Thanks to UVA Research, You Might Live to 120. But Can Society Handle That?

May 12, 2023 By Eric Williamson, williamson@virginia.edu Eric Williamson, williamson@virginia.edu

The University of Virginia’s Class of 2023 will soon stride down the Lawn to the cheers and tears of parents and grandparents. Bittersweetly, graduation means getting older. Though the future may hold additional degrees, schooling – like one’s youth – can’t go on forever.

But what if you were told someday that you could prolong your healthy lifespan, remaining both mentally and physically sharp? And what if the increase wasn’t just a little bit more? What if you could boost those good years by as much as 50%?

In March, University of Virginia researchers reported extending healthy lifespan by that dramatic percentage in two biological models – yeast and roundworms. They also reported finding proof of the same regenerative process at work in humans. Biologist Eyleen O’Rourke and her all-UVA team first shared the enticing results in the journal Current Biology.

The researchers say the gene they identified controls aging through removing toxic byproducts of fat. They call the process “AMAR.” It stands for “Alcohol and aldehyde-dehydrogenase Mediated Anti-aging Response.”

The acronym also cleverly doubles as the Sanskrit word for immortality.

AMAR joins a growing body of anti-aging research. New understandings and innovations are arriving on a daily basis. Aging, it seems, is on its way to becoming negotiable – and by decades. The question now appears to be not, “Will there be anti-aging therapeutics?” but “When?”

“There was once this perception in the scientific community, and there is this perception still in the lay public, that aging is something that is unavoidable, that as time passes, we’ll age,” said O’Rourke, an associate professor and member of the Robert M. Berne Cardiovascular Research Center. “But in our bodies, in our genes, we have the capacity to either accelerate or slow down this process.”

Related Story

Portrait of Eyleen O'Rourke in the lab
Eyleen O’Rourke put together the team that made the groundbreaking discovery. She is an associate professor of biology and a member of the Robert M. Berne Cardiovascular Research Center. (Photo by Dan Addison, University Communications)

It’s perhaps ironic then that O’Rourke, in sharing the story behind the research, is among those currently thinking aloud about the pros and cons of engineering dramatically longer lives.

The researcher said firmly, “There’s a discussion around anti-aging therapeutics that society needs to have.”

Working Out the Wrinkles

Scientists have known for more than a decade now that several genetic and biochemical pathways can either extend or shorten a person’s life. The long answer to why the genome evolved this way is complex, O’Rourke said. The short answer resides in reproduction.

“Nature cares about organisms becoming healthy reproductive adults,” she said. “But once we have produced as many babies as we are capable of, nature doesn’t care about our health.”

Should our muscles atrophy, or remain firm and tight? We can obviously improve our muscle tone by exercise, for example. But at some juncture, instructions meant to optimize development and survival earlier in life begin to tell the body to slow down. Obsolescence is in our genetic programming.

In that regard, our bodies are complex communication networks. The inputs and middle links in aging communication were identified prior to the UVA research. And acting on that accumulated knowledge, previous scientists indeed figured out ways to slow down, and even reverse, aging in animals such as lab mice.

But one reason you may not have heard about all the developments has been the ugly tradeoffs: compromised immunity, cancer.

“The problem with playing around with many of the input and middle-link genes is that – as they are such important players in the cell and control so many things – it is very hard or even impossible to find a condition in which you can only get the good effects of changing their activities,” O’Rourke explained.

In her attempt to solve this problem, O’Rourke assembled a Hoos-who of UVA scientists.

The team that yielded the revelatory research was led by biology graduate student Abbas Ghaddar and postdoctoral fellow Vinod Mony, with the contributions of graduate students Swarup Mishra, Elisa Enriquez-Hesles and Mary Kate Horak; undergraduate students Samuel Berhanu, Emma Harrison, James C. Johnson and Aaroh Patel; and aging expert Jeffrey S. Smith, a professor of biochemistry and molecular genetics.

