Scientists Aubrey de Grey and Peter Fedichev Spar Over Their Visions of How to Defeat Aging

Highlights

• Aubrey de Grey believes we can add hundreds of years to our lives by addressing chemically detectable aspects of rejuvenation, such as cellular waste accumulation and loss of stem cells.
• Peter Fedichev thinks we will only add 10 to 20 years to our lifespans by treating chemically detectable damage and recommends focusing research on slowing entropy — a gradual decline toward biological disorder.
• Aubrey de Grey received 38 points at the end of the debate, while Peter Fedichev received 42, making Peter Fedichev the debate’s winner.

Aubrey de Grey, the head of the longevity research-focused LEV Foundation, and Peter Fedichev, the CEO of Gero, a biotech company that also researches possible age-slowing techniques, squared off in a debate over which facets of aging are feasible to reverse. The debate took place in San Francisco on May 27, 2024 and was sponsored by the non-profits Foresight Institute, Open Longevity, and Say Forever.

Aubrey de Grey’s Take on Aging

In the debate, de Grey offered his picture of aging, which encompasses two types of damage: chemically detectable damage and chemically undetectable damage (also called informatic damage). According to de Grey, both arise from changes occurring at the molecular level due to metabolism during aging. Chemically detectable damage includes the age-related accumulation of cellular waste like amyloid plaques, believed to serve as precursors of Alzheimer’s disease, and reduced stem cell abundance. The other type of damage, informatic damage, is also known as epigenetic damage. It refers to genetic mutations and changes in chemical modifications to DNA and the proteins it wraps around, called histones. Importantly, these types of damage cumulatively contribute to age-related diseases and pathology, which also drive further damage from faulty metabolism in a feedback loop.

According to de Grey, he and Fedichev agree that it is possible to remove the first type of damage — chemically detectable damage. They disagreed, however, on how difficult it is to fix informatic damage.

“We know that [informatic damage] can be removed if you’ve got some kind of oracle, an external source of information that says, this is damage, this is not damage,” Aubrey said. “But we don’t have that oracle, and we certainly don’t have a way to communicate that oracle to cells.”

At the same time, de Grey is optimistic because of “informatic redundancy,” the conception that the information about each cell type’s “pristine” epigenetic information is retained somewhere. This may be the case even with the accumulation of a certain amount of epigenetic damage.

Evidence for this comes from partial cellular reprogramming — a technique where the activation of certain genes called Yamanaka factors rejuvenates cells to a more youthful state — which restores this information. It does so without the need for an “oracle,” or an external source of information.

Aubrey is still not completely certain that experiments using partial cellular reprogramming confirm the “informatic redundancy” hypothesis. He does believe, though, that recent research suggests this idea may be true. In line with evidence from partial reprogramming research, de Grey made the statement that “the amount of rejuvenation we can do without an oracle is much greater than it might seem.”

As for how epigenetic information can be restored, Harvard’s Dr. David Sinclair uses a helpful metaphor. He likens partial cellular reprogramming to removing scratches from an old CD. The scratches represent epigenetic damage that obscures epigenetic information. Removing these scratches with partial cellular reprogramming can restore the epigenetic information up to a certain point. Dr. Sinclair also suspects that there is a “backup copy” of this epigenetic information hidden somewhere in the cell, although he does not have conclusive evidence.

Peter Fedichev’s Ideas On Aging

As for Fedichev’s theory of aging, it borrows heavily from his background in physics. Through analysis of biological data that included how epigenetic information changes with age, he detected two types of changes. One of these changes in epigenetic information increased linearly over time, while the other increased exponentially.

Fedichev’s interpretation of the linear epigenetic changes is that normal cellular processes produce heat, which inevitably causes some degree of damage like genetic and epigenetic alterations. These alterations are random and unrelated to each other, resulting in cells accumulating different patterns of these changes. Fedichev also believes that these cellular heat-produced linear epigenetic changes represent entropy — a law of thermodynamics where a system like an organism declines into disorder.

The linear changes, possibly arising from entropy, are often benign. Yet, with time, they start altering cellular function. This scenario creates stress for cells, and the body reacts by activating an array of compensatory mechanisms.

Moreover, because all of these processes in the body are tightly tied together, problems that occur with one mechanism create problems for another. As such, the organism becomes out of balance, leading to the exponential changes that occur in the body along with increased morbidity and mortality, which Fedichev correlated with exponential epigenetic changes.

