An important part of my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY drafted in May 2008 has been the dietary supplement regimen. This post announces a new set of revisions to that regimen based on recent research results, mainly changes with respect to folic acid, PQQ, glucosamine, and phosphatidylcholine.
The treatise and the dietary supplement regimen
The basic organizing concept followed in writing the treatise was: 1. To identify and characterize the major existing theories of what causes aging, accepting that those theories are far from independent of each other. 2. For each theory of aging, assuming that theory is correct to identify what can practically be done to slow, halt, or even possibly reverse aging according to that theory. Specifically to identify lifestyle patterns and dietary supplements that could be taken to combat aging according to that theory. For example, given the oxidative damage theory of aging, lifestyle patterns would include avoiding many toxic substances like heavy metals and the suggested dietary supplements would include antioxidants. Thus I introduced for each theory of aging the idea of a lifestyle firewall and a dietary supplement firewall. 3. Finally, I combined the lifestyle firewalls for all the theories of aging to get a combined lifestyle regimen, and I combined the dietary supplement firewalls for the different theories of aging to get a combined dietary supplement regimen.
I have revised, updated and expanded the treatise every few weeks since writing it. But this basic organization still exists. While I started out with 14 basic theories of aging, in the course of time I added 6 more to the treatise and have discussed several additional ones in this blog. The suggestions in the dietary supplement regimen are based on own independent reviews of research. That is, each supplement is in the regimen only because I have read specific independent research publications, usually multiple ones, that have convinced me that the supplement exercises credible health-producing or anti-aging effects based both on both solid theoretical grounds and demonstrable experimental results. Because the theories of aging are not independent of each other many of the suggested dietary supplements are protective of health and against aging according to multiple theories. My firewall approach to longevity is a simple and practical one. When I drafted the first version of this document in 2008, I saw this approach as appropriate for older people given the current state of knowledge and our relative ignorance compared to what will be known in coming decades. And I still see it that way. However, my views have been far from static. As I have learned more about the sciences of longevity and the overall state of knowledge has expanded, I have continued to revise the firewalls regimens. For example, by November of 2010 there was more published knowledge about telomerase biology and telomerase and the depth of my personal knowledge about this field had increased very significantly. Based on this knowledge I decided to discontinue use of cycloastragenol or any other specialized commercial “telomerase activator.” See the March 2011 blog entry The epigenetic regulation of telomeres.
I announce and explain the new changes here. My regular readers have possibly seen a few of these coming.
I am keeping this supplement in the regimen at a level of 900mcg a day but with a caution that a suggested daily dose of 1,200 mcg not be exceeded. This could happen, for example, by taking a folic acid supplement and two B-complex capsules daily, each of which contain 900mcg of folic acid. The research that has led me to this shift is detailed in the February 2011 blog entry The many faces of folic acid.
On reflection after generating the April 2011 blog entry PQQ – activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis, I have decided to commence supplementation with PQQ at a level of 10mg per day. The health and longevity-benefits research case for doing this are described in the blog entry.
I am keeping this supplement in the regimen at level of 1,500 mg a day but with caution suggesting that daily dosage not exceed that level.
This decision is a consequence of a few quite-recent studies. The first was published in October 2010 which points out a couple if important negative consequences of consumption of glucosamine: decreased SIRT1 levels and apoptosis of pancreatic cells. The publication is Hexosamines stimulate apoptosis by altering Sirt1 action and levels in rodent pancreatic beta-cells. “The activity and levels of Sirt1, which promotes cell survival in several models, are linked to glucose concentrations and cellular energy metabolism. The present study aimed at determining whether impaired Sirt1 activity is involved in the induction of apoptosis by the nutrient-sensing hexosamine biosynthesis pathway (HBP). Pancreatic Nit-1, Rinf-m5F and Min6 beta-cells were acutely treated at different doses and times with glucosamine, which directly enters and stimulates the HBP. Sirt1 levels were genetically modulated by retroviral infection. Expression levels, cellular localization, and activity of apoptosis-related markers were determined by qPCR, immunoblotting and co-immunoprecipitation. Glucosamine dose- and time-dependently induced cell apoptosis in all cell lines studied. HBP stimulation time-dependently modified Sirt1 protein levels, notably in the cytoplasm. This was concomitant with increased E2F1 binding to the c-myc promoter. In both NIT-1 and min6 beta-cells, genetic knockdown of Sirt1 expression resulted in higher susceptibility to HBP-stimulated apoptosis, whereas overexpression of Sirt1 had the opposite impact. These findings indicate that reduction of Sirt1 levels by hexosamines contributes to beta-cell apoptosis.”
