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Researchers at the University of California, Irvine have identified a promising method to counteract key biological features of brain aging and Alzheimer’s disease using naturally occurring compounds. In a study published in GeroScience, the scientists found that combining nicotinamide—a form of vitamin B3—and a green tea antioxidant known as EGCG can restore levels of a key energy molecule in neurons and stimulate a cellular cleanup process that helps remove toxic protein build-up.
The rationale behind this research centers on a specific energy molecule called guanosine triphosphate, or GTP. GTP plays a central role in powering essential neuronal processes, including the transport and clearance of damaged proteins. Aging is known to cause a general decline in cellular energy levels, including GTP, but most research has focused on another molecule, ATP.
The researchers suspected that GTP might be a previously underappreciated factor in Alzheimer’s disease, especially since GTP powers autophagy—a process by which cells break down and recycle damaged components, including toxic proteins like amyloid-beta. With this in mind, they set out to investigate whether restoring GTP levels in aged neurons could improve autophagy and reduce protein accumulation.
“The strongest risk factor for Alzheimer’s that everyone knows is age. As we age, we have less energy. We developed a technique to measure a particular kind of energy in brain cells called GTP,” said study author Gregory J. Brewer, a professor of biomedical engineering at the University of California, Irvine.
“We saw in mouse neurons that GTP levels were lower in old age. This led us to try to raise GTP levels with an energy precursor molecule that’s very safe, nicotinamide. At the same time, as our bodies age, we build up damaged DNA, lipids and proteins from oxidation (like rust of iron). This is worsened in Alzheimer’s. So I wondered if a wildly safe and known antioxidant compound found in green tea called EGCG would help with the oxidation problem.”
To test their hypothesis, the researchers conducted a series of experiments using cultured neurons taken from a well-established mouse model of Alzheimer’s disease known as the 3xTg-AD mouse. These mice carry human genes associated with Alzheimer’s and develop hallmark features of the disease, including intracellular amyloid-beta aggregates. The researchers also used neurons from healthy non-transgenic mice as controls. Neurons were isolated from mice at three age ranges—young (2–6 months), middle-aged (8–11 months), and old (17–28 months)—to track how GTP levels change over time and across genotypes.
The scientists used a specialized biosensor, GEVAL, that allowed them to measure free and bound GTP inside living neurons. Their results showed that GTP levels declined with age in both healthy and Alzheimer’s-model neurons, but the decline was steeper and occurred earlier in the Alzheimer’s neurons. In non-Alzheimer’s neurons, free GTP levels rose slightly in middle age before falling in old age. In contrast, Alzheimer’s neurons exhibited a significant loss of GTP by middle age, and levels remained low into old age.
In healthy young neurons, much of the GTP was found in the mitochondria—the cell’s energy factories—suggesting that this is where it is produced and used most actively. However, in old neurons, particularly those from Alzheimer’s mice, mitochondrial GTP levels fell sharply. At the same time, GTP became trapped in abnormal vesicle-like structures, hinting at a breakdown in the cell’s ability to use GTP for normal processes like autophagy and endocytosis.
To determine whether this energy shortfall could be reversed, the researchers treated old neurons with a combination of nicotinamide and EGCG. Nicotinamide boosts levels of NAD+, a key molecule involved in energy metabolism, while EGCG activates Nrf2, a transcription factor that regulates antioxidant defenses and helps maintain redox balance in cells. Together, these compounds aim to support both the production of cellular energy and the control of oxidative stress.
After just 16 hours of treatment, the researchers observed a restoration of GTP levels in aged neurons, bringing them close to levels seen in young cells. This increase was associated with a drop in the number and size of GTP-bound vesicles, suggesting improved cellular function. Importantly, the treatment also led to enhanced activity of key GTP-dependent proteins involved in vesicle trafficking, including Rab7 and Arl8b, which are essential for transporting toxic waste to the cell’s lysosomes for disposal.
The restoration of GTP and vesicular activity had additional downstream effects. In Alzheimer’s-model neurons, the treatment led to a reduction in intracellular amyloid-beta aggregates. It also reduced markers of oxidative protein damage, such as tyrosine nitration, which tend to increase with age and neurodegeneration. These findings indicate that improving GTP levels not only revives cellular housekeeping functions but may also lower the burden of toxic proteins that contribute to Alzheimer’s pathology.
“I was surprised how well the combination of nicotinamide and EGCG worked to clear an important protein in Alzheimer’s called amyloid and to lower oxidized proteins,” Brewer told PsyPost.
To confirm that the treatment was activating the intended cellular pathways, the researchers tracked the location of Nrf2, which is normally kept in the cytoplasm. After treatment, Nrf2 rapidly moved into the nucleus—an indication that it was being activated—and increased the expression of antioxidant genes such as NQO1. This response was swift, peaking within 30 minutes, suggesting that the compounds were having a rapid and coordinated effect on the cells’ stress-response systems.
The study also explored how GTP was used during autophagy. When the researchers blocked autophagy with a compound called bafilomycin, they observed a buildup of free GTP, indicating that autophagy normally consumes GTP. In contrast, stimulating autophagy with rapamycin led to GTP depletion, particularly in neurons from healthy mice. This further supports the idea that impaired GTP availability in aging may hinder autophagy and contribute to protein buildup.
The researchers also found that the Alzheimer’s neurons had greater accumulations of Rab7 and Arl8b—proteins that mark vesicles in the process of autophagy. This accumulation suggests a backlog in the system, possibly due to insufficient GTP to complete the recycling process. Treatment with nicotinamide and EGCG reduced these accumulations, suggesting that improving energy supply helped clear the logjam.
Another notable finding was that treatment improved overall neuronal viability in old Alzheimer’s neurons by about 22 percent. This increase in survival suggests that restoring GTP levels may not only clear harmful proteins but also support the overall health of aging brain cells.
“These compounds are available in your vitamin section of your grocery store as supplements, but other studies indicate that taking these supplements orally doesn’t work because they get inactivated in the blood,” Brewer said. “Therefore, new ways are needed to get them to the brain more directly.”
Despite the promising results, the researchers emphasize that their study was conducted in mouse neurons in vitro. This setup allows for tight experimental control but does not fully replicate the complexity of a living brain, which includes glial cells, blood vessels, immune responses, and other factors that influence disease progression. Additional studies in live animals and human cells are needed to confirm these findings and explore their potential clinical applications.
“These studies were done in mouse neurons in a dish,” Brewer noted. “They need to be confirmed in human neurons and in randomized, placebo controlled blinded trials. Also, these drugs have been given orally in human trials of Alzheimer’s and not succeeded because they were so quickly inactivated in the blood.”
The study, “Treatment of age-related decreases in GTP levels restores endocytosis and autophagy,” was authored by R. A. Santana, J. M. McWhirt, and G. J. Brewer.
