The science of reversing aging

A glimpse into a boundless future

The Fountain of Youth, 1546, by Lucas Cranach the Elder

By Yuri Deigin

A few days ago, the entrepreneur and Y Combinator co-founder Paul Graham tweeted the following graph of human life expectancy changes over the past two centuries. “The survival curve inflates like a sail,” he noted, “but the far end of it doesn’t move much.” By this he meant that while median lifespans have almost doubled, maximal lifespans have largely stayed put.

This astute observation sparked a heated debate about whether extending the maximal human lifespan is possible or even desirable. As many, including myself, are quite passionate about this subject, the discussion quickly caught the attention of influential figures. Elon Musk weighed in on the debate, opining that “aging can obviously be fixed,” but suggesting that it ought not be: Death, he suggested, might be necessary for social change; the benefits of a society without aging may not be as obvious as some might believe.

Tim Urban, a strong supporter of longevity, disagreed, saying we should indeed fix aging. He argued that something as special as human consciousness should exist for more than 90 years. I wholeheartedly agree with this sentiment: Aging is the biggest cause of human pain, suffering, and death on the planet.

In light of this debate and the considerable interest it has generated, I would like to share my thoughts and provide an overview of the current state of aging research.

The goal

Imagine waking up one day to find that your body has reversed its aging process, making you feel decades younger. Your skin is firm and supple, your energy levels through the roof. Your chronic ailments have vanished. Recent breakthroughs in aging research have made this dream as close to reality as it has ever been.

I am a longevity drug developer, and my perspective is undeniably skewed. My life’s work has been transforming the once-distant fantasy of conquering aging into a real possibility. I’m on a quest not only to add years to our lives but to ensure those years are filled with health and vitality. The ultimate prize is the ability to live as long as we want, free from the shackles of our biology.

Until now, medicine has primarily helped to “inflate the sail”—to compress morbidity and rectangularize the survival curve without significantly extending maximal lifespan. However, today’s longevity researchers are working hard to move the far end of the curve through new approaches to hacking our epigenetics, such as partial reprogramming.

I firmly believe that eventually humanity will triumph over aging. Scientific and technological progress accelerates year after year. Groundbreaking advances such as CRISPR, mRNA therapies, and genetic manipulation were once the stuff of science fiction. Now they are part of our everyday lives. So while there are obviously no guarantees about the timeline, I’m very optimistic that within the next few decades we could witness the development of therapies that significantly delay or even reverse aging, especially if funding and talent flow into research.

What is aging? 

Aging is a process that leads to the gradual decline of the body and its ability to maintain homeostasis. Homeostasis, crucial for the proper functioning of all bodily systems, refers to the maintenance of a stable internal environment within the body. As we age, our capacity to maintain homeostasis diminishes, giving rise to age-related diseases such as cardiovascular disease, cancer, and neurodegenerative disorders.

Aging results, over time, in an escalating risk of mortality. For humans and many other mammals, this rise is exponential: After age 10, our chances of dying double every eight years (with a brief plateau between ages 20 and 30). At 35 years of age, our odds of dying within a year are one in a thousand. However, these odds rapidly increase as we age; by age 65, those odds are about one in a hundred, and by age 80, they’re one in ten.

Battling age-related diseases often feels like an unwinnable war, reminiscent of the mythical hydra that grows three new heads for every one that is severed. The only way to permanently eradicate all those diseases is by overcoming the underlying condition: aging itself.

The root of aging: biology and genetics

Why do we age? At its core, aging is rooted in our biology, which holds us hostage. More precisely, we are prisoners of our genes, which exist to further their own objectives rather than fulfill our desires. Genes are a form of self-replicating information, and we serve as their copying machines. Just as we have no qualms about discarding a used copier, our genes have no reservations about discarding us.

To halt aging, we must alter our biology, aligning it with our goals. For centuries, we have employed science to adapt biology to our needs, making extraordinary breakthroughs in the process—from improved hygiene and modern sanitation to surgery, vaccines, antibiotics, IVF, organ transplants, and gene therapy. 

These and other medical advances have significantly extended the median duration of a healthy human life: as evidenced by the graph posted by Paul Graham, in developed countries, the median lifespan has increased from about 45 to about 80 years over the past 150 years, meaning that today at least half of the people live to age 80 rather than age 45, as they did 150 years ago. However, as Paul highlighted, these advances have barely moved the needle on extending maximal lifespan. For that, we need to intervene in the aging process itself, at least slowing it down, or, ideally, putting an end to it altogether.

The plausibility of halting aging

Some people, even within the longevity field, claim that stopping aging is impossible. I disagree. Why do I believe that halting aging is possible? The answer is simple: There’s no law of nature that forbids it. What we can understand, we can control. What we can control, we will control. Historically, comprehending a given biological process has been followed by mastery over it. Take, for instance, the precise editing of the human genome through genetics or the development of in-vitro fertilization. We have understood and mastered the beginning of life; it’s now time to master the end.

