Supplementation to correct NAD+ deficiency repairs vision damage in Mice

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Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in the cells of all living creatures (3,4) and is critical for communication between the cell nucleus and the mitochondria that power the cells (5,6,7)

LOWER NAD+ LEVELS AS WE AGE

Everyone experiences lower NAD+ levels throughout the body as we age, effecting the communication within every cell of our bodies.

Scientists have known for some time that this loss of NAD+ leads to many different age related diseases as the cells lose ability to perform basic tasks and repair damage due to oxidative stress. (8)

HEALTH ISSUES RELATED TO DECLINING NAD+ LEVELS

  • Neural cognitive dysfunction (1,2,3)
  • Decreased Energy and muscle strength (23,24)
  • Higher Blood Sugar Levels and Increased Insulin resistance (20,21,22)
  • Chronic Inflammation resulting in hypertension and heart disease( 12,13,14)
  • Fatty Liver Disease (NAFLD and AFLD)(15,16,17)
  • Increased belly fat (18,19)
Conclusion: Declining NAD+ levels are implicated in many age related disease and chronic conditions

NAD+ DEFICIENCY IMPLICATED IN RETINAL DISEASE

In addition to the chronic age related diseases found to be related to declining NAD+ levels, the study below finds impaired NAD+ biosynthesis in many diverse retinal diseases among young and older mice.

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

This study published in cell magazine published sep 27, 2016 found that

  • Limiting the natural NAD+ synthesis in the photoreceptors in Mice results in loss of vision
  • Supplementation to increase NAD+ reverses the damage and restores vision
  • Mouse models of retinal dysfunction exhibit early retinal NAD+ deficiency
  • NAD+ deficiency causes retinal metabolic dysfunction

Vision depends on the 2 classes of photoreceptors the rods and cones. Many different diseases such as Retinitis Pigments (RP), Age-Related Macular Degeneration (AMD), Rod and Cone Dystrophies, and Leber Congenital Amaurosis (LCA) all attack the photoreceptors thru diverse pathways that lead to photoreceptor death and blindness.

Photoreceptors are known to have high energy requirements, but limited reserves so are dependent on constant synthesis of NAD+ to meet energy needs. (Ames et al., 1992, Okawa et al., 2008)

The authors theorized that NAD+ biosynthesis plays a key role in healthy vision. They noted that the leading cause of blindness in children, LCA, is caused by a mutation in the enzyme NMNAT1 which results in impaired synthesis of NAD+.(Falk et al., 2012, Koenekoop et al., 2012, Sasaki et al., 2015)

In mammals, NAM is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT) as the first step in biosynthesis of NAD+.

In this study, researchers created knockout mice that lack NAMPt in rod photoreceptors which disrupts the normal NAD+ biosynthesis, resulting in a 26-43% reduction in retinal NAD+ levels.

Within 6 weeks, these mice exhibited significant photoreceptor death and vision loss. The results very closely matched the degeneration seen in patients with Retinitis Pigments and other degenerative vision disease.

According to the authors:

NAD+ deficiency caused metabolic dysfunction and consequent photoreceptor death…these findings demonstrate that NAD+ biosynthesis is essential for vision

SUPPLEMENTATION TO INCREASE NAD+ PREVENTS PHOTORECEPTOR DEGENERATION AND RESTORES VISION

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To confirm the cause of vision loss, researchers supplemented knockout mice with daily injections of NMN, bypassing the need for NAMPT in the first step of NAD+ synthesis. Those mice receiving NMN experienced significant recovery of retinal function.
(Figures 3A–3C).

These data clearly demonstrate that NAMPT-mediated NAD+ biosynthesis is necessary for the survival and function of both rod and cone photoreceptors, as promoting NAD+ biosynthesis in the retina with NMN supplementation can compensate for Nampt deletion, thereby reducing photoreceptor death and improving vision.

NAD+ DEFICIENCY IS COMMON IN MANY RETINAL DISEASES

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Researchers were able to determine that NAD+ deficiency is common in many vision problems.

Mice subjected to light exposure retinal damage had significant reduction in NAD+ levels (Figure 3H)

Similar reductions in NAD+ levels were found in mice with streptozotocin (STZ)-induced diabetic retinal dysfunction compared to non-hyperglycemic controls (Figure 3I).

Lastly, they compared 18-month-old vs 6 month old mice. As with the light exposed and diabetic induced mice, the older mice exhibited diminished vision along with decreased retinal NAD+ levels (Figure 3J).

These findings support the idea that NAD+ deficiency may be a shared feature of retinal dysfunction.

SUPPLEMENTATION TO INCREASE NAD+ PROTECTS VISION

screen-shot-2016-10-04-at-10-12-49-amAfter demonstrating that light induced retinal dysfunction was linked to decreased NAD+ levels, researchers were able to show that supplementation to increase NAD+ could protect against retinal damage.

Mice that were given injections of NMN for 6 days prior, and 3 days after light exposure exhibited improved retinal function vs those that did not receive NMN injections (Figures 4A–4C).

Conclusion: Results from this study suggest that supplementation to increase NAD+ deficiencies can help repair macular damage and may be an effective treatment for many common degenerative vision problems.

IMPLICATIONS FOR HUMANS

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This study was very specific for the impact of NAD+ on Retinal disease in Mice, but is also further evidence that the absence of sufficient NAD+ has dire consequences, and that replacement of NAD+ can repair damage.

Researchers are experimenting with various techniques for raising NAD+ levels in mice and humans such as:

NMN
The 2013 study by Dr David Sinclair that demonstrated increased levels of NAD+  reverses age related degeneration in mice also used injections of NMN (25).

While effective at raising NAD+ in mice, NMN is not currently available for use in humans and it is not known if oral supplementation will be safe or effective.

NICOTINAMIDE RIBOSIDE
Other studies with mice and human subjects use supplementation with Nicotinamide Riboside (NR) to raise NAD+ levels.

NR is a precursor the body can use to manufacture NAD+. It has been shown to be safe and effective at raising NAD+ levels in humans in dosages of around 250mg a day.

CD38
Another approach to boosting NAD+ levels is preventing the drop in NAD+ levels in the first place.

Recent studies have demonstrated that the enzyme CD38 becomes elevated as we age, possibly in response to increasing inflammation levels, and corresponds with declining NAD+ levels.

QUERCETIN
Flavonoids such as Quercetin are proving effective at lowering CD38 levels which results in higher circulating levels of NAD+ in the bloodstream.

Dr Sinclair recently published this article on CD38 and concluded that:

  • Combating the rise of CD38 is a promising approach to protect NAD+ levels.
  • The efficacy of NAD+ precursors may be enhanced by co-supplementation with CD38 inhibitors
  • Conclusion: Inhibiting CD38 to prevent NAD+ destruction AND supplementing with NAD+ precursors so the body can create more NAD+ is a promising new avenue in the anti-aging battle