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Turn. Like in turn back time. Shift. From what was thought as the inevitable to now being viewed as the reversible. Rejuvenate. Youth. And Altos is a Spanish word which means ”high” or ”heights”. Let’s interpret that as a symbol for the pushing of boundaries of human longevity.

Turn Bio, Shift Biosciences, Rejuvenate Bio, YouthBio Therapeutics and Altos Labs* have one thing in common. These biotech companies are all about the Hottest Thing in aging biology and longevity science right now: partial reprogramming of cells.

* The name Altos Labs is likely derived from Los Altos Hills above Palo Alto, where billionaire Yuri Milner’s ”super-mansion” is located. A meeting at Milner’s house led to the formation of the company.

Partial reprogramming. That sounds kinda dull, right? But take another look at the names of these companies. They suggest that this technology might indeed be the closest thing we have to an actual fountain of youth.

”If we're able to reverse […] the aging process, which I think partial reprogramming, like repeated partial reprogramming, can accomplish, then we can then even rejuvenate people and decrease their mortality risk”, Yuri Deigin, CEO of YouthBio Therapeutics, said in a recent talk. (You’ll hear much more from Yuri below!)

Our genome is essentially identical in all of our cells. Another molecular system, the epigenome, orchestrates which genes should be expressed in our approximately 200 different cell types. This is something to be thankful for. Just imagine the chaos if they didn't. Your skin cells trying to pump blood, your liver cells attempting to form memories, and your brain cells secreting digestive enzymes. Quite the mess.

Then again, as this system becomes increasingly overwhelmed with time, it can no longer function optimally. Genes that should be activated or upregulated might instead be deactivated or downregulated, and vice versa. Mayhem ensues. We call this aging.

But as Yuri Deigin points out, it appears possible to restore the epigenetic landscape and rejuvenate cells and tissues. In fact, the last few months have seen some dramatic advancements in this area.

Before I get to them though, just a few words about how this week’s newsletter is structured.

You'll discover:

Alright, on to the latest headlines!

✅ Life Biosciences are currently in preclinical stages and targeting optic neuropathies (more specifically NAION, or so-called ”eye stroke”, as well as glaucoma), with promising results in non-human primate models. Clinical trials are planned for 2025.

Here’s Sharon Rosenzweig-Lipson of Life Biosciences talking about the company’s rapid advances:

✅ Rick Klausner, Chief Scientist at Altos Labs, revealed that their reprogramming approach using Yamanaka factors in mice led to weight gain, rejuvenated skin, quick wound healing, and a 25% increase in average lifespan. The findings, based on experiments with around 1,000 mice (a huge number), are preliminary and unpublished. I wrote more about that here.

✅ Harvard scientist David Sinclair (one of the co-founders of Life Biosciences) was recently interviewed by Aspen Institute and said that his lab has been working on reversing hearing loss, ALS and rejuvenating skin, kidneys and liver in animal models. They’ve also been able ”to reverse aspects” of Alzheimer’s disease in mice.*

* It wasn’t immediately clear, however, if he was talking about the field in general, or only work from his lab.

✅ Scientists at Stanford demonstrated that partial reprogramming can increase or induce neurogenesis in old mice.

✅ YouthBio Therapeutics, led by CEO Yuri Deigin (check out my big interview with him below!), aims to translate the technology into potential therapies, particularly for neurodegenerative diseases like Alzheimer's. Their research, independently validated by another study, demonstrates promising results in mouse models, including reduced amyloid beta levels, lower brain plaque burden, and improved cognitive performance. By targeting specific brain regions and cell types, YouthBio's approach aims to rejuvenate neurons while maintaining their functionality. This research is done in collaboration with Alejandro Ocampo’s lab. As you’ll soon learn, Ocampo is one of the central figures in the partial reprogramming field.

”On our end at YouthBio, we’re hoping to see our partial reprogramming gene therapy for Alzheimer’s to get to the clinic by 2027”, Yuri Deigin wrote on X.

