‘We need to get comfortable with being wrong about aging’

Editor of new book on the science of aging believes the key breakthroughs may yet come from ‘outliers’ in the field.

Hot off the press, a new book has been published that explores our current understanding of the aging process, and the work being undertaken to try and reverse it. Aging: How Aging Works, How We Reverse Aging, and Prospects for Curing Aging Diseases summarizes where the science stands today along with a forward-looking view of where clinical medicine is heading. Drawing on published research conducted over past 20 years, the book explores the latest aging models, the progress towards potential interventions, and the obstacles and risks standing in our path.

Longevity.Technology: With chapters authored by top aging researchers, including Peter Nilsson from Lund University, Houston Methodist’s John Cooke and Mayo Clinic’s Jim Kirkland, Aging explores various systems in the body, from the brain and cardiovascular systems to the lungs, bone, and skin. Dr Michael Fossel, the book’s editor and founder of telomerase gene therapy company Telocyte, wrote his first textbook on aging some 20 years ago. We caught up with him to find out his views on progress in the field since then.

One of the great positives that Fossel sees today is that the world appears to have embraced the idea that the aging process is something that can be intervened in – to some extent, at least.

“Almost everybody you see, whether in TED talks or at conferences, is talking about minor improvements and tweaks to longevity,” he says. “As a result, most people globally now think it might be possible to slow aging, or at least deal with some of the symptoms of it.”

Telocyte's gene therapy funded through to clinical trials
Aging researcher Dr Michael Fossel is the founder of telomerase therapy company Telocyte.

Reversing aging a reality

More recently, however, Fossel is excited that the focus of the longevity field has increasingly turned towards far more significant potential benefits.

“We’re now talking about a fundamental shift in the entire field, which is reversing aging – preventing and curing age-related diseases,” he says.

Using progress in senolytics as an example, Fossel says that, while the field’s initial focus was on removing senescent cells (aged, dysfunctional cells that accumulate in the body) to combat certain conditions, there is an increasing emphasis on approaches capable of resetting those cells to make them younger again.

“This is not about ameliorating or treating symptoms, not treating biomarkers, not treating hallmarks, but actually reversing the process of aging,” he says. “It’s a totally different way of looking at things.”

Many unknowns still exist

Despite these positives, Fossel is under no illusion of the challenges that lie ahead, using the slow progress in gene therapy as an example.

“We’ve known for a long time that the potential is there to replace an abnormal gene, a certain allele, that’s causing a disease,” he says. “That’s been known for decades, but we’re only barely capable of doing it today. We’re still not at the point where this is a routine medical intervention.”

When it comes to reversing aging in humans, Fossel says the science has even further to go. Back in 1996, he gave the first ever lecture on reversing cellular aging at the National Institutes for Health and says there has been “remarkably little” progress since then.

“Reversing aging is not easy,” he says. “It is almost certainly doable, and to some extent it has been done. We know that we can reverse the aging process in human cells and tissues in the lab, and even in some organisms in vivo. But there are unknowns and technical limits and problems to be overcome – even within cells and tissues, there are limits, concerns, caveats, and risks.”

“That’s the next step. What are those limits, and how do we address them in the next few years?”

AI needs the right questions

Recent developments in AI have led to growing optimism that machine learning will help us find the answers to these questions. Fossel isn’t so sure.

“AI is an enormously valuable tool that is very good at answering questions where there’s a lot of data, and you already know the right question,” he says. “But sometimes we don’t know the right question.”

To illustrate his point, Fossel goes back more than 200 years to the death of George Washington, whose infection was treated using the advanced medical interventions of the time – enemas and bloodletting.

“If those physicians had access to quantum computing, AI, gene-wide surveys, precision medicine, and so on, by now we’d have the best possible bloodletting and enemas,” he says. “And that’s because they were asking the wrong question. If we ask the right question, AI can help us, but two centuries ago it couldn’t have made that intuitive leap to ask, ‘Hey, what about invisible microbes?’”

Fossel believes this is the fundamental issue with expecting AI to provide the answers to reversing aging.

“If I use AI to find the best drug to use to improve mitochondrial function because that’s what I believe causes aging, then I’ll get an answer,” he says. “But what caused mitochondrial aging in the first place? That question is a problem for AI because it takes an intuitive leap.”  

“If we want to use AI, we first need to ask ourselves, what assumptions are we making that are unwarranted? How do we look at the data with fresh eyes?”

Get comfortable with being wrong

Making a significant breakthrough in aging is, according to Fossel, probably going to require those working in the field to be willing to admit they may be wrong. He recalls speaking to a Big Pharma scientist recently, who had spent 40 years of her life working on the assumption that the accumulation of beta amyloid plaque in the brain was the cause of Alzheimer’s.

“It’s now being suggested that beta amyloid is not the right model to use, and that it’s a downstream outcome rather than a cause,” he says. “But for her to make that leap would imply that for 40 years of her professional career, she’s wasted her time, and that’s not something any of us want to admit to and live with.”

According to Fossel, everything we think we know about aging should be up for debate, and that includes his own lifelong body of work in the field.

“I sometimes say everything is more complicated than we think it is, and that’s true in aging too,” he says. “I believe that the way I and some others look at aging is a more accurate reflection of reality than most. But we’re still not right… we’re just closer.”

The major breakthroughs in aging have likely yet to be made, and Fossel suspects that these are more likely come from outliers in the field than from within the current mainstream.

“Seldom does an innovative idea come out from the mainstream, because the mainstream is already dedicated to what they’ve been doing for a long time, probably their whole lives – it’s the nature of the beast,” he says.  “Of course, most of the outliers are crazy. And their ideas won’t work. But some of them will. When Lister proposed handwashing to prevent infection, people thought he was crazy. People knew Einstein was wrong, they knew Bohr was wrong. And yet, things changed, thanks to the outliers.”

READ MORE: Telocyte’s gene therapy funded through to clinical trials