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A single injection slows down aging in mice in first study of its kinds

WHY THIS MATTERS IN BRIEF

Imagine if you could slow down your aging process with just a single injection, well this is a tentative first step.

 

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Despite several advances in anti-aging tech 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 life, at least for mice. Given a single injection in young adulthood, they aged more slowly compared to their peers.

 

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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 body’s T cells – a 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. They’re now close to tackling other medical problems, such as auto-immune disorders, asthma, liver and kidney diseases, and even HIV.

The new study took a page out of CAR T’s 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 “zombie cells,” 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.

 

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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.

“If 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,” said Amor Vegas in a press release.

Zombie cells aren’t always evil. They start out as regular cells. As damage to their DNA and internal structures accumulates over time, the body “locks” 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 body’s immune system – including T cells – to clear them out. Like spring cleaning, this helps keep the body functioning normally.

 

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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. Senolytics – drugs that destroy these cells – improve these conditions and increase life span in mice. But like a pill of Advil, senolytics don’t last long inside the body. To keep zombie cells at bay, repeated doses are likely necessary.

Here’s where CAR T cells come in. Back in 2020, Amor Vegas and colleagues designed a “living” senolytic T cell that tracks down and kills zombie cells. All cells are dotted with protein “beacons” that stick out from their surfaces. Different cell types have unique assortments of these proteins. The team found a protein “beacon” 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 metabolism – both of which contribute to age-related diseases.

Can a similar treatment also extend health during aging?

 

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The team first injected senolytic CAR T cells, that they’re calling living anti-aging drugs, 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 mice’s 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 treat—a 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.

 

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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 “train” the immune system to learn about a new threat – in this case, senescent cells.

“T cells have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug,” said Amor Vegas. “With CAR T cells, you have the potential of getting this one treatment, and then that’s it.”

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.

 

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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 aren’t 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 there’s the cost factor. CAR T therapies are out of reach for most people – a single dose is priced at hundreds of thousands of dollars for cancer treatments.

Despite these problems, the team is cautiously moving forward.

“With CAR T cells, you have the potential of getting this one treatment, and then that’s it,” said Amor Vegas. For chronic age-related diseases, that’s a potential life-changer. “Think about patients who need treatment multiple times per day versus you get an infusion, and then you’re good to go for multiple years.”

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