Forever young
Scientific advances in recent decades have made the world’s population healthier — and also much, much older. The number of people over the age of 60 recently surpassed one billion and is projected to double by 2050. However, while the medical community has made great strides in reducing infant mortality, malnutrition and communicable diseases, advanced treatments for the maladies associated with aging have been limited.
But what if conditions like Alzheimer’s disease, Parkinson’s disease and arthritis could be delayed or even reversed? That’s a question that Irina Conboy, professor of bioengineering, has been researching for the last 20 years. Describing her work as “developing solutions to keep humanity healthier and younger for additional decades,” Conboy is studying the role blood plays in the aging process and its connection to such seemingly distinct diseases as dementia and certain cancers.
Conboy and her collaborators — including her husband, Michael Conboy, a research scientist and lecturer in the Department of Bioengineering — are aiming to determine if the secret to vitality truly lies within the bloodstream. “We want to figure out why people age synchronously,” she says. “It’s not like your head is young and your hands are old. You age systemically, all at once, which suggests that there is something in blood that controls healthspan and longevity.”
After almost two decades of research, scientists at the Conboy lab have now identified crucial mechanisms underlying the aging process: the overabundance of specific blood proteins. These proteins, at levels that are vital for our health when we’re young, become elevated and counterproductive as we age, bringing about disrepair and its related gerontological conditions.
Most promising, their studies of plasma dilution suggest that the actual key to rejuvenation may lie in targeting these molecular excesses, providing a safer and more effective alternative than other treatments, such as infusing patients with youthful blood or its related components.
Understanding rejuvenation
In a groundbreaking 2005 study published in Nature, the Conboys were lead scientists on the team that surgically connected young to old mice. What they found was significant: certain markers of aging were reversed in the old mice, while aging was induced in the young mice.
The study looked at how well muscle tissue recovered and how well liver cells regenerated; in both cases, old mice with preexisting conditions healed much quicker when connected to young mice than did mice in the control group. (The study also examined how well new brain cells were formed, but those findings were published six years later, in a different study.)
The evidence also suggested that it wasn’t the young blood cells that were beneficial, but rather, that the blood-exchange process rejuvenated the regenerative capacity of the old stem cells in the old tissues. The process wasn’t like rehydrating a thirsty body — it was more about triggering specific signaling mechanisms to get older cells to act more like their younger selves.
“We started to ask ourselves, what if, instead of exchanging old blood with young blood, we exchanged it with something that has no age?”
In 2016, Conboy and her team published a better-controlled study that examined the underlying reasons why mice experienced rejuvenation or aging in a matter of days. The researchers used a new experimental technique to exchange blood between the mice, helping to pinpoint the effects of blood alone and allow for more precise measurements.
When looking at liver health, agility, cognition, neuroinflammation and senescence, the study showed that young mice that received old blood manifested declines in many of these areas.
“There were some positive effects of young blood [on old mice], but not in the brain,” says Conboy, “and the young mice became immediately aged by a single transfusion of old blood, manifesting neuroinflammation and problems with agility and cognition.”
Because the benefits were not evident in the brain, the researchers theorized that young blood by itself may not reverse the process of aging. Rather, it may be the reduction of specific proteins found in old blood that was the benefit.
Hitting the reboot button
By the early 2020s, Conboy recalls, “we started to ask ourselves, what if, instead of exchanging old blood with young blood, we exchanged it with something that has no age?” So instead of parabiosis or blood exchange, they experimented with plasmapheresis, the dilution of natural blood plasma with a saline solution and albumin, which replenished natural albumin lost during the procedure.
“We expected this would be a negative control,” Conboy says. “We thought that if we simply diluted 50% of the blood plasma there would be no effects. But the effects were actually huge,” rejuvenating tissue “to such an extent that in many of the tests we did, the old mice were statistically the same as young mice.”
In a 2020 study, the researchers found that young blood was unnecessary for significant rejuvenation, and that a single “neutral” blood exchange yielded significant improvement across multiple physiological systems in the muscles, liver and brain.