Sometimes, the answer becomes clear only when it is in hand. Until the 1960s, science believed that cell development was a one-way process: from the embryo's unspecialized stem cells to adult cells with highly specialized functions. However, there was a significant issue with this doctrine: if it had been entirely true, life as we know it would not have been possible.

A sperm and an egg are two types of gametes (reproductive cells). When they merge, something highly remarkable happens (beyond what transpires nine months later). In humans, the fertilized egg, or zygote, receives 23 chromosomes from the sperm cell and 23 chromosomes from the egg cell. Before their union, the sperm and egg contained the same genetic material (albeit only half the full set) as practically all other cells in the man's and woman's bodies, respectively. The difference between specialized cell types lies in the epigenetic regulation that controls which genes are active or inactive. In the zygote, this regulation is reset*. The zygote becomes what researchers call totipotent, meaning it has the potential to develop into all cell types. It's akin to Benjamin Button's lifelong rejuvenation happening in an instant.

* While the zygote immediately gains the potential to develop into all cell types, recent research suggests that the complete epigenetic rejuvenation is a gradual process. The epigenetic age of the cells continues to decrease for several days after fertilization, reaching a minimum around the time of gastrulation (a stage in the early embryonic development).

This ability to reset to the beginning of life is not exclusive to gametes. In the 1960s, British cell biologist John Gurdon conducted a now-legendary experiment in which he replaced the nucleus of an unfertilized frog egg cell with the nucleus from a mature intestinal cell taken from a tadpole. From this, a cloned frog developed.

When the first mammal was cloned from a specialized adult cell in 1996, it generated headlines all over the world. Dolly the sheep led many to hastily conclude that human cloning was imminent. While this remains a topic of science fiction, the cloning of other mammals has continued. In the EU, cloning livestock for milk and meat production is prohibited, but it is permitted for scientific research and efforts to save endangered species.

Gurdon's frogs and Dolly's days in the spotlight paved the way for the explosive development of modern stem cell research. ”Dolly the Sheep told me that nuclear reprogramming is possible even in mammalian cells and encouraged me to start my own project”, the Japanese professor Shinya Yamanaka has said.

It was, one must admit, quite a project.

In the early 2000s, Shinya Yamanaka studied pluripotent stem cells, which, unlike totipotent cells, cannot give rise to cells that form the placenta but can develop into almost any other cell type.

He aimed to identify the genes that keep these cells in their immature state. Armed with a collection of gene candidates, he introduced them into connective tissue cells from mice. After numerous experiments, he discovered that just four transcription factors* were sufficient to revert a connective tissue cell to a pluripotent state. Soon after, he demonstrated that the same technique worked with human cells. These four proteins are now known as Yamanaka factors and the technique is called induced pluripotent stem cells (iPS). In 2012, John Gurdon and Shinya Yamanaka were awarded the Nobel Prize ”for the discovery that mature cells can be reprogrammed to become pluripotent”. As the Nobel Assembly at the Karolinska Institute noted, ”textbooks have been rewritten.”

The discovery of Yamanaka factors came at an opportune time. Research involving stem cells derived from embryos faced strong ethical criticism and was banned in many countries. With the advent of iPS technology, these ethical barriers were lifted, and suddenly, the only limits were the laws of physics and the power of imagination.

* Transcription factors are proteins that help turn specific genes on or off by binding to nearby DNA. They play a key role in controlling which genes are active in a cell and thus determine the cell’s function. More on them later on.

Researchers use stem cells to deepen our understanding of how tissues and organs develop, their roles in various diseases, and how aging affects their functions. New drug candidates can be tested on tissues grown from stem cells.

Another significant promise lies in regenerative medicine, where adult cells are induced to pluripotency and then—with the help of various chemical signals—re-specialized into cells like neurons, liver cells, or heart muscle cells.

In 2014, Japanese researchers took skin cells from a 70-year-old woman and transformed them into retinal pigment epithelial cells via pluripotency, aiming to treat age-related macular degeneration. The woman's vision improved. At the end of August 2022, the National Eye Institute in the USA announced the treatment of the first patient in a clinical phase 1 trial, also targeting age-related macular degeneration. However, in this case, the cells were derived from blood, not skin.

