I have been taking nicotinamide/niacinamide - a 'semi' vitamin (and amide form of) niacin/B3, for a long time without the herb resveratrol, as advised by anti-aging researchers and wanted to find out if niacinamide is safe as 'monotherapy' – ie, it does not promotehuman cellular aging. Researchers note that nicotinamide suppresses Sir2 in yeast, an anti-aging gene, thus causing premature cell death, and the human 'homologue' to yeast Sir2 is Sirt1. Thus, will niacinamide decrease human longevity by inhibiting Sirt1?
The following article succinctly answers my question.
Nicotinamide extends replicative lifespan of human cells
"Sir2‐mediated lifespan extension in yeast has been shown to be abrogated by nicotinamide treatment (Anderson et al., 2003)."
"We found that an ongoing application of nicotinamide to normal human fibroblasts not only attenuated expression of the aging phenotype but also increased their replicative lifespan, causing a greater than 1.6‐fold increase in the number of population doublings."
"Taken together, in contrast to its demonstrated pro‐aging effect in yeast, nicotinamide extends the lifespan of human fibroblasts, possibly through reduction in mitochondrial activity and ROS production."
Why did niacinamide shorten the lifespan of yeast cells? Nicotinamide has anti-microbial activity against yeast, viruses and bacteria. I think this anti-microbial activity (through inhibition of yeast Sir2) has been misinterpreted as an anti-anti-aging effect (and transposed) to humans.
Other examples of nicotinamide anti-microbial activity:
Vitamin B3 as a novel approach to treat fungal infections
"The current study shows that a C. albicans enzyme, known as Hst3, is essential to the growth and survival of the yeast. Researchers found that genetic or pharmacological inhibition of Hst3 with nicotinamide, a form of vitamin B3, strongly reduced C. albicans virulence in a mouse model."
“In addition, nicotinamide prevented the growth of other pathogenic Candida species and Aspergillus fumigatus (another human pathogen), thus demonstrating the broad antifungal properties of nicotinamide.”
“Nicotinamide greatly increased the ability of the immune system to kill pathogens - there were very few left surviving [after 24 hours],” researcher Adrian Gombart, associate professor at the Linus Pauling Institute at Oregon State University, told FoxNews.com. “On the surface, it looks very promising, but we need to do studies in humans.”
Four antibiotics used for killing the tuberculosis bacterium, M. tuberculosis, are derived from niacin or nicotinamide.
Isoniazid is an analogue of niacin/nicotinic acid:
"For example, it can be mentioned the importance of anti-tuberculosis first-line drug isoniazid, which is an analogue of isonicotinic acid, an isomer of nicotinic acid."
The following article notes that Dapsone, #1 leprosy antibiotic, rifampicin #2 TB & leprosy antibiotic and pyrazinamide, are starting to be used in Lyme/borreliosis therapy and co-infections.
Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-
Borne Co-Infections, and Autoimmune Disease?
“The Dapsone and PZA protocols were the most effective for resistant Lyme and autoimmune symptoms, with PZA being the most efficacious for the dermatological manifestations of Bechet’s and arthritic/granulomatous changes.”
“Conclusion: Further scientific studies are needed on the role of intracellular bacteria and mycobacterium drugs like Dapsone and pyrazinamide in the treatment of both chronic persistent bacterial infections and resistant autoimmune phenomena.”
I can only conclude that nicotinamide's gene suppression of Sir2 in Saccharomyces cerevisiae is its method of killing this particular strain of yeast and does not reflect a decrease of human longevity. It just means nicotinamide kills yeast.
But what about the other half of the equation, resveratrol for longevity?
Mechanism of human SIRT1 activation by resveratrol
“Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro.”
"Our results have considerable implications for the general use of resveratrol as an in vivo activator of Sir2 homologues from a wide variety of organisms. In particular, because resveratrol activation appears to be specific for SIRT1, it would seem prudent to readdress the previously published studies linking yeast Sir2 and resveratrol to common cellular processes, such as lifespan increase via calorie restriction and gene silencing."
So resveratrol does nothing to lengthen the cell life of yeast thru Sir2 (and nicotinamide kills yeast thru Sir2) – consequently the yeast-to-human life extension analogy by resveratrol is out the window. And the narrative of niacinamide shortening the life spans of human cells is a refuted idea.
