns of those old damaged retinal cells, pushing them back to a younger state.

Right.

They're literally trying to tell an old cell to forget its age and function like a young one again.

It is the definition of cellular reprogramming happening right now inside human trials.

So I want to leave you with this.

If we are standing on the precipice of a world where we can tell ourselves to forget their age, where a rebuilt biological engine isn't just a metaphor, but a medical reality, how will that fundamentally change the way you plan your life, your career, and your family? It's a fascinating future to prepare for. To help us process what all this means for us right now, let's send it back to Orshi.

We are only a few years from having much better human data on whether some of these therapies can actually change the trajectory of aging. And for me, this is personal. I watched my dad slowly decline over about 20 years, from his mid-60s into his 80s.

He became frail, hunched over, he was shuffling his feet when he was walking, eventually had solo energy that he was falling asleep constantly. He struggled to stay mentally engaged and even to regulate emotionally. Watching that slow deterioration was really heartbreaking.

And I remember thinking, I don't want to age this way myself. That's really where my obsession with health optimization and the longevity space comes from. I don't know about you, but I want to age differently.

I believe that we can change the trajectory of how we age because I want to stay strong, sharp, independent and fully engaged with life all the way to the end.

And I'm going to keep following the XPRIZE closely and I'm planning interviews with the finalist team so you can hear directly from the people building these amazing technologies. The full article all my sources are on substack where you can read or listen for free.

And if you like this first rabbit hole, let me know and subscribe to the Optimized Woman so you don't miss the next one. You'll find this episode's show notes, my writing and links to everything I'm [email protected] Thanks for being here.

I appreciate you more than you know. This podcast is for informational and educational purposes only, and it is not intended as medical advice.

Always consult a qualified healthcare provider.