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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.

 

NAD+ DOES CROSS THE BLOOD BRAIN BARRIER

 

There are claims that both NMN and NAD+ are "TOO LARGE", and cannot enter cells directly, but must first be broken down to NR.

We recently wrote this article refuting that theory.

On September 1 2018, more proof was published proving that NAD+ crosses the blood brain barrier, enters the hypothalamus INTACT, and raises NAD+ levels.

Even better, just 1 Mg/kg a day decreased hunger, increased energy expenditure and fat burning for up to 24 hours after dosage.

For reference, most research providing mice with NMN or NR in drinking water uses 300 to 400 Mg/kg a day.

This study found both IV and IP injections had similar results. The results with 1-3 Mg/Kg by IP is extremely promising, as we note that sublingual delivery can be even more effective than IP delivery.

NAD+ DOES ENTER CELLS INTACT

Once in the bloodstream NAD+ was thought to be too large to cross the cell membrane, making it ineffective at restoring the NAD+ contents inside the cells of many tissues. In this article we show that is not true for heart and brain, and perhaps other tissues.

In fact, this research published in March 2018 shows NAD+ is able to cross the blood brain barrier and quickly increases levels of NAD+ in the hypothalamus, while NR and NMN do not.

Administration of 1 mg/kg of NAD+ reduced hunger and weight gain, and increases energy expenditure and fat burning in mice (r).

Elevating NAD+ levels the hypothalamus has great impact throughout the body, as it regulates hunger and energy expenditure.

Restoring NAD+ levels in the hypothalamus to those of a young animal is very likely to have a positive impact on organs and tissues throughout the body.

(more about the importance of hypothalamus as master regulator of metabolism below)
 

Even more tantalizing are the possible implications for aging itself.
That the hypothalamus as master aging clock, is a credible theory on aging.

Hypothalamus controls 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.
 

NMN and NAD+ enter tissues directly

Exogenous nicotinamide adenine dinucleotide regulates energy metabolism via hypothalamic Connexin 43 (Roh, 2018)
In conclusion, our results demonstrate that exogenous NAD is effectively imported into the hypothalamus and increases hypothalamic NAD content. Therefore, NAD supplement can constitute a therapeutic method for metabolic disorders characterized by hypothalamic NAD depletion in humans.
In this study published in September 2018, administration of LABELED NAD+ by IP and IV injection 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. This study also shows that NR and NMN can not utilize the cd43 gap to cross the blood brain barrier! This might explain why NAD+ clinics have found success treating addictions and other brain imbalances, but NR and NMN have not been used in similar fashion. Exogenous NAD Blocks Cardiac Hypertrophic Response via Activation of the SIRT3-LKB1-AMP-activated Kinase Pathway (Pillai, 2009)
Bruzzone et al. (21) have shown that connexin 43 (Cx43) channels are permeable to extracellular NAD
Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. “Taken together, our findings strengthen the hypothesis that eNAD crosses the plasma membrane intact" “In the present study we report that exposure to eNAD substantially increases the dinucleotide cellular pool, suggesting plasma membrane permeability” Nicotinamide adenine dinucleotide is transported into mammalian mitochondria (Baur, 2018)
Here we present evidence that mitochondria directly import NAD Taken together, our experiments confirm that despite the lack of any recognized transporter, mammalian mitochondria, like their yeast and plant counterparts, are capable of importing NAD at least two studies have previously reported evidence for uptake of NAD, leading the authors to propose that intact NAD crosses the plasma membrane and subsequently enters the mitochondria directly This observation suggests that a mitochondrial transporter for NMN may also await discovery In summary, we show that mammalian mitochondria are capable of directly importing NAD (or NADH). This finding strongly suggests the existence of an undiscovered transporter in mammalian mitochondria
Detection and pharmacological modulation of nicotinamide mononucleotide (NMN) in vitro and in vivo (Fermenting, 2009)
evidence that intracellular NMN contents promptly increase when the nucleotide is added to the culture media indicates that plasma membrane is permeable to this nucleotide
Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair and Apoptosis
Although the canonical view considers NAD unable to permeates lipid bilayers (Di Lisa and Ziegler, 2001), several studies report evidence for exogenous NAD (eNAD) uptake by different cells " These findings are at odds with the hypothesis that eNAD increase iNAD contents because of extracellularly-formed NAD precursors
Nicotinamide adenine dinucleotide is transported into mammalian mitochondria
mitochondria do not synthesize NAD at all, but rather take it up intact from the cytosol, which in turn, can take up NAD from the extracellular space  While mammalian mitochondria are generally considered to be impermeable to pyridine nucleotides (32,33), at least two studies have previously reported evidence for uptake of NAD leading the authors to propose that intact NAD crosses the plasma membrane and subsequently enters the mitochondria directly

RESEARCH WITH NAD+

Energy and metabolism

Exogenous nicotinamide adenine dinucleotide regulates energy metabolism via hypothalamic Connexin 43 In this study, administration of LABELED NAD+ by IP and IV injection 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. This study shows that NAD+ levels in the blood have a direct effect on the levels of metabolic activity in the body. They also show that NR and NMN can not utilize the cd43 gap to cross the blood brain barrier. This might explain why NAD+ clinics have found success treating addictions and other brain imbalances, but NR and NMN have not been used in similar fashion.
In mice, exogenous NAD may be transported to the hypothalamus via Cx43 at the blood-brain barrier [48] thereby increasing hypothalamic NAD content and decreasing food intake and weight gain.
The study below also showed injecting  just 1 mg/kg for 4 weeks weighed less and had more energy Effects of Chronic NAD Supplementation on Energy Metabolism and Diurnal Rhythm in Obese Mice
Chronic NAD supplementation significantly attenuated weight gain in obese mice fed a high-fat diet. Furthermore, NAD treatment recovered the suppressed rhythms in the diurnal locomotor activity pat- terns in obese mice.
Mice that received NAD+ weighed less, were more active, and had better glucose control than mice that received placebo

Age-related damage

Increased NAD+ levels protects against mitochondrial and age-related disorders (Srivastava,2016)
Reduced NAD+/NADH ratio is strongly implicated in mitochondrial disorders and, age-related disorders including diabetes, obesity, neurodegeneration and cancer [26, 53, 60, 71]. NAD+ levels also decline during aging in multiple models including worms, rodents and human tissue [17, 45, 67, 72]. Increasing evidence suggests that boosting NAD+ levels could be clinically beneficial, as it activates the NAD+/sirtuin pathway which yields beneficial effects on multiple metabolic pathways

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)