A preventative anti-aging therapy seems like wishful thinking.
Yet a new study led by Dr. Corina Amor Vegas at Cold Spring Harbor Laboratory describes a treatment that brings the dream to lifeāat least for mice. Given a single injection in young adulthood, they aged more slowly compared to their peers.
By the equivalent of roughly 65 years of age in humans, the mice were slimmer, could better regulate blood sugar and insulin levels, and had lower inflammation and a more youthful metabolic profile. They even kept up their love for running, whereas untreated seniors turned into couch potatoes.
The shot is made up of CAR (chimeric antigen receptor) T cells. These cells are genetically engineered from the bodyās T cellsāa type of immune cell adept at hunting down particular targets in the body.
CAR T cells first shot to fame as a revolutionary therapy for previously untreatable blood cancers. Theyāre now close to tackling other medical problems, such as autoimmune disorders, asthma, liver and kidney diseases, and even HIV.
The new study took a page out of CAR Tās cancer-fighting playbook. But instead of targeting cancer cells, they engineered them to hunt down and destroy senescent cells, a type of cell linked to age-related health problems. Often dubbed āzombie cells,ā they accumulate with age and pump out a toxic chemical brew that damages surrounding tissues. Zombie cells have been in the crosshairs of longevity researchers and investors alike. Drugs that destroy the cells called senolytics are now a multi-billion-dollar industry.
The new treatment, called senolytic CAR T, also turned back the clock when given to elderly mice. Like humans, the risk of diabetes increases with age in mice. By clearing out zombie cells in multiple organs, the mice could handle sugar rushes without a hitch. Their metabolism improved, and they began jumping around and running like much younger mice.
āIf we give it to aged mice, they rejuvenate. If we give it to young mice, they age slower. No other therapy right now can do this,ā said Amor Vegas in a press release.
The Walking Dead
Zombie cells arenāt always evil.
They start out as regular cells. As damage to their DNA and internal structures accumulates over time, the body ālocksā the cells into a special state called senescence. When young, this process helps prevent cells from turning cancerous by limiting their ability to divide. Although still living, the cells can no longer perform their usual jobs. Instead, they release a complex cocktail of chemicals that alerts the bodyās immune systemāincluding T cellsāto clear them out. Like spring cleaning, this helps keep the body functioning normally.
With age, however, zombie cells linger. They amp up inflammation, leading to age-related diseases such as cancer, tissue scarring, and blood vessel and heart conditions. Senolyticsādrugs that destroy these cellsāimprove these conditions and increase life span in mice.
But like a pill of Advil, senolytics donāt last long inside the body. To keep zombie cells at bay, repeated doses are likely necessary.
A Perfect Match
Hereās where CAR T cells come in. Back in 2020, Amor Vegas and colleagues designed a ālivingā senolytic T cell that tracks down and kills zombie cells.
All cells are dotted with protein ābeaconsā that stick out from their surfaces. Different cell types have unique assortments of these proteins. The team found a protein ābeaconā on zombie cells called uPAR. The protein normally occurs at low levels in most organs, but it ramps up in zombie cells, making it a perfect target for senolytic CAR T cells.
In a test, the therapy eliminated senescent cells in mouse models with liver and lung cancers. But surprisingly, the team also found that young mice receiving the treatment had better liver health and metabolismāboth of which contribute to age-related diseases.
Can a similar treatment also extend health during aging?
A Living Anti-Aging Drug
The team first injected senolytic CAR T cells into elderly mice aged the equivalent of roughly 65 human years old. Within 20 days, they had lower numbers of zombie cells throughout their bodies, particularly in their livers, fatty tissues, and pancreases. Inflammation levels caused by zombie cells went down, and the miceās immune profiles reversed to a more youthful state.
In both mice and humans, metabolism tends to go haywire with age. Our ability to handle sugars and insulin decreases, which can lead to diabetes.
With senolytic CAR T therapy, the elderly mice could regulate their blood sugar levels far better than non-treated peers. They also had lower baseline insulin levels after fasting, which rapidly increased when given a sugary treatāa sign of a healthy metabolism.
A potentially dangerous side effect of CAR T is an overzealous immune response. Although the team saw signs of the side effect in young animals at high doses, lowering the amount of the therapy was safe and effective in elderly mice.
Young and Beautiful
Chemical senolytics only last a few hours inside the body. Practically, this means they may need to be consistently taken to keep zombie cells at bay.
CAR T cells, on the other hand, have a far longer lifespan, which can last over 10 years after an initial infusion inside the body. They also ātrainā the immune system to learn about a new threatāin this case, senescent cells.
āT cells have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug,ā said Amor Vegas. āWith CAR T cells, you have the potential of getting this one treatment, and then thatās it.ā
To test how long senolytic CAR T cells can persist in the body, the team infused them into young adult mice and monitored their health as they aged. The engineered cells were dormant until senescent cells began to build up, then they reactivated and readily wiped out the zombie cells.
With just a single shot, the mice aged gracefully. They had lower blood sugar levels, better insulin responses, and were more physically active well into old age.
But mice arenāt people. Their life spans are far shorter than ours. The effects of senolytic CAR T cells may not last as long in our bodies, potentially requiring multiple doses. The treatment can also be dangerous, sometimes triggering a violent immune response that damages organs. Then thereās the cost factor. CAR T therapies are out of reach for most peopleāa single dose is priced at hundreds of thousands of dollars for cancer treatments.
Despite these problems, the team is cautiously moving forward.
āWith CAR T cells, you have the potential of getting this one treatment, and then thatās it,ā said Amor Vegas. For chronic age-related diseases, thatās a potential life-changer. āThink about patients who need treatment multiple times per day versus you get an infusion, and then youāre good to go for multiple years.ā
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- Source: https://singularityhub.com/2024/02/05/a-one-and-done-injection-to-slow-aging-new-study-in-mice-opens-the-possibility/
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