Pluripotent cells have an extraordinary ability to give rise to all the cell types necessary to build a fully developed organism. However, this process requires a precise interplay with a chemical signaling system that guides the pluripotent cells. When this guidance fails, the cells lack direction and begin to specialize at random, leading to the formation of teratomas* - tumors that, quite fittingly, take their name from the Greek word for ”monstrous”. These tumors can contain a mix of tissues, such as hair, teeth, eyes, and even brain matter. Google it if you dare, but don't say I didn't warn you.

While the risk of developing a teratoma is low, when it does occur, these tumors typically form in the ovaries or testicles. However, when implanting re-specialized cells, it is crucial to ensure that no pluripotent “free-riders” - cells with the potential to form teratomas - are inadvertently included.

* ”The biggest risk associated with partial reprogramming is not teratoma formation, as is commonly misconceived, but rather the potential for organ failure in key organs”, notes Yuri Deigin in the interview below.

As cell biologists work to address this challenge, they are also developing stem cell treatments for neurological, autoimmune, and cardiovascular diseases. Meanwhile, researchers at Kyoto University in Japan are exploring the creation of artificial sex cells. The potential implications are staggering. For instance, a gay couple could potentially use cells from their own bodies to create both sperm and eggs through iPS technology. Delving into the ethical complexities, it is theoretically possible for a single person to produce both sex cells, resulting in what bioethicist Henry Greely has termed a ”unibaby” created by a ”uniparent”. Greely also cautions that, although unlikely, it might be possible to generate artificial sex cells from cells obtained from embryos or even from those we shed in daily life, such as those left on beer bottles or wine glasses. Celebrities, take note.

One critical characteristic of induced pluripotent stem cells is worth emphasizing: they become epigenetically young again. When re-specialized, these cells retain their youthful properties. For example, an old skin cell can be transformed into a young epithelial cell, or a frail liver cell can become a healthy heart muscle cell. Additionally, iPS cells not only resemble embryonic stem cells in their epigenetic landscape but also in other ways: their mitochondria are more vigorous, their telomeres are lengthened, and oxidative stress levels are reduced. Remarkably, this reprogramming process has even succeeded with senescent ”zombie” cells and cells from people over 100 years old.

Talking about senescent cells, one can revisit the contributions of the renowned biologist August Weissman from the late 19th century. Weissman, celebrated for his groundbreaking work in cell biology, proposed the theory of programmed cell death more than half a century before Leonard Hayflick, who recently passed away (more on that below), established a critical biological concept. This concept, now known as the Hayflick limit, refers to the maximum number of times a cell can divide before it becomes senescent, or ceases to divide.

But in an ironic twist of fate, Weissman was also the first to describe the jellyfish Turritopsis dohrnii, though he was unaware of its extraordinary abilities.*

Turritopsis dohrnii, often referred to as the ”immortal jellyfish” possesses a remarkable biological trait: not only can it avoid death, but it can also reverse its aging process, effectively becoming younger when necessary. As Weissman theorized about the inevitability of programmed cell death, the millimeter-sized jellyfish he discovered were defying this very principle, oscillating between states of youth and old age.

* Notably, Weissman was aware of the regenerative capabilities of plants and simple animals, such as hydroids, where almost any part can generate a new individual. However, the discovery of Turritopsis dohrnii's biological immortality happened in the 1990s.

Many have drawn parallels between the jellyfish’s ability to rejuvenate and the effects of Yamanaka factors on fully developed specialized cells. However, resetting cells in culture is one thing; achieving this in a living organism is another matter entirely.

Just as a ”fun” thought experiment: if all 37 trillion cells in a human body were made pluripotent in an instant, the cells might momentarily become young again, but the person would not survive the process. The person’s body would rapidly lose its recognizable human form and disintegrate into a puddle of undifferentiated cells and organic matter, as the structure is entirely dependent on the differentiation and organization of cells into tissues and organs.