Moreover, numerous species live much longer than humans, which should both inspire us and make us feel slightly embarrassed. Are we truly the most intelligent species if we’ve traveled to the Moon and split the atom, but still can’t figure out how to live as long as a turtle?

The good news is that our aging is not dictated by fundamental laws of physics or chemistry—observed lifespans in nature range from hours in bacteria or days in insects to centuries in sharks, whales, turtles, and clams, or even millennia in trees. Even closely related species can have drastically different lifespans: A mouse lives for two or three years, while a naked mole rat can live up to 40. Even within the same Sebastes genus we can observe a nearly 20-fold variation: the shortest-lived species of rockfish lives for just 12 years while the longest-lived, over 200.

Furthermore, there is mounting evidence that aging might be controlled not just genetically but epigenetically as well, giving a new meaning to the phrase “DNA is not destiny.” Social animals provide striking examples of twins, sharing identical DNA, with wildly different lifespans: worker bees live for weeks, while queen bees live for years. In black garden ants, the disparity is even more pronounced: Workers rarely live for more than a year, while queens can live up to 30 years—a lifespan longer than that of most mammalian species.

Non-social animals also exhibit epigenetic control of aging. For example, summer-born Monarch butterflies live for only a few weeks, but those born in the fall and tasked with migrating to Mexico for the winter have been known to live for over nine months. A similar phenomenon has been observed in the Montane vole, a mammal.

The Indian jumping ant provides further evidence of epigenetic control of lifespan. In this species, queens live for years, while non-breeders have much shorter lifespans. However, if the queen dies, a non-breeding ant can be epigenetically reprogrammed to become a breeder, resulting in a six-fold increase in lifespan.

The most compelling and relevant evidence of epigenetic control of aging comes from recent research on cellular reprogramming. Studies have demonstrated that cells can be fully rejuvenated by reprogramming, even cells from hundred-year-old donors. Furthermore, studies of in vivo reprogramming provide early indications of the potential for organismal-level rejuvenation. This research is truly inspiring and contributes to the growing body of evidence suggesting that our aging, too, could be controlled epigenetically, meaning that we could potentially slow it down or even reverse it through epigenetic modulation. 

The miracle of reprogramming

Recent breakthroughs in our field are bringing us closer to unlocking nature’s secret of eternal youth. We’ve learned to replicate in the lab what occurs naturally in fertilized cells—resetting the aging clock. It’s fascinating to consider why babies are born young when each fertilized egg has the same age as its mother. After fertilization, however, the egg undergoes rejuvenation, and the manifestations of aging accumulated during its time in the mother disappear.

Until recently, only fertilized cells had access to this rejuvenation mechanism. But now, we’ve been able to replicate it in a lab, and we’re making progress in using it to slow down aging and even potentially to rejuvenate adults. In 2006, Japanese scientists Yamanaka and Takahashi discovered a process for reprogramming adult cells, returning them to an embryonic state while rejuvenating them. This process involves epigenetically reprogramming adult cells to return to their developmental “ground state.” In the code of life, four transcription factors—Oct4, Sox2, Klf4, and c-Myc—act as a Ctrl-Alt-Del combination for resetting cells.

This breakthrough led to a question: Could this process coul be used to rejuvenate adult organisms as well, not just cells in a Petri dish? The breakthrough came in 2016 when Alejandro Ocampo et al. demonstrated that this is indeed possible by using partial reprogramming—activating OSKM factors for short bursts, but not enough to fully reprogram the cells. They managed to extend by as much as fifty percent the lifespans of progeric mice, which carry a mutation that causes rapid aging.

This inspired me, in 2017, to start the first company dedicated to partial reprogramming. After a somewhat slow start, this paradigm has gained many more adherents: By now, there are quite a few other companies working on this technique, such as Turn Bio, Life Bio, Reverse Bio, Shift Bio, Retro Bio, Rejuvenate Bio, NewLimit, and the entrant who made the biggest splash in our field with their announced US$3 billion seed funding—Altos Labs.

I don’t want to overstate this. There’s still quite a way to go. The in vivo reprogramming approach is in its infancy. But we’ve taken a very important step. We’ve discovered a way to replicate nature’s own rejuvenation mechanism. We hope we can translate this serendipitous discovery into a therapy soon—and enjoy its benefits—even if we don’t yet fully understand all the intricacies of aging.

Is it ethical to let people live longer?

