In this week’s newsletter

✅ Introduction to Episode 8 with Yuri Deigin, CEO of YouthBio Therapeutics. ✅ The incredible promise of partial reprogramming. ✅ A list of companies trying to turn back time.  ✅ Taking a stance against those who promote healthspan over lifespan. ✅ Yuri’s personal quest to defeat Alzheimer’s. ✅ Detailed show notes.

”I'd love to have therapies against Alzheimer's be ready in time for my parents to use as well”

Yuri Deigin doesn't just tiptoe around the idea of extending human life; he openly and unapologetically talks about actually solving aging. He doesn't hide behind healthspan euphemisms or shy away from the ambitious goals that this field embodies.

As the CEO of YouthBio Therapeutics, his candidness is hard to overstate. In an industry where many leaders are overly cautious with their words, Yuri's straightforward approach signals a shift in how we discuss and tackle the challenges of aging.

Yet this is only the second most important aspect of Yuri’s work. At the top of the list is the fact that YouthBio is actively working on actually solving the problem. Their primary aim is to prevent Alzheimer's disease through partial reprogramming and, in the long run, it might even be possible to reverse the disease.

What makes our conversation with Yuri even more compelling is his personal connection to the mission. He's courageously open about his genetic predisposition to Alzheimer's - a revelation that adds a profound layer of urgency and authenticity to his work.

In this episode, you'll get a crash course in epigenetics and gain a deeper understanding of how partial reprogramming works, the promises it brings, and the challenges that remain before we can bring this therapy to humans. Of course, you can also take a look at my deep dive into the topic (which, by the way, also features Yuri).

Is partial reprogramming the fountain of youth humanity has dreamed of for millennia? We can't say for sure yet, but it is certainly the closest we've come thus far.

You can watch the episode below - and we’d be very happy if you subscribe to our Youtube channel! LEVITY is also available wherever you listen to podcasts.

A detailed overview of the episode

Yuri's background

• Drug developer for nearly 15 years.

• Became interested in aging research around 2011-2012.

• Influenced by Peter Fedichev and Mikhail Batin.

• Key realization: Age-related diseases are consequences of the aging process itself.

• Quote: ”We're just kind of playing whack-a-mole with the consequences of aging, whereas if we really want to eradicate all these diseases and prevent all these diseases from happening, the most efficient way is to go after the kind of the root cause, the cave of the moles where they all live and breed, which is the aging process”.

Key concepts

Epigenetics and aging:

• Epigenetics: Control of gene expression ”above” genetics.

• Importance in multicellular organisms with different cell types.

• Yuri developed the ”strong epigenetic theory of aging”.

  • Believes epigenetic changes driving aging are programmed.

• Contrasts with what Yuri’s sees as David Sinclair's ”weak epigenetic theory of aging”. (Sinclair himself calls it ”the information theory of aging”.

  • Sinclair, according to Yuri, views epigenetic changes as consequences of stochastic processes like DNA damage.

• Quote: ”What begins as a developmental program then continues as an aging program, and this aging program, as is the developmental program, is carried out by epigenetics”.

Aging Clocks:

• Epigenetic clocks measure biological age based on DNA methylation patterns.

• Horvath clock: Uses 353 CpG sites to estimate age.

• Panmammalian clock: Works across multiple mammalian species.

  • Developed by Steve Horvath.

  • Tracks aging trajectory across ~300 mammalian species.

• First 10% of lifespan spent on development (exponential pace).

• Remaining 90% shows linear progression.

• Quote: ”And this panmammalian clock can be used to accurately predict age or get the age of the cells in a mouse and a human.”

  

  Steve Horvath.

Yamanaka Factors and Cellular Reprogramming:

• Shinya Yamanaka won Nobel Prize in 2012 for discovery of induced pluripotent stem cells.

• Four transcription factors (OSKM: Oct4, Sox2, Klf4, c-Myc) can reprogram adult cells to embryonic-like state.

• Challenged the Waddington landscape dogma of unidirectional cellular differentiation.

• Full reprogramming resets cellular age but loses cell identity.

• Side effect: Reprogrammed cells show physiological rejuvenation.

• Quote: ”And what then was noticed by our field, the longevity field or aging research field, was a very nice side effect of this process is that the cells that get reprogrammed are also rejuvenated, physiologically rejuvenated, and all the cellular hallmarks of aging that you observe in the starting cell are gone”.

Partial reprogramming research

• 2013: Manuel Serrano’s group’s first attempt with continuous expression led to mouse deaths and teratomas.

• 2016: Ocampo et al. (Belmonte lab) showed successful partial reprogramming in mice.

  • Used transgenic mice with inducible Yamanaka factors.

  • 2 days on, 5 days off cycling for expression.

  • Observed 50% lifespan extension in progeria mouse model.

• Quote: ”And what happened was that that actually worked, that was both safe and it was therapeutically effective in that the mice lived longer.”

Delivery methods for partial reprogramming

• mRNA delivery (e.g., Turn Bio - see video below).

  • Shortest-lived approach, degrades within days.

• Inducible gene expression systems (e.g., doxycycline-inducible).

  • Allows controlled activation of reprogramming factors.

• Viral vectors:

  • Lentivirus (Youth Bio): Larger cargo capacity.

  • AAV (David Sinclair's approach): Smaller, requires split vector system.

