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Do NMN and NAD⁺ have different effects on the body?

Researchers use supplementation with NMN, NR and NAD⁺ to restore levels of NAD⁺ in mice, making them look and behave like they did when young and extending their lifespan.

Although they have similar effect in some organs, there may be differences in the effect they have in other tissues throughout the body.

NAD⁺ not effective in drinking water or in capsule form
The NAD⁺ molecule is twice as large as NR or NMN, and is totally degraded in the gastrointestinal tract, so researchers do not use NAD⁺ in drinking water of mice and it is not sold in capsule form for humans.

NAD⁺ in IV or IP injections
Research has been successful using NAD⁺ injections in mice.

In humans, clinics that provide NAD⁺ by IV are exploding in popularity, even though they charge over $1,000 a day and require the patient to be hooked up to a drip IV for 8 hours.

NMN and NR poor bioavailability in capsules
NMN and NR capsules are only partially digested in the stomach, but are almost totally metabolized in the liver and excreted as NAM (Liu, 2018).

Sublingual delivery solves the bioavailability problem

Molecules like NMN, NR and NAD⁺ that have low molecular weight and are hydrophilic can be absorbed through the capillaries under the tongue directly into the bloodstream. This is called Sublingual (under the tongue) delivery.

Sublingual delivery can bypass the stomach and liver.

This may solve the bioavailability problem of capsules that get digested in the stomach, so NAD⁺ can be used instead of NAD⁺ precursors. It also may  improve the effectiveness of NMN.

Why is there no sublingual NR?

Nicotinamide Riboside is not stable by itself, so Chromadex adds Chloride to make it stable.

ALL NR sold is actually Nicotinamide Riboside with CHLORIDE.
Unfortunately, the taste is not acceptable for sublingual use.

So NR is only available in capsule form, which much pass through the stomach and liver where it is metabolized to the less effective Nicotinamide (Liu, 2018) .

NAD+ SUPPLEMENTATION

The hypothalamus is the master regulator of metabolism which impacts the entire body, and is theorized to be a central clock that controls aging itself.

NAD+ crosses the blood brain barrier to increase NAD+ in the hypothalamus to increase energy expenditure and decrease hunger (more below).

Administration of LABELED NAD+ by IP and IV injection of just 1 mg/kg a day demonstrated that exogenous NAD+ crosses the blood brain barrier to enter the hypothalamus INTACT, reduces hunger and weight gain, and increases energy expenditure and fat burning in mice.

They also show that NR and NMN can not utilize the cd43 gap to cross the blood brain barrier.

This might explain why In humans, NAD+ clinics have found success treating addictions and other brain imbalances, but NR and NMN have not been used in similar fashion.

Importance of Hypothalamus for Energy Metabolism

Hypothalamic circuits regulating appetite and energy homeostasis:  pathways to obesity

The hypothalamus in particular has emerged as an integrating, superordinate master regulator of whole-body energy homeostasis.

In summary, the hypothalamus plays a key role in the regulation of appetite and food intake both in humans and rodents.

Hypothalamic inflammation impairs the effects of insulin and leptin, contributing not only to hyperphagia and obesity development but also to the associated dysregulation of glucose homeostasis.

Brain regulation of appetite and satiety

Energy homeostasis is controlled mainly by neuronal circuits in the hypothalamus and brainstem.

Brain Regulation of Energy Metabolism (Roh, 2016)

The hypothalamus is the region of the brain that controls food intake and body weight.

Leptin and insulin signal the status of body energy stores to the hypothalamus.

Hypothalamic regulation of energy homeostasis (Sainsbury, 2002)

These peripheral hormones influence their effects on energy homeostasis either by activating or inhibiting the activity of the orexigenic or anorexic peptides within the hypothalamus.

Hypothalamus as master aging clock

Building the Case that Aging is Controlled from the Brain

Is there an Aging Clock in the Hypothalamus?

Hypothalamic programming of systemic ageing involving IKK-b, NF-kB and GnRH (Zhang, 2014)

Nutrition to boost NAD+

OTHER WAYS TO INCREASE NAD+

There are a number of lifestyle changes you can make  to increase NAD+ in you body.

It’s well known that Calorie Restriction  (CR) can extend longevity by 30–50% in many mammals (32)

CR has also been shown to increase NAD+ levels in the body , thru these pathways:

  • Lowering blood glucose levels minimizes inflammation, which consumes NAD+.
  • The ketone body BHB signals to increase AMPK to produce more NAD+
  • Burning Ketones for fuel instead of glucose requires 1/2 as much NAD+

– Ketone bodies mimic the life span extending properties of caloric restriction (veech,2017)

 KETOSIS BOOSTS NAD+

Ketosis is a metabolic state in which fat provides most of the fuel for the body. It occurs when there is limited access to glucose (blood sugar), which is the preferred fuel source for many cells in the body.

Ketosis can occur in many different diet plans whenever carb intake is low, but is most often associated the Ketogenic Diet, as that is a much easier method for restricting carbs (3, 4, 5, 6).

Recent research now shows Ketosis  provides the benefit in life extension, lowering inflammation and boosting NAD+ (3,9).

Intermittent or Periodic Ketosis is also effective at extending lifespan and likely achieves much of the benefit (36,37).

Some research even shows more benefit from a cyclical rather than a full time Ketogenic Diet (71).

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice (Newman, 2017)

The Red bars in the chart at left show the increased levels of the Ketone Body BHB produced from a cyclical Keto diet, resulting in Increased NAD+ and greatly improved neurological function and health.

Exercise to boost NAD+

EXERCISE THAT BOOSTS NAD+

Researchers are finding that 2-3  short bouts of High Intensity Interval Training  (HIIT) per week is far more effective at lowering inflammation (and increasing NAD+), especially among older adults (55)

Exercise is very effective at boosting AMPK and NAD+, especially when performed at times of low blood glucose levels  ( more about HIIT ).

Short bouts of HIIT accomplishes the goal, while avoiding overtraining from endurance workouts  which increases inflammation and consumes NAD+ (55).

SUMMARY

    • Sublingual delivery may help NAD+ metabolites and precursors avoid digestion in the stomach and liver.
    • NAD+ clinics use slow drip IV of NAD+ to avoid the stomach and liver. They are exploding in popularity, but the extreme cost and time required for treatment severely limit their application for the general public.
    • Sublingual NAD+ delivery may help solve the bioavailability problem and mimics the slow drip delivery used successfully by NAD+ IV clinics.
    • We believe the ability of NAD+ to increase metabolism through the hypothalamus has a great impact on the entire body.