As the global population ages, the number of individuals affected by Alzheimer’s disease continues to rise, placing increasing urgency on the search for effective treatments adn preventative measures. A new study from the National University of Singapore offers a potential breakthrough, identifying a naturally occurring molecule that may restore lost memory function in models of the disease. Researchers are investigating calcium alpha-ketoglutarate (CaAKG) as a potential “geroprotective” strategy – one that addresses the underlying aging processes contributing to cognitive decline,rather than simply managing symptoms. The findings, published in aging Cell, represent a novel approach to combating Alzheimer’s and preserving brain health.
As the population ages, so does the prevalence of cognitive decline and neurodegenerative diseases like Alzheimer’s. Now, a new study suggests a naturally occurring molecule in the body may hold the key to restoring some memory function lost to the disease, offering a potential avenue for maintaining brain health in later life.
Researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), have found that calcium alpha-ketoglutarate (CaAKG), a metabolite frequently studied for its role in healthy aging, can help restore essential brain functions related to memory in experimental models of Alzheimer’s disease. The research, published in the journal Aging Cell, could offer new insights into combating age-related cognitive impairment.
The study focused on CaAKG’s ability to improve synaptic plasticity – the brain’s capacity to strengthen connections between neurons – in brains affected by Alzheimer’s. Researchers also investigated whether the molecule could restore signaling pathways involved in memory, protect neurons from early degenerative changes, and promote healthier cognitive aging. This approach aligns with the concept of “geroprotective” strategies, which target the fundamental biological processes of aging rather than just the symptoms of individual diseases.
Experiments demonstrated that CaAKG improved communication between nerve cells in Alzheimer’s disease models. Specifically, the molecule restored weakened signals between neurons and rebuilt associative memory, one of the first cognitive functions to be impacted by the disease. Levels of alpha-ketoglutarate naturally decline with age, leading researchers to believe replenishing these levels could support healthier brain aging.
To understand how CaAKG works, the team examined long-term potentiation (LTP), a process where connections between neurons strengthen, crucial for learning and long-term memory formation. LTP is severely impaired in Alzheimer’s disease, but administration of CaAKG brought LTP levels back to normal in the studied models. The molecule also stimulated autophagy, the cell’s internal “cleaning” system responsible for removing damaged proteins and maintaining neuronal health.
Researchers identified a newly discovered pathway where CaAKG increases neuronal flexibility by activating L-type calcium channels and calcium-permeable AMPA receptors, without involving NMDA receptors – often affected by amyloid accumulations. NMDA receptors are located on neurons and respond to a neurotransmitter called glutamate. The team also found CaAKG restored a synaptic mechanism that helps the brain link information and events occurring close together in time, supporting associative memory and more complex learning, which are early casualties of Alzheimer’s.
“Our goal was to see if a compound initially studied for extending healthy lifespan could also be useful in Alzheimer’s disease,” said Dr. Sheeja Navakkode, the study’s first author and a researcher within the Healthy Longevity Translational Research Programme, according to a press release.
The findings open new avenues for research into the role of natural metabolites in supporting cognitive function as we age and in the context of neurodegenerative diseases. While further research is needed, this study suggests a promising direction for developing potential therapies to combat Alzheimer’s and promote healthy brain aging.