The human life extension idea by resveratrol supplementation is just that, an unproven idea, and it may take years to answer this question. The reason why I say this is because many claims about resveratrol have been made, a lot of hype, but ‘in vivo’, what evidence supports the many claims?
Resveratrol in Red Wine, Chocolate, Grapes Not Associated With Improved Health
“In conclusion, this prospective study of nearly 800 older community-dwelling adults shows no association between urinary resveratrol metabolites and longevity. This study suggests that dietary resveratrol from Western diets in community-dwelling older adults does not have a substantial influence on inflammation, cardiovascular disease, cancer, or longevity.”
I tried resveratrol about 3 years ago and could not perceive any benefit so it was a three month trial and on to the next herbal supplement. Everyone’s body reacts differently to supplements/drugs and someone may have a better response to resveratrol than I did.
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I also did a three month high dose trial of resveratrol with no apparent benefit. Resveratrol at high dose is a fairly expensive experiment compared to other supplements I have tried. Another issue with resveratrol is it seems to have relatively poor shelf life compared to many other supplements, but I imagine that can vary significantly depending on the source.
I wrote this long (follow up) post to be read first then researched second. So I recommend you read it through then pick and choose which articles interest you. (I wrote it to be read without having to read the whole text of the articles.)
Supplemental Niacinamide Mitigates Anxiety Symptoms: Three Case Reports
"Vitamin B3 can be absorbed directly from the stomach, but most of its absorption occurs within the small intestine."
Jump to a Parkinson's disease study:
Small intestinal bacterial overgrowth in Parkinson's disease.
"... SIBO was significantly associated with lower constipation..."
"CONCLUSIONS: This is the largest study to date on SIBO in PD. SIBO was detected in one quarter of patients, including patients recently diagnosed with the disease. SIBO was not associated with worse gastrointestinal symptoms, but independently predicted worse motor function. Properly designed treatment trials are needed to confirm a causal link between SIBO and worse motor function in PD."
Small Intestine Bacterial Overgrowth and Environmental Enteropathy in Bangladeshi
Children
"Deficiencies in cobalamin, thiamine, riboflavin, pyridoxine, and nicotinamide have been documented. SIBO has also been shown to lead to increased GI permeability and alteration of mucosal immunity....."
MY COMMENT: It is true the conditions in which SIBO in Bangladeshi children are different than PwP but the associated B vitamin deficiencies/uses are well documented in PD.
Riboflavin Has Neuroprotective Potential: Focus on Parkinson’s Disease and Migraine
SIBO Wikipedia - "Certain species of bacteria are more commonly found in aspirates of the jejunum taken from patients with bacterial overgrowth. The most common isolates are Escherichia coli, Streptococcus, Lactobacillus, Bacteroides, and Enterococcus species."
"Intestinal bacteria may play a causal role in the dermatological condition rosacea. A recent study subjected patients to a hydrogen breath test to detect the occurrence of SIBO. It was found that significantly more patients were hydrogen-positive than controls indicating the presence of bacterial overgrowth (47% v. 5%, p<0.001)."
Effect of High Concentrations of Nicotinic Acid and Nicotinamide on Growth of some Streptococci and Pneumococci
"Results with some representative cultures are shown in figures 1 to 4. Growth of a group A hemolytic streptococcus was modetately retarded by 10,000, 15,000 or 20,000 ug of nicotinic acid per ml. Nicotinamide, on the other hand, exerted definite inhibition in like amounts."
TOPICAL NICOTINAMIDE COMPARED WITH CLINDAMYCIN GEL IN THE TREATMENT OF INFLAMMATORY ACNE VULGARIS
"Conclusions. These data demonstrate that 4% nicotinamide gel is of comparable efficacy to 1% clindamycin gel in the treatment of acne vulgaris. Because topical clindamycin, like other antimicrobials, is associated with emergence of resistant microorganisms, nicotinamide gel is a desirable alternative treatment for acne vulgaris."
MY COMMENT: What is so interesting about the above article is the authors compare the effectiveness of niacinamide to the antibiotic clindamycin, yet attribute niacinamide's skin protective effect to its anti-inflammatory properties (and not its antimicrobial action.)
Nicotinamide's anti-inflammatory effect:
WIKIPEDIA: "Tumor necrosis factor (TNF, tumor necrosis factor alpha, TNFα, cachexin, or cachectin) is a cell signaling protein (cytokine) involved in systemic inflammation..."