As we consider the prospect of reversing aging and extending the human lifespan, a number of ethical and practical concerns suggest themselves. One of the most debated issues is whether extending life would lead to overpopulation and the exhaustion of resources. Overpopulation fears date back to the days of Plato and Aristotle. In the 18th century, demographer Thomas Malthus predicted imminent starvation when the world population was still below a billion. Despite these concerns, humanity has grown eightfold even as the average standard of living and health has significantly improved—thanks to science and technology. Strikingly, many developed countries are experiencing a decline in birth rates. At this rate, underpopulation might become a more pressing concern. Ultimately, our planet’s sustainable future relies on efficient and equitable resource management, not population size.

Others worry that socioeconomic inequalities will be exacerbated if longevity treatments are only available to the wealthy. Advocates of life extension argue that like any other medical breakthrough, the initial cost of such therapies will likely be high, but will decrease over time. Ensuring equitable access to these treatments should be a primary concern as the field advances.

The idea that death might be necessary for social change, as Musk suggested, is not compelling. Social change is a complex and dynamic process influenced by numerous factors, including technological change, cultural shifts, and global events. The assumption that social change requires aging and death is simplistic and overlooks the diverse drivers of societal transformation.

The accumulated wisdom and experience over an extended life could in fact contribute to more effective problem-solving and decision-making. In fact, if people in positions of power were to live longer, they would perhaps develop longer planning horizons, leading to decisions that prioritize the long-term well-being of society. These leaders, cognizant of their extended lifespans, would become more invested in creating a better future, recognizing that they themselves would experience the outcomes of their choices.

They would also know that they would not escape the consequences of their actions by dying, leading, perhaps, to a greater sense of responsibility for the impact of their decisions. There is no après moi, if you are immortal—just le deluge. This could well motivate leaders to act with greater foresight, integrity, and concern for the collective good.

If, as Musk agrees, aging “can obviously be fixed,” then choosing not to address it raises serious ethical concerns. By not pursuing the potential solutions to aging, we are condemning billions to suffer and die from age-related disease. Withholding the antidote out of an unproven fear of stifling progress is utterly immoral, particularly because that fear isn’t even compelling in theory. Scientists have taken much bigger risks for much less prospective gain: The physicists who detonated the first atomic bomb weren’t entirely sure they wouldn’t set fire to the whole world’s atmosphere and vaporize the earth.

The benefits of conquering aging would extend far beyond those who directly experienced extended lifespans. Reducing age-related diseases would have a profound impact on healthcare systems, freeing up resources to take on other endeavors (like colonizing Mars, if that’s your thing). It’s certainly important to weigh the risks and benefits of any scientific undertaking. But in the case of longevity research, the potential benefits far outweigh the risks.

Addressing skeptics and naysayers

Some skeptics argue that making significant strides in extending lifespan is impossible without reprogramming the human genome before birth. They contend that because lifespan is a genetically encoded trait, altering the genetic mechanisms that govern lifespan in adult organisms is unattainable.

But it is important to recognize that while genes do determine the lifespan of each species, the expression of those genes is governed by epigenetic mechanisms. Fortunately, we now possess the tools and knowledge to modulate both the genetics and epigenetics of adult organisms, invalidating the original contention. Moreover, we also have the tools to change the germline genome (as evidenced by the CRISPR babies), so even if that was indeed a requirement for significantly prolonging human lifespan, we have the ability to do it.

Others have emphasized the potential pitfalls and side effects of tinkering with complex biological systems. While it is trivially true that we face unknown unknowns should we start extending the human lifespan, these would be good problems to have compared to the status quo in which most of us die at the age of 80. Advances in computation and machine learning will help us unravel these intricate systems and develop better-targeted interventions to minimize undesirable consequences.

Finally, naysayers claim that life extension only appeals to the vanity of the wealthy and longevity researchers are feeding this vanity in the hope of profiting from it. Nonsense. There is no one alive to whom this prospect doesn’t appeal. That wealthy people, like the rest of us, are intrigued by it hardly means the research is meritless. The overwhelming majority of longevity researchers and entrepreneurs are driven by the mission, not the money. Most are making less money in longevity than they would have made in areas such as traditional drug development.

The future of aging research

While I am certainly partial, I feel strongly that the partial reprogramming paradigm holds immense promise. Attracting additional talent and resources to this field of research is scientifically valuable. It has the potential to positively affect all human societies, contributing to the betterment of human health and well-being, paving the way for a future when age-related diseases are a distant memory.

Albert Schweitzer once wrote, “Reverence for Life affords me my fundamental principle of morality, namely, that good consists in maintaining, assisting and enhancing life, and to destroy, to harm or to hinder life is evil.” Scientific progress has finally given us the tools to assist, enhance and, most importantly, prolong life. It is now in our power to do good by the world and to deliver it from the evils of pain, suffering, death, and grief brought about by aging.

So let’s do it. 

---

Yuri Deigin is a longevity advocate and a biotech entrepreneur currently focused on developing rejuvenating gene therapies.¹

1. Claire—he was also one of the first to point out that yes, Covid could have come from a lab, and no, this was not a ridiculous idea at all.