The biological clean-ups that could combat age-related disease
Could targeting autophagy — often likened to a cellular trash management system — extend life? Some researchers are unconvinced.
When it comes to drugs with broad autophagy-inducing potential, several medicines already being widely used seem to fit the bill. For example, metformin, a common diabetes treatment, and the immunosuppressant rapamycin, which is used to prevent transplant rejection, both fire up autophagy signalling through their effects on mTOR, a master regulator of several steps on the autophagy pathway.
In worms and mice, these drugs increase lifespan and overall well-being. But because they have many molecular effects, “you can never be sure what is due to autophagy,” says Beat Nyfeler, a chemical biologist at the Novartis Institutes for BioMedical Research in Basel, Switzerland.
Unfortunately, the molecular promiscuity of mTOR signalling, which also controls protein synthesis, and the nonspecific nature of the drugs can also result in unwanted side effects. “I think to really address the power of activating autophagy one would need to find something mTOR-independent,” Nyfeler says.
By repurposing an existing drug, David Rubinsztein, a cellular neurobiologist at the University of Cambridge, UK, has identified a blood-pressure medication that induces autophagy through other means. Called felodipine, it works by blocking calcium channels, both to relax blood vessels — hence its use to treat hypertension — and to increase autophagic activity.
In mouse models of Parkinson’s and Huntington’s disease, Rubinsztein and his colleagues have shown that the drug promotes the clearance of aggregate-prone proteins from the brain, resulting in behavioural and functional improvements9. A clinical trial is now planned to evaluate whether felodipine treatment can reduce levels of mutant huntingtin protein in the spinal fluid of people with early-stage Huntington’s disease.
Other companies, meanwhile, are looking to develop selective autophagy-activating agents directed at different therapeutic targets. At Samsara Therapeutics, scientists have approached the problem by exposing cultured cells to tens of thousands of drug compounds and then running assays designed to detect any changes in autophagy function. This work has yielded three promising drug leads, Hamley says, which the team is now trying to validate.
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