Through a single, 30-minute procedure, half of the plasma in mice was replaced with the saline-albumin solution. This single therapeutic blood exchange made older mice demonstrate better muscle repair, reduced fattiness and fibrosis in the liver, improved formation of new neuronal cells in the brain, better cognition, reduced neuroinflammation and reduced brain senescence.
Young blood by itself may not reverse the process of aging. Rather, it may be the reduction of specific proteins found in old blood.
Why were the results so robust and rapid? The answer came from comparative proteomics, where signaling proteins that circulate in blood were studied before and after the procedure.
As Conboy explains, when blood is diluted, it’s like hitting the reboot button on a computer so that the cells overproducing proteins recalibrate to a younger, healthier profile. Although plasma proteins turn over and get replaced constantly, changes in the systemic milieu over time, such as an excess of certain circulatory proteins, interfere with tissue. For example, one such signal is TGF-beta, a protein that is crucial for embryonic development and for adult health, but becomes overproduced in the old as a response to cellular damage.
“You have insult after insult, injury after injury,” Conboy says, and every time protein levels go up, they reach the point where they start inhibiting the levels of beneficial proteins in the body. “It’s like an army of old bureaucrats,” she adds. “They’re not capable of doing the job anymore, but they don’t want to be replaced by a new generation.”
“A youthful recalibration”
Mice are one thing, but how relevant are these findings to humans? Early results from a clinical study in 2022 are promising.
Working with clinical doctor Dobri Kiprov and Joel Kramer, a neuropsychologist at UCSF, Conboy and her team studied the effects of multiple rounds of plasmapheresis on humans, in which their plasma was replaced with saline and purified albumin, similar to the neutral blood exchange in mice.
The researchers examined blood samples before and after the subjects underwent the procedure. In addition to other markers, says Daehwan Kim, a postdoctoral researcher in the Conboy lab, they analyzed levels of “inflammaging,” or the process by which “the immune system becomes less effective at fixing infected or damaged tissues and clearing dead cells.” Inflammaging can lead to the accumulation of inflammatory molecules and the harmful overactivation of immune cells.
The study, published in the journal GeroScience, showed that this process of diluting blood plasma by 60-70% had dramatic results in humans. Not only was inflammaging reduced, but protein markers for neurodegeneration and even cancer were diminished. In their paper, the researchers described plasmapheresis as providing “a youthful recalibration of canonical signaling pathways” that regulate tissue health.
One of the biggest initial advances from the 2022 study was the identification of 10 novel protein biomarkers, which, when deregulated by age, lead to an increase in a person’s biological age; these markers might help in the development of rejuvenating therapies. “We are trying to find and sample more,” says Kim, “because 10 probably isn’t all it takes to provide rejuvenation.”
The researchers emphasize, however, that plasmapheresis isn’t being looked at as a potential treatment for aging or its associated diseases. Conboy stresses that the circulatory system is a closed loop for a reason. When blood is removed for plasmapheresis, it travels through plastic tubing and then into a device where the cells themselves are spun or filtered out and then returned to the body along with the saline and albumin. “But that procedure alone might be damaging for cells and deregulate clotting factors,” she cautions. “They can clot, they can be shredded and they can even activate a native immune response.”
Rather, the long-term goal of their work is to produce safe therapeutics that will extend a healthy, enjoyable life. The researchers are hopeful that it will yield insights into the larger process of cellular signaling; in time, the benefits of the crude “oil-change” model of blood exchange may even be replicable in pill form.
In recognition of the promise of this research, the grantmaking organization Open Philanthropy recently awarded Conboy over $3 million to develop tools to track and reveal the fundamental mechanisms of aging — and eventually attenuate, reverse or even prevent this process.
As for Conboy, who always publishes her results as quickly as she can, “that’s success in academia. Not having a trade secret but being collaborative and altruistic so more people can be involved and move the work forward.”
Ultimately, Conboy, who has had a curiosity about the elderly since her childhood, finds it gratifying that her life’s work may be a critical link in protecting people from the declines associated with aging. “Working on this is a rational decision,” she says. “It’s almost like you’re on an airplane that you know is going to crash. It doesn’t help to panic, but if you have the materials to make a parachute, why not start putting it together and see how far you can get?”
