Friday, March 26, 2021

Pharmacokinetics of NMN

 



How does one decide on delivery method of NMN (eat, sublingual, nasal drip, intravenous) and how much, scientifically IE empirically? Clear answer is 'howsoever the doctor tells'. But what if a supplement, too early to have experience in, be interpreted empirically! Suddenly, the answer can only be 'as the conversation starter', factored for how smart that person is. But what if the starter says don't know or ASK ME IN 3 YEARS! That starter is me, and the best way then is to ape the big shot, then look at the image and Horvath results reported by Dr. Sinclair, the big shot, looks 40, bioage 40 at 50! Smarter than other solutions. Dr. Sinclair mentioned name of buying company and recommended amount and dosage, and got in to very hot legal matters. He now tells his amounts and never discloses his supplier. Complicates my life but that is how the cookie crumbles. To avoid problems, I have a nice disclaimer and mention what I do! It is reporting by self with my rationality, the answer I give may change and your troubles, then on, are yours!

The delivery method chosen me, after sublingual methods, is intravenous. Any iv solution must be inserted by properly accredited nurse and only be done in extension of doctor office! Totality of my aging ingredient are (sirtuin 1-9), parp and parp are aging targets, mtor not)

sirtuin: 1gm of NMN/day (start with 500mg/day of iv), 1gm/day of resveratrol (finish before pterostilbene 200 mg kicks in) [endothelial cells lining blood path)

parp: 2gm metformin (have diabetes, 1gm of healthspan extension I hope), 3*day acarbose some for healthspanm extension too),

mtor (Nothing yet)

The stupidest thing doable is greatly manipulate amounts since under amounts will not have right response (even appreciable) and way over can be very hurtful! Mind you, much larger doses of NMN will not hurt but is way expensive.


That being the case, the Pharmacokinetics of NMN is important, all the others are noise. Rest of this note is for those competent to understand and derive better dosing schedule.


https://www.nmn.com/news/pharmacokinetics-the-missing-metric-to-determine-dosage


Why NAD+?


Strict Age decline, know not why, effects all cells (every body in human and even mammals).


Liver Function?

Key enzymes in NAD+ signaling pathways are known to protect the liver from fat accumulation, fibrosis, and insulin resistance, which are related to the development of fatty liver diseases, such as NAFLD and NASH.Raising NAD+ levels back to those of young or lean mice has been particularly effective at preventing and treating obesity, alcoholic steatohepatitis, and NASH, while improving glucose homeostasis and mitochondrial dysfunction. NAD+ boosting appears to not only improve the health of the liver, but also increase its capacity for regeneration and protect it against hepatotoxicity. 

Kidney Function?

Several lines of evidence indicate that reduced levels of NAD+ in aged kidneys are largely responsible for reduced kidney function and resilience with age

Skeletal Muscle Function?

Treatment with NAD+ dramatically improves muscle function, reverses detrimental age-associated changes in muscle by increasing mitochondrial function, increasing ATP production, reducing inflammation, and switching glycolytic type II muscle to a more oxidative fiber type (Gomes et al., 2013).

Cardiac Function?

NAD+ levels are critical for normal heart function and recovery from injury. NMN treatment either 30 min before ischemia (500 mg/kg, i.p.) or repetitive administration just before and during reperfusion provides marked protection against pres- sure overload and ischemia-reperfusion injury, reducing infarct size by as much as 44% (Hsu et al., 2009; Karamanlidis et al., 2013; Pillai et al., 2005; Yamamoto et al., 2014).

Endothelial and Vascular Function?

Cardiovascular and cerebrovascular diseases contribute to the greatest decline in quality of life after 65 and are directly responsible for about one-third of all deaths (Nichols et al., 2014; Ungvari et al., 2010).  Treatment of mice with NMN (500 mg/kg/day in water for 28 days) improves bloodflow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary den- sity (D.A.S., unpublished data). Thus repleting NAD+ levels in the vascular endothelium is an attractive approach to increasing mobility in the elderly and treating conditions exacerbated by decreased blood flow, such as ischemia-reperfusion injury, slow wound healing, liver dysfunction, and muscle myopathies. 