Indeed, when researchers conducted similar experiments on mice, the outcomes were disastrous. The 2013 study, titled Reprogramming in vivo produces teratomas and iPS cells with totipotency features*, underscored the significant hurdles at the early stages of the field. Clearly, any result involving the production of teratomas is something to avoid at all costs.

Yuri Deigin remarked in a recent talk, ”I don't think anybody reading that paper's title would be very inspired”.

* The senior author of that paper is Manuel Serrano, a renowned figure in aging and cancer biology. He discovered the tumor suppressor gene p16, is one of the contributors to the Hallmarks of aging papers and has for the past few years continued his research at Altos Labs.

The disappointing results made researchers ponder the following: If the Yamanaka factors are the cells' time machine, can it make stops at several stations? Can a specialized cell retain all important functions while regaining its previous youthful vigor?

In the mid-2010s, Juan Carlos Izpisúa Belmonte - and his postdoc Alejandro Ocampo - then working at the Salk Institute for Biological Studies in California, decided to answer those questions.

Their lab provided progeria mice with the Yamanaka factors. But in sharp contrast to previous experiments, they were only activated when the mice received an antibiotic. This way, the researchers could control when the genes were turned on and off.

The weeks were divided into two periods: for two days, the factors were active, and for the rest of the time, they were at rest. This cyclical process gave researchers the answer they had hoped for. The time machine has several stops, and at the first stop - long before the pluripotent final destination - the cell has shaken off many of the characteristics that signify aging. The mice did not develop cancer; instead, they lived 50 percent longer* than the control group.

* Specifically, these mice lived 50% longer than mice that didn't have the Yamanaka factors and 33% longer than mice that had the genes but weren't treated with the drug to activate them.

This technique is, as you’ve probably guessed, known as partial reprogramming. In less than a decade, it has produced one remarkable breakthrough after another. Let’s take a look:

✅ Izpisúa Belmonte's lab subjected middle-aged but otherwise healthy mice to long-term treatment (equivalent to 15 years for a human) with partial reprogramming. The treatment had a rejuvenating effect on several organs, including skin and kidneys. Wound healing improved, as did several indicators of metabolic health. Even better: the researchers saw no trace of teratoma tumors.

✅ Manuel Serrano's lab in Barcelona reported that a single week-long treatment could yield rejuvenating results.

✅ Researchers in the UK announced that they had taken human skin cells from people in their 50s and turned back their epigenetic clock by 30 years. This made the cells produce more collagen and heal wounds faster. But the most fascinating aspect of the study was that the researchers continued past the time machine's first stop and went significantly closer to the final pluripotent destination. This made the rejuvenation effect more dramatic without the cells losing their identity.

✅ In a much-discussed experiment, researchers at David Sinclair's lab crushed the optic nerve in young mice, then activated the Yamanaka factors, and saw how the time machine brought the nerve cells back to a younger stage. After the study was published in Nature at the end of 2020, Sinclair's lab has also restored vision in older rodents.

✅ In another 2023 study by Sinclair’s lab they conducted an experiment to accelerate and then reverse aging in mice. By inducing DNA breaks in non-coding regions, they accelerated aging without causing mutations, leading to cellular and tissue deterioration. The researchers then used three of the Yamanaka factors to restore the mice's cells, tissues, and organs to a youthful state, effectively reversing parts of the aging process. According to Sinclair this supports the idea that aging is driven by epigenetic changes rather than genetic mutations.

All this progress has led Juan Carlos Izpisúa Belmonte to equate regenerative reprogramming with a life elixir (yes, I am not the only one making references to ancient alchemist ideas). He sees no reason to doubt that humans' maximum lifespan can be extended by at least 30 years. ”I am convinced”, he has said, “that within two decades we will have tools to not only treat symptoms but also to predict, prevent, and treat diseases thanks to cell-level rejuvenation”.

And David Sinclair paints a beautiful vision of the future in his book Lifespan.

”Gray hair would disappear. Wounds would heal faster. Wrinkles would fade. Organs would regenerate. You would think faster, hear higher-pitched sounds, and no longer need glasses to read a menu. Like Benjamin Button, you would feel 35 again. Then 30. Then 25.”

