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NAD+ replenishment with NMN and NR shown to prevent and repair cognitive impairment in mice

2 studies were recently released within a few weeks of each other that show similar results for improving cognition in older mice.

NAD+ levels decline in many body tissues with age, including the hippocampus and other parts of the brain, and is thought to contribute to the progression of many neurological diseases such as Parkinson’s, Alzheimers and other forms of dementia.

These studies found supplementation of NAD+ precursors NR (Nicotinamide Riboside) and NMN (Nicotinamide Mononucleotide) was able to restore NAD+ levels in the hippocampus and partially reverse age related decline in short term memory and increased anxiety.

In the first study, mice given 300 mg per kg of bodyweight of NMN by oral gavage for 3 weeks.

CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves

The second study ran for 3 months, during which subjects were fed NR in their chow equivalent to 400 mg per kg of their bodyweight.

Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice

Both studies used relatively high dosages as 300 mg/kg of NMN and 400 mg/kg of NR equate to approximately 1500 and 2000 mg per day for a 70 kg human. It was a bit surprising to see the second study used NR in chow. This technique was somewhat more common 5 years ago, but is not used often lately. Some have theorized that NAD+ precursors are less available in food that when used in drinking water. It is nice to see that researchers

Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD+ levels are reduced in multiple tissues and organs, including the brain. We found that NAD+ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase (Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase (Cask) as a potential downstream effector in response to age-associated NAD+ reduction in the hippocampus. Cask expression is responsive to NAD+ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD+ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD+ availability through supplementation of NAD+ intermediates, such as NMN.

Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice

Nicotinamide adenine dinucleotide (NAD) supplementation to repair the disabled mitochondria is a promising strategy for the treatment of Alzheimer’s disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5 g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3 months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests. The change of body weight, the activation of microglia and astrocytes, the accumulation of Aβ and the level of serum nicotinamide phosphoribosyltransferase (NAMPT) were determined for the evaluation of pathological processes. We found that NR supplementation improved the short-term spatial memory of aged mice, and the contextual fear memory of AD mice. Moreover, NR supplementation inhibited the activation of astrocytes and the elevation of serum NAMPT of aged mice. For AD model mice, NR supplementation inhibited the accumulation of Aβ and the migration of astrocyte to Aβ. In addition, NR supplementation inhibit the body weight gain of aged and APP/PS1 mice. Thus, NR has selective benefits for both AD and aged mice, and the oral uptake of NR can be used to prevent the progression of dementia.

CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves

Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD+ levels are reduced in multiple tissues and organs, including the brain. We found that NAD+ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase (Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase (Cask) as a potential downstream effector in response to age-associated NAD+ reduction in the hippocampus. Cask expression is responsive to NAD+ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD+ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD+ availability through supplementation of NAD+ intermediates, such as NMN.

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