Immunity and Inmation?

There is a growing body of evidence that NAD+ precursors can have anti-inflammatory effects. Treatment of 24-month-old mice with NMN for 1 week reduced the expression of inflamma- tion markers such as TNF-a and IL-6 in skeletal muscle (Gomes et al., 2013). Similarly, NR significantly reduced inflammation in a mouse model of ataxia telangiectasia (AT) autoimmunity (Fang et al., 2016) and in the muscular dystrophy MDX mouse model.  NAM has been effective in the treatment of various inflammatory skin conditions (Niren, 2006), reduces the area of infiltration and demyelination in experimental autoimmune encephalomyelitis mouse models (Kaneko et al., 2006), and prevents photo-immunosuppression and photo-carcinogenesis (Damian et al., 2008; Gensler, 1997; Yiasemides et al., 2009).

Neuronal Function?

Numerous studies have reinforced the view that NAD+ levels are key to neuronal function and survival.  In addition to protecting damaged neurons, NAD+ precursors have shown promise in delaying the effects of several neurodegenerative diseases. In models of Alzheimer’s disease (AD), NAD treatment improved cognition and synaptic plasticity in mice and rats (Gong et al., 2013; Hou et al., 2018; Long et al., 2015; Sorrentino et al., 2017; Wang et al., 2016). NAM increases cell viability in a Drosophila model of Parkinson’s disease (PD) (Jia et al., 2008), and several studies have also suggested that an NA-rich diet both reduces the risk of developing PD and improves the physical functioning of individuals with PD (Alisky, 2005; Fall et al., 1999; Hellenbrand et al., 1996).NAD-boosting regimens prevent and in some cases can reverse neuronal degeneration associated with hearing loss, prion toxicity, retinal damage, traumatic brain injury (TBI), and periph- eral neuropathy (Brown et al., 2014; Dutca et al., 2014; Hamity et al., 2017; Lin et al., 2016; Vaur et al., 2017; Yin et al., 2014; Zhou et al., 2015).

Aging and Longevity?

Total NAD+ levels were once considered extremely stable. Recently, however, it has become clear that a steady decline in total NAD+ levels over time is a natural part of life for all species, from yeast to humans (Balan et al., 2008; Belenky et al., 2007; Lin et al., 2004; Massudi et al., 2012; Mouchiroud et al., 2013; Zhang et al., 2016; Zhu et al., 2015). This decline, along with the decreased activity of NAD+ signaling proteins, is believed to be one of the major reasons organisms, including humans, age.

Why or why not NR?

Key enzymes in NAD+ signaling pathways are known to protect the liver from fat accumulation, fibrosis, and insulin resistance, which are related to the development of fatty liver diseases, such as NAD and NASH. Raising NAD+ levels back to those of young or lean mice has been particularly effective at preventing and treating obesity, alcoholic steatohepatitis, and NAD, while improving glucose homeostasis and mitochondrial dysfunction. NAD+ boosting appears to not only improve the health of the liver, but also increase its capacity for neural regeneration and protect it against hepatotoxicity. 

Kidney Function?

Several lines of evidence indicate that reduced levels of NAD+ in aged kidneys are largely responsible for reduced kidney function and resilience with age

Skeletal Muscle Function?

Treatment with NAD+ dramatically improves muscle function, reverses detrimental age-associated changes in muscle by increasing mitochondrial function, increasing ATP production, reducing inflammation, and switching glycolytic type II muscle to a more oxidative fiber type (Gomes et al., 2013).

Cardiac Function?

NAD+ levels are critical for normal heart function and recovery from injury. NMN treatment either 30 min before ischemia (500 mg/kg, i.p.) or repetitive administration just before and during reperfusion provides marked protection against pres- sure overload and ischemia-reperfusion injury, reducing infarct size by as much as 44% (Hsu et al., 2009; Karamanlidis et al., 2013; Pillai et al., 2005; Yamamoto et al., 2014).

Endothelial and Vascular Function?