”But unlike Benjamin Button, that’s where you would stop. The prescription would be discontinued […] The Yamanaka factors would fall silent. Biologically, physically, and mentally, you would be a couple of decades younger, but you’d retain all your knowledge, wisdom and memories.”

David Sinclair's confidence in partial reprogramming is so profound that he has even proposed the information theory of aging. It posits that aging results from the gradual loss of epigenetic information, which, unlike stable genetic information, is susceptible to environmental influences, and that age reversal can be achieved by retrieving this information through epigenetic reprogramming.

While many of his peers remain skeptical of this theory, it’s worth noting that the skepticism surrounding partial reprogramming itself is beginning to wane as the perceived hurdles appear increasingly surmountable.

There’s been question marks around the efficacy in normal mice (as opposed to transgenic* models) and the problem where only a small percentage of cells are fully reprogrammed in vitro. And what about long-term safety should we need prolonged partial reprogramming? Not to mention the most important challenge of all: how to rejuvenate that most vital organ located behind our eyes?

* A genetically modified mouse that has had a foreign gene (transgene) deliberately inserted into its genome.

Recent research, however, is addressing these concerns head-on.

✅ A study from Rejuvenate Bio has demonstrated lifespan extension in normal (or ”extremely old”) wild-type mice using gene therapy-based partial reprogramming, challenging the idea that the benefits are limited to transgenic models.

✅ As for the in vitro reprogramming efficiency, researchers have uncovered an important distinction between full reprogramming and partial reprogramming effects.

While complete reversion to a pluripotent state may occur in only a small percentage of cells in vitro, the initial stages of the reprogramming process - which are associated with rejuvenation - appear to affect a much larger proportion of cells. This insight comes from studies showing that the early epigenetic changes and chromatin remodeling* induced by reprogramming factors occur in nearly all cells exposed to them, even if most cells don't progress to full pluripotency.

* Chromatin remodeling is the adjustment of DNA packaging in cells (also see the image below), making certain genes more accessible and kickstarting the process that can revert cells to a more youthful state.

It's these early changes that are believed to drive the rejuvenating effects. Thus, in the context of partial reprogramming, where the goal is rejuvenation rather than full cellular reprogramming, the ”efficiency” is potentially much higher than previously assumed.

✅ The safety of long-term partial reprogramming has also been put to the test. A 10-month study (with Izpisúa Belmonte as senior author) showed not only the safety of prolonged Yamanaka factor induction but also continued therapeutic benefits.

✅ Perhaps most excitingly (as we’ve seen) the holy grail of brain rejuvenation is no longer out of reach. Pioneering work by groups like YouthBio Therapeutics is showing promise in tackling age-related cognitive decline and neurodegenerative diseases such as Alzheimer's. By utilizing targeted delivery methods and cell-specific approaches, researchers are demonstrating improved cognitive function, reduced amyloid beta levels, and, to reiterate, increased neurogenesis in aging brains.

Partial reprogramming involves exposing cells to transcription factors, like the Yamanaka factors, but only for a short period or in a controlled way. The goal is not to fully revert the cells to a pluripotent state, but rather to ”reset” some of the epigenetic marks associated with aging, rejuvenating the cells without losing their original identity.

What are transcription/reprogramming factors?

Transcription factors are proteins that bind to specific DNA sequences and regulate the transcription of genes, which is the process of copying DNA into RNA. They are essential for turning genes on or off in response to various signals and/or upregulating (increasing) or downregulating (decreasing) the expression of specific genes.

This regulation is crucial for controlling cellular functions, development, and responses to environmental changes. Without transcription factors, cells wouldn’t know which genes to activate or suppress, making it impossible for them to perform their specific functions and maintain the proper organization and operation of the body (”the mess” I described above).

As we age, this finely tuned system will begin to malfunction, leading to the misregulation of genes. This contributes to various age-related issues, such as decreased cellular function and increased susceptibility to diseases.

What are Yamanaka factors and how do they differ from other transcription factors?