A discussion of the implications of this research can be found in the October 2010 Science Daily article Too Much Glucosamine Can Cause the Death of Pancreatic Cells, Increase Diabetes Risk, Researchers Find. “In vitro tests conducted by Professor FrÃ©dÃ©ric Picard and his team revealed that glucosamine exposure causes a significant increase in mortality in insulin-producing pancreatic cells, a phenomenon tied to the development of diabetes. Cell death rate increases with glucosamine dose and exposure time. “In our experiments, we used doses five to ten times higher than that recommended by most manufacturers, or 1,500 mg/day,” stressed Professor Picard. “Previous studies showed that a significant proportion of glucosamine users up the dose hoping to increase the effects,” he explained. — Picard and his team have shown that glucosamine triggers a mechanism intended to lower very high blood sugar levels. However, this reaction negatively affects SIRT1, a protein critical to cell survival. A high concentration of glucosamine diminishes the level of SIRT1, leading to cell death in the tissues where this protein is abundant, such as the pancreas. — Individuals who use large amounts of glucosamine, those who consume it for long periods, and those with little SIRT1 in their cells are therefore believed to be at greater risk of developing diabetes. In a number of mammal species, SIRT1 level diminishes with age. This phenomenon has not been shown in humans but if it were the case, the elderly — who constitute the target market for glucosamine — would be even more vulnerable. — “The key point of our work is that glucosamine can have effects that are far from harmless and should be used with great caution,” concluded Professor Picard.””
A December 2010 publication O-GlcNAc modification, insulin signaling and diabetic complications speaks to a form of glycation damage which could possibly be exacerbated by intake of dietary glucosamine. “O-GlcNAc glycosylation (O-GlcNAcylation) corresponds to the addition of N-acetylglucosamine on serine and threonine residues of cytosolic and nuclear proteins. O-GlcNAcylation is a dynamic post-translational modification, analogous to phosphorylation, that regulates the stability, the activity or the subcellular localisation of target proteins. This reversible modification depends on the availability of glucose and therefore constitutes a powerful mechanism by which cellular activities are regulated according to the nutritional environment of the cell. O-GlcNAcylation has been implicated in important human pathologies including Alzheimer disease and type-2 diabetes. Only two enzymes, OGT and O-GlcNAcase, control the O-GlcNAc level on proteins. Therefore, O-GlcNAcylations cannot organize in signaling cascades as observed for phosphorylations. O-GlcNAcylations should rather be considered as a “rheostat” that controls the intensity of the signals traveling through different pathways according to the nutritional status of the cell. Thus, OGT attenuates insulin signal by O-GlcNAcylation of proteins involved in proximal and distal steps in the PI-3 kinase signaling pathway. This negative feedback may be exacerbated when cells are chronically exposed to elevated glucose concentrations and could thereby contribute to alterations in insulin signaling observed in diabetic patients. O-GlcNAcylation also appears to contribute to the deleterious effects of hyperglycaemia on excessive glucose production by the liver and deterioration of Î²-cell pancreatic function, resulting in worsening of hyperglycaemia (glucotoxicity). Moreover, O-GlcNAcylations directly participate in several diabetic complications. O-GlcNAcylation of eNOS in endothelial cells have been involved in micro- and macrovascular complications. In addition, O-GlcNAcylations activate the expression of profibrotic and antifibrinolytic factors, contributing to vascular and renal dysfunctions.”
An April 2011 publication casts another dark shadow on the potential impact of glucosamine supplementation: Oral glucosamine increases expression of transforming growth factor Î²1 (TGF Î² 1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: Implications for human efficacy and toxicity. “Lean Zucker rats were dosed orally for 6 weeks with glucosamine hydrochloride at doses (0 – 600 mg/kg/day) that produced peak serum concentrations of <1 – 35 Î¼M, spanning the human exposure range. Relative expression of both TGFÎ²1 and CTGF mRNA were significantly increased up to 2.3-fold in liver, kidney and articular cartilage when evaluated 4 hours after final dose. Apparent threshold serum glucosamine (C(max)) concentration required to increase TGFÎ²1 expression in cartilage was 10 – 20 Î¼M. These increases were associated with significant increases in UDP-N-acetylglucosamine concentrations suggesting increased hexosamine flux. Both TGFÎ²1 and CTGF are mediators of chondrocyte proliferation and cartilage repair. Study demonstrates that oral glucosamine doses that produce clinically relevant serum glucosamine concentrations can induce tissue TGFÎ²1 and CTGF expression in vivo and provides a mechanistic rationale for reported beneficial effects of glucosamine therapy. Induction of renal TGFÎ²1 and CTGF mRNA suggests that potential sclerotic side-effects may occur following consumption of potent glucosamine preparations.”
Together, these studies suggest that negative health and longevity effects could well result from the prolonged taking of large doses of glucosamine.
Efficacy of glucosamine for averting or treating osteoarthritis is another matter with some studies supporting its capability to address joint diseases and other studies suggesting that the existence of such a capability is questionable. The last study cited above suggests it may be efficacious. Also in that category is the work reported in the March 2011 publication Effects of glucosamine derivatives and uronic acids on the production of glycosaminoglycans by human synovial cells and chondrocytes. “Glucosamine (GlcN) has been widely used to treat osteoarthritis (OA) in humans. However, its chondroprotective action on the joint is poorly understood. In this study, to elucidate the chondroprotective action of GlcN, we examined the effects of GlcN-derivatives (GlcN and N-acetyl-D-glucosamine) and uronic acids (D-glucuronic acid and D-galacturonic acid) (0.1-1 mM) on the production of glycosaminoglycans (GAG), such as hyaluronic acid (HA), keratan sulfate and sulfated GAG by human synovial cells and chondrocytes. — Together these observations indicate that GlcN may exhibit chondroprotective action on joint diseases such as OA by modulating the expression of HA-synthesizing enzymes and inducing the production of HA (a major component of GAG contained in synovial fluid) especially by synovial cells.”