The Role of TNF-Mediated Dopaminergic Neurotoxicity in Parkinson's Disease: Novel
Anti-TNF Biologics as Biochemical Tools and New Therapeutic Agents
Back to the first article in this thread (Supplemental Niacinamide Mitigates Anxiety
Symptoms: Three Case Reports).
Anxiety patient 1:
"Her panic attacks completely stopped and her acne was much improved as well."
"Niacinamide’s therapeutic mechanism of action was likely related to the correction of subclinical pellagra,the correction of an underlying vitamin B3 dependency disorder, its benzodiazepine-like effects, its ability to increase the production of serotonin, or its ability to modify the metabolism of blood lactate (lactic acid)."
Parkinsonian features in a case of pellagra: a historical report.
"Pellagra is characterized by a complex clinical picture, which can include neuropsychiatric symptoms and Parkinsonian features. Interestingly, pellagra and Parkinson's disease could share some basic pathophysiological mechanisms at the level of nicotinamide metabolism, resulting in mitochondrial dysfunction and alterations in dopaminergic pathways."
"To treat pellagra, the World Health Organization (WHO) recommends administering nicotinamide to avoid the flushing commonly caused by nicotinic acid. Treatment guidelines suggest using 300 mg/day of oral nicotinamide in divided doses, or 100 mg/day administered parenterally in divided doses, for three to four weeks."
The nicotinamide analogue TB antibiotic pyrazinamide can cause pellagra:
"Because of the similarity in structural formulas between pyrazinamide, isoniazide, and nicotinamide, the substrate competition is the mechanism most likely involved."
"A 42-year-old female first presented to my private practice on May 16, 2004, for chief complaints of constipation and anxiety."
"Instead of 3,000 mg daily she lowered the dose to 2,000 mg per day. Her constipation was not a problem and she was having one bowel movement daily. Her anxiety was much improved on this dose and the previous shakiness had completely resolved."
Anxiety Patient #2:
"She was also prescribed 5-hydroxytryptophan (5-HTP) at a dose of 100 mg twice daily for her mild depression, and 2,000 mg of vitamin C to be taken daily for the thrombocytopenia."
According to Hinz, et al.....as in the 'Hinz Protocol' dovepress.com/amino-acid-ma... ....5-HTP (as monotherapy) should not be used for depression.
"She discontinued all the prescribed treatments except for the niacinamide. She found her anxiety and depression to be much relieved due to being at home and not teaching during the summer months. When she felt anxiety she would take niacinamide and it would help. In her words, 'I take the niacinamide and I’m fine afterwards.' "
Vitamin B3 for arthritis, anxiety, behavioral problems, diabetes and maybe even
Alzheimer's
Dr. Arturo M. Volpe
"Since tryptophan is often in short supply in the body, taking niacinamide can help spare it and make more available for serotonin production. As a result, niacinamide has complex interactions with body and brain function as well as wide-ranging benefits."
The effect of niacinamide on osteoarthritis: A pilot study
"Niacinamide improved the global impact of osteoarthritis, improved joint flexibility, reduced inflammation, and allowed for reduction in standard anti-inflammatory medications when compared to placebo."
"Nicotinamide may be converted by the body back to tryptophan and this is the raw material for the pathway that includes 5-HTP, serotonin and melatonin. This pathway will have profound effects on mood and sleep."
Increased plasma tryptophan in HIV infected patients treated with pharmacologic doses of nicotinamide
METHODS: "After receiving approval from the institutional review board, we treatedHIV-infected patients for 2 months with high-dose niacin in the form of oral nicotinamide."
RESULTS: "There was an average 40% increase in plasma tryptophan (P50.01) in the four
HIV-infected individuals who completed the 2-mo protocol."
"Pharmacologic doses of nicotinamide in excess of 3 g/d have been used in other disease models, such as type I diabetes. The existence of a body of literature on the safe use of high doses of nicotinamide allowed us to proceed with some confidence that these doses would be non-toxic, an expectation borne out in our small study group."
"Although only preliminary data are available, evidence suggests that antiretroviral and nicotinamide treatments can boost plasma tryptophan concentrations in HIV-1-infected patients and impact the secondary effects of tryptophan depletion."
In the article "Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease?" (original post), the authors treat Lyme/borrelia infection with pyrazinamide, here is what they proscribed to prevent liver toxicity from pyrazinamide:
"We monitored her liver function every two weeks and provided liver support with alpha lipoic acid 600 mg PO BID and milk thistle 250 mg PO BID."