• Quote: ”And so the way we package it, we use a lentiviral system because you need a lot of space for the cargo. You've got to pack the four Yamanaka factors in your cassette and you've got to pack this inducible, tetracycline-inducible cassette also in your therapeutic vector.”

Therapeutic applications

• Lifespan extension:

  • Ocampo et al. (2016): 50% increase in progeria mouse model.

  • Rejuvenate Bio: 7.5% increase in wild-type mice (124 weeks old).

  • Altos Labs: Claimed 25% increase in average lifespan (unpublished).

• Vision restoration (David Sinclair's lab):

  • Reversal of vision loss in mouse models of glaucoma and NAION (non-arteritic anterior ischemic optic neuropathy).

• Alzheimer's disease prevention (YouthBio, Altos Labs).

• Quote: ”We really want to test this in humans, get to a clinical trial where we can test where the partial reprogramming can prevent the onset of Alzheimer's symptoms, or at least slow it down. And if we can reverse it, that would be the holy grail”.

Companies in the field

YouthBio (Yuri Deigin's company):

• Founded in 2017 as Youthereum Genetics.

• Focus on tissue-specific partial reprogramming.

• Primary target: Brain (Alzheimer's disease).

• Uses lentiviral vectors with inducible OSKM expression.

• Observed prevention of Alzheimer's symptoms in mouse models.

• Quote: ”We plan to start a fundraise in the next few weeks to get this funding that will allow us to get there [to clinical trials].”

Turn Bio:

• Founded in 2018 by Vittorio Sebastiano and Jay Sarkar (Stanford).

• Uses mRNA delivery of six reprogramming factors.

• Targeting skin and ex vivo T cell rejuvenation.

Life Biosciences:

• Uses three Yamanaka factors (OSK) delivered via AAV.

• Targeting eye indications, planning clinical trial in 2024 for NAION.

• Demonstrated vision restoration in mouse and non-human primate models.

Rejuvenate Bio:

• Founded by Noah Davidson (from Sinclair and Church labs at Harvard).

• Reported lifespan extension in wild-type mice using OSK factors.

• 109% increase in remaining lifespan for 124-week-old mice (equivalent to 80-year-old humans).

Altos Labs:

• Well-funded ($3 billion) startup.

• Reported 25% lifespan extension in mice (unpublished).

• Exploring partial reprogramming for kidney transplants.

• Demonstrated prevention of Alzheimer's symptoms in mouse models.

Challenges and future directions

Safety concerns:

• Avoiding problematic tissues (e.g., liver, small intestine).

  • Ocampo's 2023 publication showed these organs cause most problems during reprogramming.

• Controlling duration of factor expression.

• Quote: ”If you avoid the liver and intestine, all mice survive for 10 days of consecutive expression of these factors.”

Delivery and targeting:

• Improving tissue-specific delivery.

• Developing cell type-specific promoters.

• Exploring different combinations of reprogramming factors for specific cell types.

Understanding mechanisms:

• Epigenetic memory and return to baseline after reprogramming.

• Decoupling aging-related and cell identity-related gene expression changes.

• Quote: ”It'll be really interesting to actually study the mechanisms responsible for this return to baseline and whether we can somehow decouple the mechanism of return to baseline of, like, the aging component of this baseline versus just the other gene expression”.

Clinical translation:

• Funding for IND-enabling studies.

• Designing appropriate clinical trials (prevention vs. reversal).

• Regulatory challenges (e.g., FDA approval for anti-aging therapies).

Philosophical aspects

Healthspan vs. Lifespan debate:

• Yuri argues against the artificial distinction.

• Criticizes the idea of extending healthspan without extending lifespan.

• Quote: ”Healthy people don't die. People die at 85 because they're very sick. If you're 85 and your health is that of a 20-year-old, you're not going to die”.

Societal attitudes towards aging research:

1. Yuri criticizes the reluctance to openly discuss extending lifespan.

2. Argues against the notion that death should be accepted as inevitable.

3. Quote: ”Having somehow be embarrassed that we're trying to eradicate aging and death is, I think, again, is ridiculous.”

Personal motivation

1. Yuri's grandmother passed away from Alzheimer's in 2011.

2. Yuri discovered he has two copies of the APOE4 allele, increasing his Alzheimer's risk.

3. Quote: ”And so I'm very cognizant of that, and just kind of on the lookout of how their cognition is progressing as they age. And definitely, I'd love to have therapies against Alzheimer's be ready in time for my parents to use as well.”

Additional scientific concepts

Epigenetic plasticity in nature:

• Indian jumping ant example: Worker ants can switch to breeder role, extending lifespan.

• Montane voles: Lifespan varies based on birth season, demonstrating epigenetic modulation.

Conclusion

• Partial reprogramming field is advancing rapidly.

• Multiple clinical trials expected before 2030.

• Potential for significant impact on age-related diseases and longevity.

• Quote: ”By 2030, yeah, I'm very optimistic that there'll be already some approved partial reprogramming therapies and we'll have future next generation therapies that are even safer, that are more targeted and potentially with different factors.”

Seeking impartial news? Meet 1440.

Every day, 3.5 million readers turn to 1440 for their factual news. We sift through 100+ sources to bring you a complete summary of politics, global events, business, and culture, all in a brief 5-minute email. Enjoy an impartial news experience.

Join for free today!