Cardiovascular and cerebrovascular diseases contribute to the greatest decline in quality of life after 65 and are directly responsible for about one-third of all deaths (Nichols et al., 2014; Ungvari et al., 2010).  Treatment of mice with NMN (500 mg/kg/day in water for 28 days) improves bloodflow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary den- sity (D.A.S., unpublished data). Thus repleting NAD+ levels in the vascular endothelium is an attractive approach to increasing mobility in the elderly and treating conditions exacerbated by decreased blood flow, such as ischemia-reperfusion injury, slow wound healing, liver dysfunction, and muscle myopathies. 

Immunity and Inmation?

There is a growing body of evidence that NAD+ precursors can have anti-inflammatory effects. Treatment of 24-month-old mice with NMN for 1 week reduced the expression of inflamma- tion markers such as TNF-a and IL-6 in skeletal muscle (Gomes et al., 2013). Similarly, NR significantly reduced inflammation in a mouse model of ataxia telangiectasia (AT) autoimmunity (Fang et al., 2016) and in the muscular dystrophy MDX mouse model.  NAM has been effective in the treatment of various inflammatory skin conditions (Niren, 2006), reduces the area of infiltration and demyelination in experimental autoimmune encephalomyelitis mouse models (Kaneko et al., 2006), and prevents photo-immunosuppression and photo-carcinogenesis (Damian et al., 2008; Gensler, 1997; Yiasemides et al., 2009).

Neuronal Function?

Numerous studies have reinforced the view that NAD+ levels are key to neuronal function and survival.  In addition to protecting damaged neurons, NAD+ precursors have shown promise in delaying the effects of several neurodegenerative diseases. In models of Alzheimer’s disease (AD), NAD treatment improved cognition and synaptic plasticity in mice and rats (Gong et al., 2013; Hou et al., 2018; Long et al., 2015; Sorrentino et al., 2017; Wang et al., 2016). NAM increases cell viability in a Drosophila model of Parkinson’s disease (PD) (Jia et al., 2008), and several studies have also suggested that an NA-rich diet both reduces the risk of developing PD and improves the physical functioning of individuals with PD (Alisky, 2005; Fall et al., 1999; Hellenbrand et al., 1996).NAD-boosting regimens prevent and in some cases can reverse neuronal degeneration associated with hearing loss, prion toxicity, retinal damage, traumatic brain injury (TBI), and periph- eral neuropathy (Brown et al., 2014; Dutca et al., 2014; Hamity et al., 2017; Lin et al., 2016; Vaur et al., 2017; Yin et al., 2014; Zhou et al., 2015).

Aging and Longevity?

Total NAD+ levels were once considered extremely stable. Recently, however, it has become clear that a steady decline in total NAD+ levels over time is a natural part of life for all species, from yeast to humans (Balan et al., 2008; Belenky et al., 2007; Lin et al., 2004; Massudi et al., 2012; Mouchiroud et al., 2013; Zhang et al., 2016; Zhu et al., 2015). This decline, along with the decreased activity of NAD+ signaling proteins, is believed to be one of the major reasons organisms, including humans, age.

Taking any B3 supplement without betaine is likely stupid. All of them, otherwise consume methyl, which is what betaine gives.

Why or why not NR?

Why is many factors - better control, better quality and guaranteed quality as patent owned and manufactured only by chromadex.

Why not: 2 away from NAD+ hence way slower, not 1 away as NMN, seems to enter cells without cleaving etc, seems to be better than NAD+ direct or NMN but less effective on crossing BBB although rest of body derived NAD+ does cross.

Why or why not NAD+ or NaDH direct?

Why is that they are direct!

Why not because appears to be worse for iv. Tried and unsatisfied with sublingual. NAD+ requires daily, not weekly infusion like NMN ! This empirical fact is that NAD+ is direct in use while NMN is 1 away and may be converted slowly and weekly is fine. One user claims that iv NMN forces raised energy level feeling that continues full week! Assuming that happens, NMN or better, by iv is going to be my weekly iv for rest of life, unless MIB-626. I believe the healthspan comes from exercise except that is a tall order for any one without brimming energy.

Why risking self,  rather than wait FDA NMN orlisten to Conboy re TPE?

my weltanschauug.


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