Aging: a biology problem, or a question of physics?

Dr Leonard Hayflick explains why he believes most research into aging and longevity isn’t asking the right questions.

When it comes to the study of aging, there are precious few with more years of experience than Leonard Hayflick, professor of anatomy at the University of California at San Francisco. More than 50 years ago, he discovered a phenomenon, known to this day as the Hayflick Limit, which relates to the number of times the cells in our body can divide before they become senescent (the “zombie state” that cells enter when they stop dividing). In case you’re wondering, our foetal cells divide somewhere between 40 and 60 times before entering senescence – cells from older donors replicate fewer times. But today, Hayflick believes we should be less concerned about “longevity determinants” like senescence, and much more focused on the fundamental questions that surround the underlying aging process.

Longevity.Technology: Dr Hayflick’s controversial 2020 paper in Biogerontology centres around the idea that most research on aging is mistakenly focused on biological processes, while the real answers lie in physics and the study of “single biomolecules and their constituent atoms.” We recently caught up with the professor himself and discovered he is as comfortable as ever taking an alternative view when it comes to his perspectives on the aging field.

“Human efforts to interfere with the aging process have been going on ever since recorded history,” says Hayflick, who, having studied aging for more than 60 years, has seen the field grow enormously since his first days in the lab.

Human efforts to interfere with the aging process have been going on ever since recorded history
Dr Leonard Hayflick has studied aging for more than 60 years.

“When I first was in this field, there were no more than five or six people who had the nerve or the chutzpah to even admit that they were working in the field of aging because it has the largest lunatic fringe of virtually any other discipline – with the possible exception of cancer,” he adds, in typically blunt fashion.

“There was a time when you couldn’t get two people to come to a lecture on aging. Today, the number of people interested in aging has skyrocketed to the point where it has become an industry, with multi-billionaires investing and hundreds of startup companies – all looking at ways to manipulate or interfere or stop or somehow deal with the aging process.”

In his article in Biogerontology, Hayflick refers to the “tyranny of the phrase ‘research on aging’”, which he explains is predominantly based on the failure to define the term because it can be applied to almost any human institution.

“I have spent years trying to get people in this field, to define the 12 most used words in this field, and I can tell you that I have not even gotten agreement on defining the first word, which is aging,” he says, pointing out that there is a major problem caused by the lack of precise communication around what aging is.

In Hayflick’s view, this failure in communication has resulted in a lack of funding for research into the etiology (cause) of aging, favouring instead a focus on age-associated diseases. He believes that resolving any of these diseases will not provide insight into the basic biology or physics of aging, and calls this a “multi-billion-dollar misunderstanding”.

“Politicians understand and are willing to fund research when you seek funds for Alzheimer’s disease, cancer, cardiovascular disease, stroke, and the leading causes of death,” he says. “But when you try to tell them that the greatest risk factor for all of them is aging, so we need to support research on aging, they don’t understand that.”

Aging: physics or biology?

With so much interest and investment in age-associated diseases in recent decades, does Hayflick see signs that more people are now focusing on the right questions? Not at all.

“In general, they have fallen into the same traps that people have fallen into for the past century,” he says. “And there is a pattern. Many of these companies start out to conduct research on interfering in the aging process, but, once having realised the difficulty of doing it, mostly because of failure to define the terms and understand the process, they retreat into research on age-associated diseases, descriptive studies, and animal studies that will provide no information on the etiology of aging.”

Hayflick is convinced that the real answers to aging lie, not in the study of biological processes, but rather in the study of physics, especially the second law of thermodynamics, which describes how energy tends to spread out or dissipate unless it is constrained.
Dr Leonard Hayflick, professor of anatomy at UCSF.

Hayflick is convinced that the real answers to aging lie, not in the study of biological processes, but rather in the study of physics, especially the second law of thermodynamics, which describes how energy tends to spread out or dissipate unless it is constrained.

“The reason that life exists is because of the constraint of chemical bonds that hold molecules together,” he explains. “But those bonds are energy bonds and, in time, the energy in those bonds is going to escape, which is what the second law describes will happen. Eventually we are going to die because the energy in some set of biomolecules in our bodies is going to dissipate, including those in the repair processes that once worked, but now don’t, because they suffer the same consequences of the second law as do their substrate biomolecules. So, aging is a problem in physics and not in biology.”

Is aging unique to humans?

Another key issue that Hayflick has with the field is a perceived failure to distinguish between so-called “longevity determinants” and aging itself.

“Aging is a catabolic process, a process of destruction or loss or dysfunction, and that’s what’s irreversible,” he says. “But longevity determinants are everything else in our anatomy that allow us to live and, secondly, to live long enough to reproduce – that’s all Nature cares about.”

Extrapolating this idea leads Hayflick to suggest that aging is a phenomenon that is unique to humans, and the animals we choose to protect, such as pets and zoo animals. He points out that wild animals do not age unless protected by humans.

“We have been ‘successful’ in dealing with the causes of death, like predation, accidents and disease, that would mostly occur after reproductive maturation and raising progeny to independence,” he says. “Average life expectancy at birth among humans over the past 100,000 years hasn’t exceeded about 40 years. Our successes in medicine, accident prevention, and getting rid of our predators, have resulted in the revelation of aging, which is a unique property of humans and the animals we choose to protect. Teleologically it was never intended to be experienced.”

Coming back to the idea of aging versus longevity determinants, Hayflick believes that we are already coming close to achieving the maximum possible average life expectancy for humans.

“We have increased our life expectation most profoundly, adding 40 years from around the year 1900 to today, and what we did in that time cannot be repeated,” he says. “We got rid of most infectious diseases, so we’re now left with chronic pathology, cancer, cardiovascular disease and stroke as leading causes of death. Even if we eliminated them as causes of death, that’s not going to make us immortal. In fact, if you eliminate all causes of death currently written on death certificates, you will find that average life expectancy at birth, currently about 80 years, will increase to no more than about 92 years.”

Compare young and old cells for answers

While Hayflick’s observations on the aging field may sound pessimistic, he is hopeful that the answers to the more fundamental questions around aging can still be found.

“Look at what is possible today that wasn’t possible 15 or 20 years ago – there have been incredible advances in our ability to look at and tamper with individual biomolecules,” he says, referring to methods including sequencing, cryo-electron microscopy, detecting, identifying, and quantifying nucleic acids, proteins, and peptides.

Crucially, says Hayflick, these methods can provide an understanding of how the molecular landscape of old cells differs from that of young cells.

“Why is it that diseases that are the major causes of death are also associated with aging? There must be something different between the molecular landscape of old cells, or cells at the end of their lineage, than the landscape of molecules in the same class of cells from a young person. And there are now ways of discovering what those differences are. This will allow us to learn why the molecular landscape of old cells increases vulnerability to disease.

“Let’s start looking at the landscape of the molecules in old cells as compared to the molecules in young cells of the same class and learn why that vulnerability to pathology has increased. That’s what our goal should be. And if that doesn’t make sense, then I have failed to convince anybody of the logic involved in it.”

Photograph: Hal Gatewood/Unsplash, Dr Leonard Hayflick, UCSF