The Yamanaka factors are called Oct4, Sox2, Klf4, and c-Myc. They are transcription factors discovered by Shinya Yamanaka. While these four are special for their reprogramming ability, there are over 1,500 other transcription factors in the human genome, each regulating different cellular functions.

Here’s the reprogramming process, step-by-step:

1️⃣ Cells are exposed to the Yamanaka factors or other similar molecules designed to alter the epigenome. This can be done using various methods, such as viral vectors (tools to introduce DNA into cells), small molecules, or even specially designed RNA sequences.

2️⃣ Almost immediately, the introduction of these factors begins to alter the cell's epigenome. Specific chemical tags (like DNA methylation and histone modifications) on the DNA and histones are changed, leading to a remodeling of the chromatin structure. 👇🏼 This change affects which genes are turned on or off.

3️⃣ The exposure to reprogramming factors is carefully controlled - usually limited to a few days. This brief exposure triggers enough epigenetic changes to reverse some signs of aging (such as improved cell function and reduced cellular stress), but not long enough to erase the cell's identity.

4️⃣ After the reprogramming factors are removed, the cells retain their original identity (like skin cells remaining skin cells), but they now function more like younger cells. This might involve improved repair mechanisms, better stress responses, or more efficient energy use.

5️⃣ The rejuvenated state of the cells can be maintained for a period, though researchers are still studying how long these effects last and whether periodic reprogramming might be needed to maintain rejuvenation.

6️⃣ While Yamanaka factors are the most well-known, other methods are being explored. Some involve different combinations of proteins, small molecules that can alter the epigenome, or even CRISPR-based techniques to target specific genes or regions of the genome for modification.

How does partial reprogramming differ from other approaches to combat aging, and why do you believe it has more potential? Related to this: do you think that David Sinclair’s information theory of aging has merit?

”Partial reprogramming has more potential because it directly targets a key driver of aging — epigenetic changes in gene expression. By restoring a more youthful gene expression pattern in targeted cells, we can rejuvenate their function, effectively reversing some of the processes associated with aging. Unlike other approaches that may address only certain aspects of aging, partial reprogramming aims to restore the entire cell to a more youthful state, and since cells are the fundamental units that carry out the work of our organs, rejuvenated cells should yield rejuvenated organs, and rejuvenated organs – a rejuvenated organism.”

”Full reprogramming, which resets cells to a pluripotent state, has been shown to ameliorate all cellular hallmarks of aging. This is what inspired researchers to explore whether the rejuvenating power of reprogramming could be harnessed in vivo without reverting cells entirely to a pluripotent state, leading to the development of the partial reprogramming approach by Ocampo et al. in 2016.”

”As for David Sinclair’s information theory of aging, I have both agreements and disagreements. In essence, Dr. Sinclair views epigenetic changes during aging as consequences of external factors like DNA damage - what I call the ”weak epigenetic theory of aging.” While I agree that environmental factors do play a role, I believe aging is predominantly driven by pre-programmed epigenetic changes encoded in our DNA, similar to processes like embryogenesis or puberty. This is what I refer to as the ”strong epigenetic theory of aging”. I explore this idea in more detail in my Medium article.

Can you elaborate on the ”therapeutic window” for partial reprogramming? How do you determine the optimal duration for rejuvenation without risking cell identity loss?

”The ’therapeutic window’ in partial reprogramming refers to the specific duration during which reprogramming factors are expressed to achieve therapeutically beneficial effects while avoiding the risk of pushing cells too far toward pluripotency. If pushed too far, cells may lose their identity or have their function disrupted, which could lead to organ failure. Striking the right balance between reversing age-related epigenetic changes and maintaining the cells' functional characteristics is crucial.”

”Determining this optimal window is a process that begins in vitro and then progresses to animal models. In these models, one then monitors health and survival outcomes to identify the safest and most effective protocols. For instance, Ocampo et al. in their 2016 paper identified the initial 2-days-on, 5-days-off OSKM* induction protocol by inducing OSKM in mice continuously and monitoring their health and survival.”

* OSKM is short for the Yamanaka factors.

