AGE/DOSE
Brain & Neurons

NAD⁺- and Metabolism-Boosting Formula Aids Neurodegenerative Diseases: British Study

Combining the NAD+ precursor NR with other metabolic activating compounds restores physical function and alleviates brain tissue death in rat models of neurodegenerative disease.

By Bennett M. Sherman

Key Points

  • A gene activity analysis of patients with Alzheimer’s disease reveals impaired function of the cell’s powerhouse – mitochondria.
  • Treating Alzheimer’s and Parkinson’s disease rat models with a combination of metabolic activators (CMA) that include nicotinamide riboside (NR), N-acetyl cysteine (NAC), L-serine, and L-carnitine tartrate (LCAT) slows brain tissue death (necrosis) and neuron degeneration.
  • The combination formula mitigates increased resting times in rats with neurodegenerative disease, indicative of restoring behavioral and physical function.

Neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, which facilitate the progressive deterioration of cognitive function, affect more than 50 million people globally. Research has linked mitochondrial dysfunction with neurodegenerative diseases but whether targeting functional aberrations of mitochondria can treat neurodegenerative diseases remains unclear.

Published in Life Sciences, Mardinoglu and colleagues from King’s College in the United Kingdom show that neurodegenerative pathology includes brain mitochondrial dysfunction based on an analysis of gene activity in human Alzheimer’s disease patients. To apply these findings, the researchers treated neurodegenerative disease rat models with a metabolism-boosting formula. This led to reduced brain tissue death and restored normal behavior. These findings point to targeting mitochondrial dysfunction with pharmaceuticals to preserve brain tissue and restore cognitive and behavioral function for those with neurodegenerative diseases.

Neurodegenerative Diseases Alleviated with Metabolic Activators

Before analyzing the rat models, Mardinoglu and colleagues confirmed that Alzheimer’s patients have mitochondrial dysfunction in brain tissue by analyzing the activity of an array of genes. They discovered that Alzheiemer’s brain tissue has altered mitochondria-related gene activity suggesting mitochondrial dysfunction. Namely, important enzymes, including ATP synthase which helps generate energy molecules within mitochondria, have less activity. These findings provide evidence that mitochondrial dysfunction in the brain is linked to neurodegenerative diseases.

The UK-based research team next treated Alzheimer’s and Parkinson’s disease rat models with the CMA. While each compound conferred benefits separately, the combination formula alleviated neuron degeneration, excessive blood flow to the brain (hyperemia), and brain tissue necrosis the most effectively for both diseases. These findings suggest that the CMA compounds work synergistically to exert their brain-preserving effects on neurodegenerative diseases.

(Turkez et al., 2022 | Life Sciences) Combining metabolic activators confers superior benefits than their independent effects. Healthy rats (CD) exhibit no brain tissue damage. Streptozotocin (STZ), used to induce Alzheimer’s, a high-fat diet (HFD) for 3 weeks (3w) or 5 weeks (5w), or STZ combined with HFD causes damage of varying severity. The metabolic activators, serine, NAC, LCAT, and NR, moderated the damage to some degree; however, the CMA conferred the most beneficial effects.

To find whether the CMA improved behavioral signs of neurodegenerative disease, the researchers treated Parkinson’s disease model rats with the compounds individually or together. The Parkinson’s disease rats showed significantly increased resting time, indicative of behavioral dysfunction. Each of the compounds contained in the CMA substantially reduced the rats’ resting times, however, this effect was enhanced with all of the molecules combined. Because less resting time is associated with physical and cognitive function, these results show that each of the compounds in the combination formula restores normal behavior, especially when they’re combined.

“We have demonstrated that [combined metabolic activator] administration improved behavioural outcomes in parallel with the neurohistological outcome in the brain,” said Mardinoglu and colleagues.

The study utilized NR, NAC, LCAT, and L-serine administered to mice separately or combined (the CMA). Research has shown that increasing the essential pro-longevity molecule nicotinamide adenine dinucleotide (NAD+) with its precursor nicotinamide riboside (NR) improves mitochondrial function and rescues neurons in a Parkinson’s disease fly model. Research has also shown that combining NR with these other metabolic activators may enhance its abilities to slow neurodegenerative disease. Mardinoglu and colleagues provided evidence for multiple pathways in mitochondrial dysfunction underlying neurodegenerative diseases by showing that the CMA confers more beneficial effects than the molecules it contains on their own.

Using Multiple Pharmaceuticals Works Better Than One

The study points to targeting multiple metabolic pathways with combinations of pharmaceuticals to counter neurodegenerative diseases’ adverse neurological effects. Interestingly, the researchers obtained their most promising results when combining the four metabolic activating compounds in this study, suggesting that together, the molecules have an enhanced effect.

Model and Dosage

Model: Female Sprague-Dawley rats

Dosage: L-serine: 1,000 mg/kg/day by oral gavage; N-acetyl cysteine: 300 mg/kg/day by oral gavage; L-carnitine tartrate: 100 mg/kg/day by oral gavage; Nicotinamide riboside: 120 mg/kg/day by oral gavage

Source

Turkez H, Altay O, Yildirim S, Li X, Yang H, Bayram C, Bolat I, Oner S, Tozlu OO, Arslan ME, Arif M, Yulug B, Hanoglu L, Cankaya S, Lam S, Velioglu HA, Coskun E, Idil E, Nogaylar R, Ozsimsek A, Hacimuftuoglu A, Shoaie S, Zhang C, Nielsen J, Borén J, Uhlén M, Mardinoglu A. Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases. Life Sci. 2022 Dec 26;314:121325. doi: 10.1016/j.lfs.2022.121325. Epub ahead of print. PMID: 36581096.

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