An FDA-approved drug routinely used to treat Alzheimer’s disease may one day help to induce a hibernation-like state in humans. The idea is not to help you survive the winter like a bear. Rather, the hope is that the drug, known as donepezil (DNP), could be repurposed to preserve human organs and tissues during medical emergencies.
From Alzheimer’s to Torpor: A Surprising Discovery
The researchers, working with tadpoles of the Xenopus laevis frog species, discovered that donepezil could put the animals into a reversible state of torpor — a form of suspended animation that slows down metabolic processes. This could potentially allow organs and tissues to survive longer without oxygen, buying valuable time in critical situations such as severe injuries or heart attacks.
Traditionally, cooling a patient’s body to reduce metabolism has been the method of choice in hospitals to minimize damage from traumatic injuries or strokes. However, this requires specialized equipment and facilities. Donepezil, already approved by the FDA and widely used in clinics, now sounds like a very promising alternative. It could be administered quickly in the field or during transport to a hospital, potentially saving millions of lives each year, according to Michael Super, Director of Immuno-Materials at the Wyss Institute and a co-author of the study.
“Interestingly, clinical overdoses of DNP in patients suffering from Alzheimer’s disease have been associated with drowsiness and a reduced heart rate — symptoms that are torpor-like. However, this is the first study, to our knowledge, that focuses on leveraging those effects as the main clinical response, and not as side effects,” said the study’s first author María Plaza Oliver, who was a Postdoctoral Fellow at the Wyss Institute when the work was conducted.
The Benefits of Biostasis
The concept of biostasis has been a major focus of the DARPA Biostasis Program, which supported this research. It is about delaying biological processes to extend the “Golden Hour” following trauma or acute illness. This Golden Hour is the first 60 minutes following a traumatic injury, which doctors consider the most crucial for ensuring patient survival.
The idea is straightforward: the quicker the treatment, the better the odds of saving a life. But behind this seemingly simple concept lies a complex interplay of medical science, logistics, and human resilience.
Delays in care can lead to a cascade of complications like shock, sepsis, or irreversible organ failure. And these can drastically reduce the chance of recovery. The principle is rooted in the fact that the body’s physiological response to trauma is time-sensitive. Every minute counts when it comes to restoring blood flow, preventing secondary injuries, and stabilizing vital signs.
A Step Towards Biostasis in Humans?
By inducing a state of temporary metabolic hibernation in trauma patients, medical teams could buy precious extra time. This could allow them to transport patients to advanced care facilities, stabilize critical injuries, and perform necessary surgeries without the immediate pressure of cellular deterioration or systemic collapse.
This technique could be especially transformative in situations where immediate care isn’t accessible. In remote areas, for mass casualty events, or for severe battlefield injuries, time is of the essence. By putting the body into a state of torpor, it may be possible to prevent the cascading effects of blood loss, shock, and multi-organ failure that typically occur within that first crucial hour post-injury.
In previous studies, the team at Wyss identified another compound, SNC80, which also induced torpor-like states. However, SNC80’s potential for use in humans was limited due to its side effect of causing seizures. Donepezil, by contrast, is already in clinical use, providing a safer starting point for human applications.
Using predictive machine learning algorithms and animal models, the team sifted through thousands of possible drug combinations until they finally identified donepezil as a candidate with a chemical structure similar to SNC80.
When tested on tadpoles, donepezil successfully induced a reversible torpor-like state, but with some toxicity concerns. To address this, the researchers encapsulated the drug in lipid nanocarriers, significantly reducing its toxicity and targeting its effects more precisely on the brain, the control center for torpor and hibernation in animals.
How Does It Work?
The mechanism by which donepezil induces a torpor-like state is still under investigation. While donepezil is known for its role in protecting neurons from metabolic stress in Alzheimer’s patients, its ability to induce torpor as a primary effect rather than a side effect is a new and exciting opportunity. The research team believes that further studies could unlock new ways to manipulate the body’s metabolic state, offering a powerful tool in emergency medicine.
“Donepezil has been used worldwide by patients for decades, so its properties and manufacturing methods are well-established,” said senior author Donald Ingber. “This study demonstrates that an encapsulated version of the drug could potentially be used in the future to buy patients critical time to survive devastating injuries and diseases.”
While the findings are promising, much work remains before this approach could be used in humans. Scaling up production of the encapsulated version of donepezil and conducting trials in larger animals are essential next steps. On the upside, with the drug already approved for other uses, the pathway to clinical application could be shorter than developing a new drug from scratch.
The findings appeared in the journal ACS Nano.