”Moving forward, we plan to refine this approach by developing tissue-specific reprogramming cocktails and induction protocols. Different cell types have varying levels of permissiveness to reprogramming, so tailoring the reprogramming process to each specific cell type will help optimize the therapeutic window and enhance safety across different tissues.”

What are the main challenges in translating partial reprogramming from animal models to human clinical trials?

”Translating partial reprogramming presents several challenges. One of the primary obstacles is ensuring that partial reprogramming can be effectively targeted to specific tissues. Each tissue type may respond differently to reprogramming, so it’s crucial to refine the approach for each organ. Initially, we must demonstrate efficacy in a single organ for a specific disease before the FDA will approve any partial reprogramming therapy.”

”Once we prove efficacy in treating a particular disease, the next logical step would be to explore the potential of using the approved therapy preventatively in healthy individuals, aiming to prevent the disease from occuring in the first place. As the technology advances, we could then potentially combine therapies that target multiple organs to achieve systemic rejuvenation. This approach has the potential to prevent a broad spectrum of age-related diseases, but it will require precise coordination and validation to ensure that reprogramming across various tissues does not lead to unintended consequences.”

”Effective delivery of gene therapies remains a significant hurdle, particularly when it comes to targeted, tissue-specific delivery with minimal off-target effects. Ensuring that reprogramming factors reach the intended tissues without affecting other parts of the body is crucial for both safety and effectiveness. This requires ongoing research into developing more precise and reliable delivery methods.”

”Finally, the cost of developing and implementing these therapies is a considerable challenge. Each new disease indication requires a separate clinical trial, which can be extremely expensive. Managing these costs effectively is essential to making the therapies accessible while still covering the extensive research and development required. Overcoming these financial hurdles will be key to bringing partial reprogramming therapies to a broader patient population, so it’s a good thing that we have multiple well-funded companies in the partial reprogramming space.”

What are the potential risks or side effects of partial reprogramming, and how are these being addressed in research?

”The biggest risk associated with partial reprogramming is not teratoma formation, as is commonly misconceived, but rather the potential for organ failure in key organs like the liver, intestine, and hematopoietic stem cells (HSCs). These organs contain cell types that are highly permissive to reprogramming, which means they are more likely to lose their specialized functions if reprogramming is pushed too far. This loss of function can lead to serious organ failure and even death.”

”Dr. Ocampo's research has demonstrated that by avoiding just the liver and intestine, the safety margin for partial reprogramming can be significantly widened — from 4 days to 10 days of consecutive OSKM expression. This highlights the importance of tissue-specific approaches in mitigating risks.”

”As for the risk of teratomas, while it’s true that these benign tumors can form if reprogramming factors are overexpressed, they are typically encapsulated and non-metastatic, meaning they don’t spread to other parts of the body. Therefore, teratogenesis is not the biggest concern with partial reprogramming; organ failure due to the reprogramming of overly permissive cell types is.”

”To address these risks, we are refining the therapeutic window to ensure that reprogramming factors are expressed just long enough to achieve rejuvenation without negative side-effects. Additionally, we are focusing on tissue-specific approaches to target only the desired cell types while avoiding those that are more prone to adverse effects. Ongoing research is also exploring safer and more controllable reprogramming factors and delivery systems to further minimize potential risks.”

YouthBio is keen on cell type-specific approaches. Why is it important? And how important is this specificity for the future of partial reprogramming therapies?

”As I mentioned above, the biggest risk associated with partial reprogramming is organ failure in key organs like the liver, intestine, and hematopoietic stem cells (HSCs). These organs contain cell types that are highly permissive to reprogramming, making them more prone to losing their specialized functions if reprogramming is overdone. This can lead to serious consequences, such as organ failure or at least inadequate functioning of the organ.”

”Different cell types respond differently to reprogramming—some are more susceptible to losing their ability to adequately perform their functions, while others are more resistant. By tailoring our reprogramming approach to specific cell types, we can maximize therapeutic benefits while minimizing the risks of disrupting the normal function of critical organs. For example, neurons in the brain are less likely to lose their identity and function during reprogramming, which makes them great targets for rejuvenation therapies. Conversely, more sensitive cell types, like those in the liver and intestine, require a more cautious approach.”