The Worms Crawl In (To Help)

Traditionally, worms have been associated with death. In science, however, worms – in particular, roundworms – have been responsible for some major health breakthroughs, winning Nobel Prizes in physiology and medicine (along with their scientists).

The type of roundworm O’Rourke and company used wasn’t the parasitic type sometimes found in our pets, but rather C. elegans, which grows to about a millimeter long and is clear-bodied. As the first multicellular organism to have had its entire genome sequenced, the roundworm is transparent in more than one way. The creepy-crawly may seem far removed from us humans, but its chemical pathways are remarkably analogous.

Microscope image of roundworms

This microscopic image from O’Rourke’s lab shows how roundworms glow for adh-1. The brightest signal is in their heads. (Contributed image)

Using the worm as a key model for this research, the team sought to decipher what happens at the end of those previously mentioned communication chains that control aging (as opposed to the inputs or middle links).

Specifically, O’Rourke wanted to find the molecular players most responsible for aging, which are those that break or repair cells, and by extension, tissues and organs. The thought was that by being at the end of the communication chain, playing around with the genes might mean fewer unwanted effects.

They set out by looking at biology’s natural process of cellular cleanup and repair, called autophagy. The command to renew cells has long been thought to underlie longevity.

“Autophagy is a process that clears the unwanted and recycles parts of the cells,” O’Rourke said. “When cell components go bad, they need to be disposed of. To this end, autophagy breaks them down to use the parts to make new cell components.

“So autophagy was the main anti-aging candidate, in particular because we had already defined that the mid-link gene we were studying acted as a switch to turn autophagy on when animals were fasting, a dietary intervention that extends lifespan.”

Goodbye Autophagy, Hello Adh-1

If their hypothesis was correct and autophagy was promoting longevity, then by stopping it, animals would not live longer.

“But that didn’t happen,” she said. “We inactivated autophagy in many different ways – genetically, with chemicals, all very well-established methods – and we confirmed that autophagy was inactivated, but the animals continued living long healthy lives. That’s when we started this one-at-a-time search through hundreds of genes to try to find the true longevity master.”

O’Rourke referred to her trial method an “omics” approach because it allowed the team to see the bigger picture at work.

The research pointed to an enzyme that in humans breaks down alcohol and reduces its toxicity in the body. Notably, the enzyme’s yeast equivalent breaks down beer. Doctors, in fact, target this enzyme to help alcoholics clean up their cells after years of abuse.

The enzyme’s name is ADH-1. The gene that controls production of the enzyme is adh-1.

The researchers then began experimenting with the adh-1 gene to slow down or speed up the production of the enzyme.

They enhanced the gene in the worms in two ways. Using a tiny needle, they squirted in multiple copies of the gene into a pregnant roundworm. They also modified the worms through CRISPR gene editing, creating lines of progeny that expressed a version of adh-1 that glows in the dark.

Meanwhile, Jeffrey Smith’s molecular genetics lab used similar genetic approaches to hyperactivate the analogous gene found in baker’s yeast. They demonstrated that the longevity boost wasn’t just a one-off in the roundworm model.

“Overexpression alone was sufficient to extend chronological lifespan,” Smith concluded.

In the worms, the improvements weren’t limited to a few more weeks of life to squirm. They received all kinds of benefits.

“So far, we have seen positive effects across the board in terms of increased muscle strength, reduced fat storage, and increased memory and learning, in addition to increased lifespan,” O’Rourke said.

“So far, we have seen positive effects across the board...” – Eyleen O'Rourke

So why do the researchers suspect that AMAR also helps with memory? Roundworms can be taught simple tasks, such as associating an odor with food. If the smell returns, either they remember and go for it, or they don’t.

Those old worms that overexpressed the adh-1 gene, it turned out, kept seeking out the grub.

Medicalizing Anti-Aging in Humans

It’s no secret that with proper diet and routine exercise, along with other self-care such as reducing stress and getting adequate sleep, humans can live longer.

