NUS Medicine Study: Promising Longevity Molecule CaAKG May Defend Against Alzheimer’s Disease

Breakthrough Discovery at NUS Medicine: CaAKG's Potential Against Alzheimer’s

A groundbreaking study from the National University of Singapore’s Yong Loo Lin School of Medicine (NUS Medicine) has identified calcium alpha-ketoglutarate (CaAKG), a naturally occurring metabolite known for its longevity benefits, as a promising compound to combat Alzheimer’s disease (AD). Published in the prestigious journal Aging Cell, the research demonstrates how CaAKG restores critical brain functions impaired in AD models, offering hope for healthier cognitive ageing.

Led by Professor Brian K. Kennedy, Chair of the Healthy Longevity Translational Research Programme (TRP) at NUS Medicine, and first author Dr. Sheeja Navakkode, the study shifts focus from symptom management to targeting the root causes of ageing-related neurodegeneration. As Singapore grapples with an ageing population, this work underscores NUS’s leadership in biomedical research.

The Growing Challenge of Alzheimer’s in Singapore and Beyond

Alzheimer’s disease, the most common form of dementia, is characterized by progressive cognitive decline due to amyloid-beta plaques, tau tangles, and synaptic loss. In Singapore, dementia affects 8.8% of adults aged 60 and above — roughly one in 11 — down from 10% a decade ago, thanks to better education and lifestyle interventions. However, with approximately 74,000 cases in 2023, projections estimate up to 152,000 by 2030 and 240,000 by 2050, straining healthcare resources.

The Well-being of the Singapore Elderly (WiSE) study highlights that over half of cases remain undiagnosed, emphasizing the need for preventive strategies. NUS Medicine’s research aligns with Singapore’s Research, Innovation and Enterprise 2025 (RIE2025) plan, prioritizing healthy longevity to add disease-free years.

Understanding CaAKG: The Body’s Own Longevity Metabolite

Calcium alpha-ketoglutarate (CaAKG) is the calcium salt of alpha-ketoglutarate (AKG), a key intermediate in the tricarboxylic acid (TCA) cycle — the cell’s energy powerhouse. AKG levels decline with age, contributing to metabolic dysfunction. Previous studies by Prof. Kennedy showed CaAKG extends lifespan and healthspan in mice by reducing inflammation and enhancing autophagy, the cellular recycling process.

• Produced naturally in mitochondria during energy production.
• Supplementation safe, as it mimics the body’s own compound.
• Previously linked to delayed ageing in animal models.

This marks the first investigation of CaAKG specifically for AD synaptic deficits, bridging longevity science and neurodegeneration.

Methodology: Cutting-Edge Experiments at NUS Laboratories

The NUS team used hippocampal slices from APP/PS1 transgenic mice, a standard AD model overexpressing amyloid precursor protein (APP) and presenilin 1 (PS1), mimicking plaque buildup and synaptic impairment. Key techniques included:

• Electrophysiology: Measured long-term potentiation (LTP) — strengthened synaptic connections underlying learning — using precise electrode stimulation in hippocampal CA1 region.
• Synaptic Tagging and Capture (STC): Tested associative memory by pairing weak and strong stimuli to tag synapses for protein capture.
• Western Blotting: Assessed autophagy markers like LC3-II.
• Pharmacological blockers confirmed pathways involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs), bypassing dysfunctional NMDA receptors.

This rigorous, ex vivo approach allowed detailed mechanistic insights without whole-animal behavioral confounders.

Key Results: Restoring Memory Pathways in AD Models

CaAKG dramatically rescued LTP deficits in AD slices, normalizing synaptic strength to wild-type levels, with stronger effects in females. It facilitated STC, restoring associative memory — an early AD casualty. Autophagy surged, evidenced by elevated LC3-II, akin to rapamycin (mTOR inhibitor). Neurons showed reduced degenerative changes and improved communication.

These findings position CaAKG as a geroprotector for AD.

Unveiling Mechanisms: From Synapses to Cellular Cleanup

CaAKG activated LTCC and CP-AMPARs, enabling calcium influx for LTP without NMDA reliance — blocked by amyloid toxicity. Enhanced autophagy cleared damaged proteins, while STC restoration supported late-phase memory consolidation. Prof. Kennedy notes: “Our findings reveal the exciting potential of longevity compounds in addressing Alzheimer’s disease.”

Dr. Navakkode adds: “Understanding how CaAKG improves synaptic plasticity sheds light on new ways to protect memory.” This pathway offers a novel therapeutic window.

Meet the Pioneers: Prof. Kennedy and Dr. Navakkode

Prof. Brian K. Kennedy, Distinguished Professor of Biochemistry, directs the Healthy Longevity TRP. A global ageing leader from Buck Institute, his lab explores geroscience interventions.Research positions in such labs abound at NUS.

Dr. Sheeja Navakkode, Senior Research Fellow in Kennedy’s lab, specializes in synaptic plasticity and neurodegeneration. Her expertise in electrophysiology drove this study.

NUS’s Healthy Longevity Ecosystem

The TRP at NUS Medicine pioneers geroprotectors, ageing clocks, and trials. Recent launches include a Clinical Trial Centre for longevity interventions. Collaborations with industry accelerate translation.Learn more about NUS longevity research.

Singapore invests heavily, with RIE2025 allocating billions for biomedical sciences.

Implications and Challenges for Alzheimer’s Therapy

CaAKG could complement anti-amyloid drugs like lecanemab, targeting synaptic health proactively. Its safety profile — natural, supplement-available — promises accessibility, but experts like NTU’s Asst. Prof. Ch’ng urge behavioral and human trials.

• Potential to delay onset in at-risk populations.
• Geroprotection: Prevent multiple age-related diseases.
• Risks: Limited human AD data; dosage optimization needed.

Future Outlook: From Lab to Clinic in Singapore

Next steps: Validate in diverse AD models, then human trials via NUS’s new centre. Ongoing AKG ageing trial (NCT05706389) paves the way.AKG trial details. Singapore’s ageing agenda positions NUS at forefront.

Read the full study: Aging Cell paper.

Photo by Google DeepMind on Unsplash

Careers in Longevity Research at Singapore Universities

NUS and peers like NTU seek talents in neuroscience, gerontology. Roles span postdocs to faculty. Explore postdoc opportunities, research assistants, and Singapore academic jobs. For advice, visit higher-ed-career-advice.

This NUS breakthrough exemplifies why Singapore is a hub for healthy longevity innovation.