TB antibiotic therapy is tough on the liver and the active Milk thistle has been successfully tested in combination with TB drugs:
"Silymarin, a traditional herbal drug extracted from milk thistle (Silybum marinums) seeds, has been used as a supplement remedy for hepatoprotection."
Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study
Drug: nicotinamide dose-escalation, 2-8 grams, oral Other Name: Vitamin B3
"Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted."
From the Oregon State University Linus Pauling Institute page on niacin:
"Predominantly localized in the nucleus, SIRT1 is a NAD+-dependent deacetylase that promotes gene silencing through heterochromatin formation. Nicotinamide has beenshown to antagonize heterochromatization of the FXN locus and upregulate frataxin expression in lymphoblastoid cells derived from Friedreich’s ataxia-affected patients, possibly through inhibiting SIRT1 activity."
MY COMMENT: Proponents of Niagen (NAD-r) claim it to be superior to nicotinamide/niacinamide because Niagen does not inhibit Sirt1. But this also means Niagen is not a possible therapy for Friedreich's ataxia because nicotinamide inhibits Sirt1 and raises frataxin levels whilst Niagen does not. Niagen is being hyped but nicotinamide has. approx 80 years of clinical research studies behind its use and a thread like this could not be written about Niagen because it's applications are not yet known. Niagen is just another supplement and we have to wait and see what it is good for.
Finally,
Nicotinamide may help people with multiple sclerosis
After investigating Sirt1 I found a couple of good articles about regularly used supplements which affect Sirt1 and are good for PD.
Chronic Silymarin, Quercetin and Naringenin Treatments Increase Monoamines Synthesis and Hippocampal Sirt1 Levels Improving Cognition in Aged Rats
"Results indicated that chronic polyphenolic treatments showed restorative effects on cognition and motor coordination consistently with the biochemical and molecular results. Polyphenols reversed the age-induced deficits in monoaminergic neurotransmitters (serotonin, noradrenaline, and dopamine), increasing TPH and TH activity."
Silymarin (from the herb Milk thistle) has many functions and is a traditional treatment for liver ailments and has been shown to be neuroprotective in PD models:
Here is a monograph of silymarin and this information will help to give criteria to which supplement is best:
"Because absorption of silymarin from the gastrointestinal tract is only moderate (23-47%), it is best administered as a standardized extract of 70-80 percent silymarin."
Finally, silymarin is non-toxic and has no MAO activity so anyone can use it.
Quercetin is a known quantity on this site and it is a potent MAO inhibitor
"Out of all compounds screened for MAO-B inhibition potential the lead Curcumin ranks first with the largest interaction surface of about 1223.91 followed by this Chlorogenic acid ranks second with 1006.37 and Quercetin ranks third with interaction of about 934.67."
Quercetin Potentiates L-Dopa Reversal of Drug-Induced Catalepsy in Rats: Possible COMT/MAO Inhibition researchgate.net/publicatio...
The bad news is if you are taking a MAO inhibitor you cannot take quercetin.
Naringenin is a flavinoid from grapefruit.
"However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with β-cyclodextrin, an FDA approved excipient."
Activation of SIRT1 by curcumin blocks the neurotoxicity of amyloid-β25–35 in rat cortical neurons sciencedirect.com/science/a...
Curcumin has been shown to be neuroprotective in multiple studies but like quercetin, cannot be used as therapy with another MAO inhibitor. Curcumin is also a blood thinner so it cannot be used with other blood thinners (and Sirt1 activator), DHA omega 3:
Omega-3 Polyunsaturated Fatty Acids Antagonize Macrophage Inflammation via Activation of AMPK/SIRT1 Pathway journals.plos.org/plosone/a...
Like curcumin, DHA omega 3s have been proven to be neuroprotective in multiple PD studies.
Summary, silymarin of Milk thistle, Quercetin from green tea, apples, onions....curcumin from Tumeric, Naringenin from grapefruit and Omega 3s activate Sirt1. Quercetin, Naringenin and Curumin are MAO-b inhibitors and cannot be used with rasagiline, selegiline or xadago. Curcumin or DHA/EPA omega 3s cannot be taken together or with other blood thinners. Quercetin is best used simultaneously with L-dopa therapy because of its MAO/COMT activity.
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