Even so, most people die before their odometer flips to 80. Though cause of death is often classified into categories, including “old age,” the reasons underlying mortality are complex – almost as diverse as humanity itself.

But one reason that unites us is the stores of fat that adh-1 works on. Caloric restriction has long been known to extend lifespan, while obesity hastens death. O’Rourke’s lab previously identified a suite of genes related to obesity: 14 that cause weight gain and three that can prevent it. The Pew Biomedical Scholar has spent her career trying to uncover the complete network of genes that govern metabolism and control aging.

She said it’s not the fat itself that makes us sick, but the byproducts of fat, “so when thinking about obesity, we need to shift from the image side of the problem.”

Medically supervised fasting has been one proven avenue for extending life. Fasting makes the body more resilient. Research shows it can help you not only ace those metabolic tests at your annual doctor’s checkup, but also bounce back more quickly from medical procedures, improve your muscle strength and achieve greater mental acuity.

That’s right, fasting, if done correctly, doesn’t starve the brain. It’s actually a neuroprotective practice.

Yet the kind of fasting that gets results is intense, making it at the very least impractical on a regular basis, and for some people, dangerous. The process typically involves reducing by a fourth the number of calories ordinarily required to maintain a healthy weight. For an adult weighing just over 130 pounds, for example, that would be a recurring drop of about 500 calories in a 2,000-calorie baseline. The results are usually achieved through what’s called “intermittent fasting,” by strategically skipping meals or a whole day of eating, then returning back to one’s normal regimen.

“It’s really, really very little food,” O’Rourke said. “And then you’ve got to be very careful about taking all your vitamins and other micronutrients that we normally get with the food.”

In poring over the long history of detailed research on fasting in humans and other mammals, O’Rourke’s team found that the most activated gene was, in fact, Adh1. That’s one reason they have confidence a viable anti-aging therapy may one day be developed based on this enzyme.

“More importantly than living longer,” the biologist said, “aging is the main risk factor for all these diseases we want to cure or at least better treat: cardiovascular disease, cancer, neurodegeneration, osteoporosis. If we could slow down aging, we could simultaneously delay the onset and reduce the incidence of many of these ruinous diseases.”

Her research currently points in the direction of a detox regimen, perhaps similar to the one for alcoholics, that would systematically remove the problematic fat-derived alcohol – glycerol – and its byproduct – glyceraldehyde. O’Rourke is seeking private partners to continue testing. Even with expert help from the pharmaceutical industry, it may take years before a drug to boost ADH-1 activity is approved.

O’Rourke is not the only UVA researcher searching for answers to aging.

Her School of Medicine colleague, assistant professor of pharmacology Irina Bochkis, sees another way into solving the problem of aging – by removing the wrinkles from our cells.

Bochkis’ research observes that the nuclear membranes that house our cells’ DNA get crinkly over time, which may be a reason for declines in functioning. Aging goes hand in hand with increased inflammation and metabolic syndrome. In the liver, this can lead to nonalcoholic fatty liver disease. Bochkis’ research directly connects the integrity of the DNA’s envelope to that condition. She believes other aspects of aging may directly relate as well.

Portrait of Irina Bochkis
AMAR isn’t the only promising anti-aging discovery UVA has made. Irina Bochkis, assistant professor of pharmacology, sees an avenue for regeneration in wrinkled cells. (Photo by Dan Addison, University Communications)

Jeffrey S. Smith’s lab, meanwhile, is investigating other pathways to longevity, including the promising amino acid L-serine.

In terms of converting any of this current anti-aging knowledge to a drug or other therapy, however, “We are nowhere near that,” Bochkis said.

Though much more work is needed, the possibility of human beings routinely living to 120 or longer doesn’t seem like a science-fiction scenario anymore. If it materializes, the UVA graduates of today could go on to become the super-senior citizens of tomorrow. A current 25-year-old might live well into the next century.

But would that be a good thing?

Feeling Out the Future

Though Jeanne Calment, a Frenchwoman who died at the age of 122 in 1997, lived history’s longest verified human life, scientists believe somewhere around 120 is about as far as the human body can stretch.

