Senolytics, once known mostly as anti-aging compounds, are now showing real promise in the fight against Alzheimer’s disease. Recent findings from Dalhousie University suggest that these compounds might not just help people live longer but could also slow or treat the progression of this devastating brain disease.
What Are Senolytics?
Senolytics are a special group of drugs that help the body remove harmful, “zombie-like” cells that pile up as we get older. These cells, called senescent cells, no longer divide, but they stick around and cause trouble by releasing inflammatory chemicals that damage healthy tissues. As Dr. Nathan K. LeBrasseur from the Mayo Clinic explained, these cells “drive things such as impaired tissue regeneration, fibrosis, degeneration, inflammation — a lot of the conditions that are clearly central to age-related diseases.” By clearing out these cells, senolytics might help slow down the aging process and reduce disease.
How Senolytics Might Help with Alzheimer’s
Alzheimer’s disease is one of the most common causes of memory loss and dementia. In this condition, the brain becomes clogged with sticky protein clumps called amyloid-beta plaques. Two enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are found near these plaques. While these enzymes usually play helpful roles in the brain, they can contribute to the disease when they attach to these plaques.
Current treatments for Alzheimer’s often block these enzymes to help with memory. However, those treatments also block the healthy forms of these enzymes, which can lead to unwanted side effects. The Dalhousie team wanted to find a smarter way to treat Alzheimer’s.
Testing Senolytics on Alzheimer’s Enzymes
In their study published in the journal Aging, Dr. Sultan Darvesh and his team tested six different compounds to see if they could block only the harmful forms of AChE and BChE that stick to amyloid-beta plaques, without touching the healthy forms elsewhere in the brain.
The compounds they tested included dasatinib and nintedanib, which are known senolytics, as well as fisetin, quercetin, GW2580, and meclofenoxate hydrochloride. Using brain tissue samples from Alzheimer’s patients, they discovered that dasatinib and nintedanib could block the plaque-linked forms of these enzymes. This is exciting because it suggests a way to treat Alzheimer’s more precisely.
As the researchers wrote in their paper, “We show that the selected senolytics and nootropic inhibit ChEs associated with plaques but not the enzymes associated with normal neural elements.” In other words, these drugs targeted only the harmful enzymes without interfering with the healthy ones that the brain needs.
Understanding How Senolytics Work in the Brain
The team also used computer models to better understand how these drugs interact with the enzymes. They found that when AChE and BChE are near the plaques, they actually change shape. This change in shape seems to make it easier for the senolytic compounds to bind to and block them.
The researchers noted that this difference in shape may explain why dasatinib and nintedanib could block the harmful forms of the enzymes but leave the healthy ones alone. “The models showed that the enzymes change shape when near plaques, making them easier for certain compounds to target,” the study explained.
How Senolytics Are Normally Used
Senolytics are not new to medicine. They are being tested in many studies for treating aging-related problems. In animal studies, these drugs have been shown to clear out harmful cells, reduce inflammation, and improve health. Dr. LeBrasseur said, “We’re really not interested in making drugs to help us live until we’re 120 and feel like we’re 120,” but rather to help people have more healthy and active years.
Some senolytics, like dasatinib and quercetin, have even been tested in people for conditions like diabetes, osteoarthritis, and lung disease. Dr. Paul Robbins, a professor at the University of Minnesota, said that “there’s a couple of repurposed drugs that are being tried and trialed” in human studies, and that includes senolytics like dasatinib.
How This Research Could Change Alzheimer’s Treatment
This new research offers a different way of thinking about Alzheimer’s disease. Instead of treating the whole brain the same way, these drugs could zero in on the areas where the disease causes the most damage. The researchers explained that by focusing on these differences between healthy and disease-linked enzyme forms, they might be able to “design more precise and effective therapies.”
This approach could be much safer than current treatments. Since the healthy enzymes would not be blocked, people might have fewer side effects, while still getting help with memory and brain function.
Dr. Clifford Segil, a neurologist at Providence Saint John’s Health Center, warned that while the lab results are promising, “there are multiple possible adverse drug effects which could occur from taking repurposed chemotherapy or pulmonary fibrosis medications as anti-aging medications.” This is why more studies are needed before these drugs can be safely used to treat Alzheimer’s in people.
What Does the Future Hold?
Experts are hopeful, but they know there is still a lot of work to do. Senolytics have already been tested in animals and small human studies for other age-related diseases. This new research suggests that the next step will be to test them in people with Alzheimer’s disease.
Because the enzymes linked to Alzheimer’s seem to change shape in the presence of plaques, researchers might be able to create new versions of these drugs that are even better at targeting these harmful forms. Dr. Darvesh and his team wrote that “these agents may exert their beneficial effects, in part, by inhibiting ChEs associated with AD pathology and providing new avenues for the development of the next generation of ChE inhibitors targeting AD pathology-associated ChEs.”
This could lead to better treatments that slow down or even stop Alzheimer’s disease before it causes too much damage.
For now, senolytics remain a promising new idea in Alzheimer’s research. The work from Dalhousie University shows that drugs originally designed to fight aging might also help protect the brain. If future clinical trials confirm these early findings, senolytics could become a powerful tool in the battle against one of the world’s most devastating brain diseases.
P.S.
Fisetin: Fisetin showed competitive inhibition of acetylcholinesterase (AChE) and uncompetitive inhibition of butyrylcholinesterase (BChE) in enzyme kinetic studies. However, during the histochemical tests in brain tissue, fisetin could not be properly evaluated. It precipitated out of solution and interfered with the staining reaction because it formed complexes with the metal ions needed for the test (copper and iron). So, while fisetin did show enzyme inhibition in the kinetic studies, it could not be confirmed in the tissue experiments.
Quercetin: Quercetin also showed mixed non-competitive inhibition in enzyme kinetic tests, which means it could bind to both the active site and allosteric sites on the enzymes. Like fisetin, quercetin also caused problems in the histochemical tests because it precipitated when added to the staining solution. This meant the tissue-based experiments could not reliably show whether quercetin blocked the plaque-linked enzyme activity in human Alzheimer’s brain samples.
