UC Irvine researchers discover naturally occurring compounds to rejuvenate aging brain cells

Researchers at the University of California, Irvine have identified a promising nonpharmaceutical treatment that rejuvenates aging brain cells and clears away the buildup of harmful proteins associated with Alzheimer's disease.

In a paper published recently in the journal GeroScience, the UC Irvine team reports that a combination of naturally occurring compounds – nicotinamide (a form of vitamin B3) and epigallocatechin gallate (a green tea antioxidant) – can reinstate levels of guanosine triphosphate, an essential energy molecule in brain cells. In tests on neurons in a dish, the treatment reversed age-related cellular deficits and improved the brain cells' ability to clear damaging amyloid protein aggregates, an Alzheimer's hallmark.

As people age, their brains show a decline in neuronal energy levels, which limits the ability to remove unwanted proteins and damaged components. We found that restoring energy levels helps neurons regain this critical cleanup function."

Gregory Brewer, lead author, adjunct professor of biomedical engineering at UC Irvine

The researchers used a genetically encoded fluorescent sensor called GEVAL to track live guanosine triphosphate levels in neurons from aged Alzheimer's model mice. They discovered that free GTP levels declined with age – particularly in mitochondria, the cells' energy hubs – leading to impaired autophagy, the process by which cells eliminate damaged components.

But when aged neurons were treated for just 24 hours with nicotinamide and epigallocatechin gallate, GTP levels were restored to those typically seen in younger cells. This revival triggered a cascade of benefits: improved energy metabolism; activation of key GTPases involved in cellular trafficking, Rab7 and Arl8b; and efficient clearance of amyloid beta aggregates. Oxidative stress, another contributor to neurodegeneration, was also reduced.

"This study highlights GTP as a previously underappreciated energy source driving vital brain functions," Brewer said. "By supplementing the brain's energy systems with compounds that are already available as dietary supplements, we may have a new path toward treating age-related cognitive decline and Alzheimer's disease."

He cautioned, "More work is going to be required to find the best way to administer this treatment, since a recent clinical trial involving UC Irvine researchers showed that oral nicotinamide was not very effective because of inactivation in the bloodstream."

Brewer's collaborators were Ricardo Santana, a UC Irvine associate specialist in biomedical engineering, and Joshua McWhirt, a UC Irvine junior specialist who's now a Ph.D. candidate at the Medical University of South Carolina. Funding was provided by the National Institutes of Health and the UC Irvine Foundation.