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NMN improves cerebral vascular function and cognition in mice

Decreased NAD+ levels are implicated in a wide range of age related impairments. There is  evidence that restoring NAD+ by treatment with nicotinamide mononucleotide (NMN) may reverse age-related dysfunction in multiple organs.

For instance, prior research showed supplementation with NMN for 2 months restored NAD+ levels, improving vascular and muscle function of old mice to that of young mice primarily through rejuvenation of endothelial cells and increased blood flow.

This study – published in June 2019 – found that decreased NAD+ resulted in diminished cerebral blood flow (CBF) and cognitive decline.

Supplying 24-month-old mice with NMN for 2 weeks restored NAD+ levels and renewed growth of endothelial cells, resulting in increased cerebral blood flow and reversed cognitive decline to that of the 3-month-old control mice.

According to this study NMN supplementation:

  • Reverses age-induced cerebrovascular endothelial dysfunction and improves NVC responses in old mice.
  • Restores NAD+ mitochondrial energetics and reduces mtROS in aged cerebromicrovascular endothelial cells.
  • Rescues cognitive performance
  • Likely applies to treatment of Alzheimer’s disease.

Test subjects were given 500 mg/kg each day, by IP (Intraperitoneal) injection for 2 weeks. This is on the high end of dosages normally used in research and equates to nearly 3,000 mg a day for a 70 kg human.

On the other hand, 2 weeks is a short time, even in mice, to demonstrate complete restoration of cerebral blood flow and cognitive function.

IP injection is somewhat more efficient at avoiding the GI tract and delivering NAD+ precursors such as NMN directly to the bloodstream compared to delivery in drinking water. However, it is much less efficient than injecting NAD+ directly into the veins (IV).

We are happy to see the use of IP delivery here, as research with other molecules suggests it most closely matches the efficiency of sublingual delivery in humans.

QUOTES FROM STUDY:

The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).

In conclusion, our findings show that NMN supplementation exerts significant cerebromicrovascular protective effects in aged mice.

Our findings, taken together with the results of earlier studies [15,19,23,24], point to benefits at several levels of cerebrovascular and systemic pathology of aging and to the potential use of NMN as therapy for prevention of aging-induced vascular cognitive impairment.

Thus, our findings are likely relevant to the treatment of AD in elderly patients as well.

In laboratory animals long-term intake of NMN is well-tolerated without side effects [24] and clinical trials have been already started to assess the tolerability of NMN in humans [67] to develop it as an anti-aging nutraceutical.

RESULTS

Cerebral Blood Flow (CBF)  restored close to that of young mice

B) Summary data showing that in aged mice NMN supplementation restores NO mediated component of NVC responses. C) In aged mice NMN supplementation improves endothelium-mediated CBF responses elicited by topical perfusion of acetylcholine.

Heart tissue NAD+ and vascular oxidation levels restored to that of young mice

In aged mouse aortas, NMN supplementation rescues acetylcholine-induced endothelium-mediated relaxation (E), increases tissue NAD+ levels (F) and attenuates oxidative stress (G).

Performance in maze and problem solving restored

A) Heatmap representing the percentage of time spent in different locations in the maze for a randomly selected animal from each group during experimental day 3. Note that the untreated aged mouse required a greater amount of time and a longer path length in order to find the hidden escape platform. Older mice also re-enter a previously visited arm multiple time, accruing working memory errors. B) Older animals have higher combined error rates throughout day 2 and 3 of the learning phase. Combined error rate is calculated by adding 1 error for each incorrect arm entry as well as for every 15 s spent not exploring the arms. C) Older animals make significantly more working memory errors (repetitive incorrect arm entries) as compared to young mice. In contrast, aged mice treated with NMN perform this task significantly better than untreated aged mice. D) The ratio of successful escapes, averaged across trial blocks, is shown for each group. Note day-to-day improvement in the performance of young mice, which was significantly delayed in aged mice. Although aged mice treated with NMN tended to be more successful at finding the hidden escape platform in comparison to untreated age-matched controls, the difference did not reach statistical significance. Average path length (Panel E) and escape latencies (Panel F) required to reach the hidden platform in the RAWM for trial blocks 1–6. Young mice find the hidden platform sooner while swimming significantly less than aged animals. In aged mice treated with NMN the escape latencies and the average path length required to reach the hidden platform did not differ from that in aged mice. G) NMN had only marginal effect on the swimming speed. H) Aged control mice exhibited longer non-exploratory behavior compared to young mice.

DISCUSSION

It is now increasingly recognized that vascular contributions to cognitive impairment and dementia (VCID) play a critical role in elderly patients [1]. There is growing evidence that NVC responses are compromised both in elderly subjects [[5], [6], [7], [8]] and aged laboratory animals [4,9], which may importantly contribute to the age-related decline in higher cortical function, including cognition [10] and gait performance [11].

The present study was designed to test the hypothesis that NMN supplementation can rescue neurovascular coupling responses in aged mice by attenuating mitochondrial oxidative stress in cerebromicrovascular endothelial cells. To achieve this goal, aged mice were treated with NMN for two weeks. Mice were behaviorally evaluated on a battery of tests for characterization of cognitive function and motor coordination, which are sensitive to alterations in NVC responses. Then, functional tests for NVC responses and cerebromicrovascular endothelial function were performed. Markers of oxidative stress and expression of genes regulating neurovascular coupling responses, antioxidant defenses and mitochondrial function were assessed. To substantiate the in vivo findings the effects of NMN on mitochondrial ROS production and mitochondrial bioenergetics in cerebromicrovascular endothelial cells derived from aged animals   were obtained in vitro.

CONCLUSIONS

NMN rescues NVC responses and improves higher brain functions.

Here we show for the first time that NMN supplementation rescues NO mediation of NVC in aged mice supporting the concept that its potent cerebromicrovascular endothelial protective effects contribute significantly to its anti-aging, neuroprotective action.

There is additional evidence that NMN supplementation also rescues endothelial NO-mediated vasodilation in the aortas of aged mice.

In that regard it is significant that NMN treatment was also shown to increase capillary density in the skeletal muscle [15].

Thus, rescue of cerebromicrovascular NO bioavailability by treatment with NAD precursors likely has clinical significance beyond restoration of NVC responses, potentially exerting diverse protective effects both on the cerebral vasculature and physiological function of other cell types.

There is a growing evidence from clinical [10,11] and experimental [12] studies that impairment of NVC responses contributes to the age-related decline in higher cortical functions.

NMN supplementation in aging is associated with improvement of multiple domains of brain function, including hippocampal encoded memory functions.

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.

 

Our NAD+ products

All of our NAD+and NMN products are designed for sublingual use.

We discontinued selling capsules in 2017 when we found that sublingual delivery was more effective.

In March of 2018, research was published confirming our notion that capsules are almost completely destroyed in the digestive tract.

 

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