A Brief Tour of the Development of Senolytic Therapies to Clear Senescent Cells

Senescent cells accumulate with age as the immune system falters in its ability to clear these cells in a timely fashion. Senolytic therapies selectively destroy some fraction of senescent cells, and first generation senolytic drugs have been demonstrated to rapidly and impressively reverse age-related disease and extend life in mice. The best of these first generation drugs are repurposed cancer therapeutics such as dasatinib and navitoclax, with the jury still out on whether plant extracts like fisetin can be competitive on their own rather than in combination with the chemotherapeutics.

The second generation senolytics presently under development aim to be more selective, have fewer side-effects, require lower or more infrequent doses, or be able to target a greater range of senescent cell types. It is becoming clear that senescence is a varied collection of states, and first generation senolytics are only effective in destroying senescent cells for some of those states, and in some tissues. With this in mind, today's popular science article takes a look at some of the companies and research groups working on a broad range of second generation senolytic treatments. There are promising programs under development; we might expect a much more diverse range of options to exist for patients and self-experimenters a decade from now than is presently the case.

Researchers are using new molecules, engineered immune cells and gene therapy to kill senescent cells and treat age-related diseases

Lurking throughout your body, from your liver to your brain, are zombie-like entities known as senescent cells. They no longer divide or function as they once did, yet they resist death and spew out a noxious brew of biological signals that can slow cognition, increase frailty and weaken the immune system. Worst of all, their numbers increase as you age. For more than a decade, researchers have been trying to see whether they can selectively destroy these cells with a variety of drugs. In a pivotal study published in 2015, a team discovered that a combination of two compounds, called dasatinib and quercetin, killed senescent cells in aged mice. The treatment made the mice less frail, rejuvenated their hearts and boosted their running endurance. The finding opened the door to a new area of medicine called senolytics.

Now, fresh results from animal studies and human clinical trials have added momentum to the field. In mice and monkeys, researchers are using genetic tools to reprogram and kill senescent cells. Others are engineering senolytic immune cells. And about 20 clinical trials are ongoing. Researchers are testing new and repurposed drugs that could have senolytic properties, in the hope of combating age-related conditions, including Alzheimer's disease, pulmonary fibrosis, and chronic kidney disease.

One key strategy in senolytics involves designing drugs that stop senescent cells from resisting apoptosis. Usually, the cells survive by producing anti-death proteins. Blocking these with drugs can force the cells to succumb to death. Unity Biotechnology is at the forefront of this approach. In a recent study, researchers found that senescent cells were more abundant in the retinas of diabetic mice than in those of healthy mice. It was possible, the team predicted, that senescent cells in the blood vessels of the eye play a part in diabetes-related vision loss. The researchers designed a drug, called foselutoclax, which blocks the action of BCL-xL, a key anti-death protein that is abundant in senescent cells. When they injected the drug into the eyes of diabetic mice, it killed senescent cells in the blood vessels supplying the retina, but not healthy cells.

Rather than making senolytics from scratch, some scientists are testing drugs that already exist. In a 2019 study, researchers used dasatinib and quercetin to remove senescent brain cells in a mouse model of Alzheimer's disease. Mice treated with the senolytics had reduced brain inflammation and improved memory compared with animals that were given a placebo. Spurred on by these promising data from mice, researchers last year conducted the first safety trial of the drug combination in people with early stage Alzheimer's disease. The team gave five people dasatinib and quercetin intermittently for three months. The researchers found that the drugs were safe and that dasatinib was present in samples of cerebrospinal fluid, suggesting it could cross into the brain. Quercetin was not detected in brain fluid samples, but researchers suspect that it did reach the brain and was rapidly broken down. The team is now conducting a larger trial to track the cognition of people with and without Alzheimer's disease for nine months after they take a placebo or the drug combination. The results should be released in 2025.

When it comes to killing cells in the body, the immune system could be of help. And some researchers have latched on to the idea of using genetically engineered immune cells called chimeric antigen receptor (CAR) T cells. These can target and kill specific cells on the basis of the molecules they display on their surface. Researchers found that old mice treated with the CAR T cells selective for a marker of senescence had reduced blood-sugar levels - a sign of improved metabolic health - and that the animals ran faster and for longer. But CAR-T-cell therapies are expensive to make. Deciduous Therapeutics is also developing a more affordable approach that harnesses a different kind of immune cell called a natural killer T cell. In 2021, researchers at Deciduous Therapeutics demonstrated the senolytic role of these cells, which naturally become less effective with age. They also found that drugs that can activate the immune cells helped to eliminate senescent cells in the damaged lungs of mice, reducing lung scarring and improving survival. Safety tests will be conducted in dogs and non-human primates later this year, and clinical trials should begin in the next two years.

Other teams such as Oisin Biotechnologies are using gene therapy to kill senescent cells. In this approach, researchers package a gene that encodes a lethal protein called caspase-9 into fatty capsules studded with proteins derived from a virus. In mice and monkeys, the capsules have been found to deliver the gene to cells in the lungs, heart, liver, spleen and kidneys. Healthy cells are spared, because the gene is activated only in senescent cells that have high levels of one of two proteins called p16 and p53. The researchers found that, over four months, a monthly dose of the therapy reduced frailty and cancer rates in old mice without causing harmful side effects.


@Reason, there is an error message saying doi not found if you hit the link. Can you fix this?

Posted by: Morpheus at May 24th, 2024 7:28 AM

I wrote my comment but it was not posted-?

Posted by: ZG at June 3rd, 2024 2:07 PM
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