The upsides to living that long, if a person were healthy, might include spending more time with family and friends, and building even further upon a career. There’s also the value of simply existing – being able to eat another delicious meal or to witness the warm glow of yet another sunrise.

Given the temptation to keep the party rolling, how many of us wouldn’t pop the magic pill before thinking through its implications?

The reality is that what performs well in simpler lifeforms, like worms and yeast, doesn’t always play out as neatly in human bodies. A therapeutic course without drawbacks may not be deliverable. It’s not hard to imagine that if anti-aging drugs, for example, do reach the market, they might come with some tradeoffs – as most pharmaceuticals already do. (Just note the long list of caveats at the end of every big-pharma TV commercial.) That’s why even discussing the topic can be controversial, with experts often split.

“In the aging field, there are two camps: increasing lifespan and improving healthspan.” – Irina Bochkis

“In the aging field, there are two camps: improving healthspan and increasing lifespan,” Bochkis said. “Some genes might contribute to both, but not necessarily. We should focus on improving healthspan and quality of life for the current lifespan before we start talking about increasing it.”

Sociology research professor Joseph Davis, co-author of the book “The Evening of Life: The Challenges of Aging and Dying Well,” put it more bluntly.

“Speaking of aging in narrowly biological terms misses crucial elements of what aging actually is, and why living to 120 would be a nightmare regardless of whether you were relatively robust,” he said.

One concern is that bodies might remain strong while minds degenerate. Alzheimer’s and other related dementias are already forecast to triple by 2050. Mariana Teles, an associate professor of psychology who studies aging, said the impact on the health care system, which is currently better at treating physical injuries than mental incapacitation, would have to be considered.

Teles noted the findings of the Virginia Cognitive Aging Project a few years back, which tracked how the brain changes in the aging population, starting with a dip in most people at around age 60.

“These studies reveal that there is a gradual but continuous decline in our cognitive abilities as we age,” she said. “A deeper decline in these abilities, coupled with a longer lifespan, would significantly affect our daily lives, making it more challenging to carry out everyday activities independently. It could make it difficult to remember important details, solve complex problems and maintain social relationships.”

Additionally, issues such as “the sandwich generation” have been identified. That’s adults caring for both older and younger generations. What if all of the sudden you not only had to care for your children, but for a mother and a grandmother, both of whom have some level of impairment?

Naomi Cahn, a UVA law professor who studies the legal problems that families encounter, said caregiving for multiple generations might significantly increase if people live longer.

Determine to Make Alzheimer’s A Memory | Learn More About What It Means to Be Great and Good in All We Do
Determine to Make Alzheimer’s A Memory | Learn More About What It Means to Be Great and Good in All We Do

Other things to think about, she added: Would the retirement age change? How would we address Social Security and other safety net issues for a group of people that was supposed to boom, then decline? And who would be entrusted to make decisions for all these seniors when they can’t?

“Americans will need to adapt laws revolving around family, relationships and care,” Cahn said. “With longer lives, with changes that we’ve seen over the past half-century in the structure of families, family law and elder law will need to respond.”

As an example, she noted that the presumption under existing law has been that a spouse will make decisions for someone who is incapacitated.

“For someone in a second or third marriage, however, they might want their children to be the ones making decisions for them,” Cahn said.

Teles, the psychologist, said that even with further adaptation required, the golden years have the potential to be exactly that.

“The anti-aging detox approach discovered by UVA Health could help reduce the incidence and prevalence rates of age-related conditions, allowing people to enjoy a longer lifespan while maintaining their cognitive abilities and independence,” she said. “It could also have a positive impact on the economy by allowing people to remain active in the workforce for longer periods, contributing to their retirement savings, and reducing the burden on social welfare systems.”

With another 40 years of healthy life, you will most certainly want to pursue a third, perhaps a fourth, graduate degree. UVA will be here if you do.

Media Contact

Eric Williamson

University News Senior Associate University Communications