A key idea of Fedichev’s theory of aging is that reversing the entropic aspect of aging will be extremely difficult. For example, breaking an egg increases the entropy of the eggshell, where the shell moves toward a more disordered state once broken. Reversing that type of entropy would require reassembling the eggshell — a very burdensome and difficult task. Imagine trying to restore thousands or millions of cellular processes disrupted by entropy. The difficulty of reversing entropy in these processes is mostly unknown at this point, but doing so may be as hard as reassembling a broken egg.

According to Fedichev, without reversing entropy in cells throughout the body, we cannot achieve actual rejuvenation. He believes, however, that with some future technology much more advanced than ours, we may be able to reverse biological entropy at some point.

Accordingly, Fedichev believes we must focus research on slowing the accumulation of damage from entropy before we can realistically try to halt or reverse human aging. Otherwise, according to his view, we can only achieve limited lifespan extension.

Hundreds of Years Versus a Couple of Decades

After both aging researchers had presented their views on the underpinnings of aging, one of the judges returned the discussion to an original topic of the debate: can we rejuvenate the human body? Aubrey de Grey answered first, saying we can definitely restore some aspects of the structure, function, and composition of the body, which he considers rejuvenation by definition. The most poignant question, though, according to de Grey, is whether we can achieve comprehensive rejuvenation. Moreover, he questioned whether there are changes to the body’s structure and composition that cannot be revamped with foreseeable technology.

“My belief is that the amount of informatic redundancy that exists in the genome and the epigenome is sufficient for us to be able to comprehensively rejuvenate the body in the foreseeable future,” said de Grey.

He added that he has always believed that fixing chemically detectable damage can only get us so far and that somewhere down the line, the accumulation of informatic damage in itself will become deadly. If we find ways to remove all other chemically detectable damage aside from informatic damage, though, he thinks we will be able to live for hundreds of years. This is because he is convinced that the contribution of informatic damage to aging is not as prevalent as chemically detectable damage.

“Peter’s contention, as I understand it, is that this limit is going to hit us within as little as 10 or 20 years beyond where we can already get. In other words, we can only get 10 or 20 years from the chemically detectable aspects of rejuvenation. I believe, actually, no, we can probably get hundreds of years,” said Aubrey.

Fedichev retorted that he thinks the longevity field and pharma industry are mostly gearing research toward chemically detectable damage. He thinks we can only expect limited gains from this approach. He remained adamant that the only way to stop aging is by preventing the growth of entropy, which he says will be quite hard to do.

The Judges Proclaim Fedichev as the Debate’s Winner

At the end, judges scored the debate as Aubrey de Grey receiving 38 points and Peter Fedichev receiving 42. This made Fedichev the recipient of the $10,000 prize.

Aubrey de Grey believes we can add hundreds of years to our lives by targeting chemically detectable damage. Only the application of future technologies that work in combination to target chemically detectable damage will show whether this is the case. Since partial cellular reprogramming will likely not be applied to humans in the foreseeable future, treatments for chemically detectable damage seem like the best option for rejuvenating the human body.

One of the drawbacks to Fedichev’s alluring idea of overcoming entropy before we can stop aging is that this proposition cannot be tested with experimentation. Fedichev even admitted in the debate that, at the moment, his model of entropy in the body is “a neat theoretical argument that relies on a certain physical intuition.” He also said that his biological entropy idea is the most natural explanation.

“I have to confess that direct evidence does not exist, because we don’t have an experiment where this damage is either reduced or stopped and then we would see some effect on lifespan” said Fedichev. “Mice simply don’t give us such an opportunity right now, so at this time, this argument flows from modeling. We have a model that relates this linear damage to this hyperbolic activation of stress responses that actually kill the animal.”

In that sense, it seems we may be stuck with trying to fix the chemically detectable damage that de Grey pointed out in his perspective on aging for the foreseeable future. The best ways we have that target chemically detectable damage seem to be compounds that increase cellular waste disposal (autophagy), clear dysfunctional cells that accumulate with age (known as senolytics), along with tissue and organ replacement therapies. While these options may not serve as a silver bullet against aging, they offer realistic hope for prolonging our lives, whether for a decade or hundreds of years, depending on which of the two aging researchers you ask.