A natural aging molecule may help restore memory in Alzheimer’s

In a study published in Aging Cell, scientists led by Professor Brian K Kennedy from the Department of Biochemistry and Chair of the Healthy Longevity Translational Research Programme (TRP), NUS Medicine, identified a promising role for calcium alpha-ketoglutarate (CaAKG). This naturally occurring and widely studied metabolite, known for its links to healthy aging, was found to restore key brain functions tied to memory that are disrupted in Alzheimer's disease.

The research set out to determine whether CaAKG could improve synaptic plasticity in the Alzheimer's brain, restore memory-related signaling, protect neurons from early degeneration, and support healthier cognitive aging overall. These findings point toward a shift in medical thinking, opening the door to geroprotective strategies -- treatments that target the biology of aging itself rather than addressing symptoms one disease at a time.

Researchers See New Potential for Alzheimer's Treatment

"Our findings reveal the exciting potential of longevity compounds in addressing Alzheimer's disease," said Prof Kennedy. "The research suggests that safe, natural compounds like CaAKG may one day complement existing approaches to protect the brain and slow memory loss. Because AKG is already present in our bodies, targeting these pathways may offer fewer risks and broader accessibility. Thanks to that, we may have a powerful new strategy to delay cognitive decline and support healthy brain aging."

The study showed that CaAKG improves how brain cells communicate in Alzheimer's disease models. It helped repair weakened signaling between neurons and restored associative memory, one of the earliest cognitive abilities affected by Alzheimer's. Since AKG levels naturally decline with age, restoring this molecule could be a promising way to support brain health over time and reduce the risk of neurodegenerative disease.

How CaAKG Supports Learning and Brain Health

To uncover how CaAKG produces these effects, the research team examined long-term potentiation (LTP), a process that strengthens connections between neurons and is essential for learning and long-term memory. In Alzheimer's disease, LTP is severely disrupted. The researchers found that CaAKG restored this process to normal levels.

CaAKG also increased autophagy, the brain's internal "clean-up" system that removes damaged proteins and helps neurons stay healthy. The molecule acted through a newly identified pathway, improving neuronal flexibility by activating L-type calcium channels and calcium-permeable AMPA receptors, while avoiding NMDA receptors that are often impaired by amyloid buildup.

Importantly, CaAKG restored synaptic tagging and capture, a critical mechanism that allows the brain to link experiences and form associative memories. This suggests the compound may support not only basic memory function but also higher-level learning abilities that tend to decline early in Alzheimer's disease.

Linking Longevity Science to Brain Protection

"Our goal was to determine whether a compound originally explored for extending healthy lifespan could be helpful for Alzheimer's disease," said Dr. Sheeja Navakkode, first author of the study and research scientist at Healthy Longevity TRP, NUS Medicine. "Understanding the cellular mechanisms of how CaAKG improves synaptic plasticity sheds light on new ways to protect memory and slow brain aging."