”The future of partial reprogramming therapies depends on this specificity. By precisely targeting the reprogramming process to specific tissues while avoiding those that are too permissive, we can significantly expand the therapeutic window and enhance the safety and efficacy of these treatments. This tailored approach is crucial not only for treating specific diseases but also for achieving broader goals like systemic rejuvenation and the prevention of multiple age-related conditions.”

How do you envision the practical application of partial reprogramming therapies in humans? Would it be a one-time treatment or require periodic ”touch-ups”?

”Currently, partial reprogramming needs to be activated repeatedly for its beneficial effects to persist. This means that for the positive impacts to continue, reprogramming has to be triggered on an ongoing basis from the time of administration until death. The need for continuous "rejuvenation touch-ups" is one of the key unanswered questions in the field, and it has even led me to establish a working group at the 2023 Foresight Institute Longevity Workshop to dive deeper into this issue:”

”One of the central challenges is understanding what drives the ’rejuvenation rebound’ after the cessation of OSKM induction. Once we figure out why the positive, rejuvenating effects tend to diminish after reprogramming stops, we might be able to extend the duration of these benefits, potentially reducing the frequency of reprogramming induction necessary to maintain them. But as of now, we do need to rejuvenate cells repeatedly because the underlying drivers of aging continue their work relentlessly. Even when we counteract their effects on the epigenetic and transcriptomic levels through partial reprogramming, these drivers don’t stop - they keep pushing the aging process forward.”

”The main question we are focused on now is determining the optimal cadence for these ’touch-ups’. How often do we need to induce reprogramming to maintain rejuvenation without causing harm? This is an area of active research, and once we have a better understanding, we can refine the treatment protocol to maximize its safety and efficacy for long-term use in humans.”

Your company is focusing on Alzheimer's disease. What makes partial reprogramming particularly promising for this condition compared to other approaches?

”Alzheimer's disease has a strong epigenetic etiology, meaning that changes in gene expression play a significant role in its development and progression. In mouse models of Alzheimer's, studies have shown that epigenetic modulation can even reverse symptoms and improve cognitive function. This is where partial reprogramming becomes particularly promising.”

”Partial reprogramming works by rewinding the epigenetic clock of cells, restoring a more youthful and functional pattern of gene expression. This approach has the potential not only to prevent but also to reverse Alzheimer’s disease by addressing the underlying epigenetic dysregulation at the core of the condition. By rejuvenating the affected brain cells, partial reprogramming can reduce the accumulation of toxic proteins like amyloid-beta and restore neuronal function, tackling multiple aspects of the disease simultaneously. So unlike other approaches that might target specific symptoms or pathways, partial reprogramming offers a more comprehensive approach by rejuvenating the cells at the core of the disease process, potentially leading to broader and more durable therapeutic effects.”

”Moreover, the brain-specific approach we’ve developed at YouthBio has already shown positive results in animal models, with these findings independently validated by other groups, including Altos Labs. This external validation strengthens our confidence that partial reprogramming could offer a more effective and comprehensive treatment option for Alzheimer’s patients.”

Can you elaborate on the delivery methods for partial reprogramming therapies, especially for targeting the brain?

”Delivery is one of the critical challenges for partial reprogramming therapies, particularly when targeting the brain. Initially, we are using direct injections into the hippocampus and other targeted brain areas to deliver partial reprogramming therapies. This method allows us to precisely focus on regions most affected by Alzheimer’s disease, such as the hippocampus, which is crucial for memory and learning. By directly injecting the reprogramming factors, we ensure they reach the specific cells that need to be targeted, maximizing the therapeutic effect.”

”However, while direct injection is effective, it is invasive and thus not ideal. In the future, we envision using non-invasive delivery methods, such as ultrasound-guided delivery, to target specific brain areas. Ultrasound-guided delivery has shown potential in opening the blood-brain barrier temporarily, which could allow for the delivery of therapeutic agents like our reprogramming factors.”