I am discontinuing inclusion of phosphatidylcholine (lecithin) in the dietary supplement regimen.
“Phosphatidylcholine (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically extracted using hexane. They are also a member of the lecithin group of yellow-brownish fatty substances occurring in animal and plant tissues(ref).”
The proximate reason for eliminating phosphatidylcholine from the regimen are laid out in the April 2011 publication Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. “Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.”
A Eurekalert writeup of this research had to say: “A new pathway has been discovered that links a common dietary lipid and intestinal microflora with an increased risk of heart disease, according to a Cleveland Clinic study published in the latest issue of Nature. — The study shows that people who eat a diet containing a common nutrient found in animal products (such as eggs, liver and other meats, cheese and other diary products, fish, shellfish) are not predisposed to cardiovascular disease solely on their genetic make-up, but rather, how the micro-organisms that live in our digestive tracts metabolize a specific lipid — phosphatidyl choline (also called lecithin). Lecithin and its metabolite, choline, are also found in many commercial baked goods, dietary supplements, and even children’s vitamins. — The study examined clinical data from 1,875 patients who were referred for cardiac evaluation, as well as plasma samples from mice. When fed to mice, lecithin and choline were converted to a heart disease-forming product by the intestinal microbes, which promoted fatty plaque deposits to form within arteries (atherosclerosis); in humans, higher blood levels of choline and the heart disease forming microorganism products are strongly associated with increased cardiovascular disease risk. — “When two people both eat a similar diet but one gets heart disease and the other doesn’t, we currently think the cardiac disease develops because of their genetic differences; but our studies show that is only a part of the equation,” said Stanley Hazen, M.D., Ph.D., Staff in Lerner Research Institute’s Department of Cell Biology and the Heart and Vascular Institute’s Department of Cardiovascular Medicine and Section Head of Preventive Cardiology & Rehabilitation at Cleveland Clinic, and senior author of the study. “Actually, differences in gut flora metabolism of the diet from one person to another appear to have a big effect on whether one develops heart disease. Gut flora is a filter for our largest environmental exposure – what we eat.” — Dr. Hazen added, “Another remarkable finding is that choline – a natural semi-essential vitamin – when taken in excess, promoted atherosclerotic heart disease. Over the past few years we have seen a huge increase in the addition of choline into multi-vitamins – even in those marketed to our children – yet it is this same substance that our study shows the gut flora can convert into something that has a direct, negative impact on heart disease risk by forming an atherosclerosis-causing by-product.” — In studies of more than 2,000 subjects altogether, blood levels of three metabolites of the dietary lipid lecithin were shown to strongly predict risk for cardiovascular disease: choline (a B-complex vitamin), trimethylamine N-oxide (TMAO, a product that requires gut flora to be produced and is derived from the choline group of the lipid) and betaine (a metabolite of choline). — “The studies identify TMAO as a blood test that can be used in subjects to see who is especially at risk for cardiac disease, and in need of more strict dietary intervention to lower their cardiac risk,” Dr. Hazen said. — Healthy amounts of choline, betaine and TMAO are found in many fruits, vegetables and fish. These three metabolites are commonly marketed as direct-to-consumer supplements, supposedly offering increased brain health, weight loss and/or muscle growth. — These compounds also are commonly used as feed additives for cattle, poultry or fish because they may make muscle grow faster; whether muscle from such livestock have higher levels of these compounds remains unknown.”
Even prior to encountering this publication I had been uncomfortable with one aspect of phosphatidylcholine: phosphatidylcholine stimulates the expression of NF-kappaB(ref)(ref)(ref). My treatise discusses how aberrant NF-kappaB signaling appears to characterize many inflammatory disease processes. “They include promotion of angiogenesis, proliferation, metastasis and invasiveness in cancer tumors, autoimmune diseases, neurodegenerative diseases and contributing to the activation of human immunodeficiency virus (HIV) leading to AIDS. — There appears to be increasing evidence that inhibition of expression of NF-kB could be a key approach for fighting cancers, controlling inflammatory diseases, AIDS, neurodegenerative conditions like Parkinson’s Disease and a number of other significant age-related maladies.” So promotion of expression of NF-kappaB is the opposite of what is wanted. In this respect, phosphatidylcholine has behaved in an opposite manner to thirty-nine pluripotent substances in my dietary regimen which suppress the expression of NF-kappaB.
This information and the other information offered in this blog or in the associated treatise is not intended for diagnosis or treatment of any medical condition and should not be construed as medical advice. The information is not a substitute for a licensed physician’s medical advice. If any opinions or suggestions herein conflict with that of a treating licensed physician, defer to the opinion of the physician. This information is intended for people in good health. The dietary supplement regimen described herein is that used by the author and may not be appropriate for other people. It is the user’s responsibility to know his or her health and medical history and ensure that supplements he or she takes do not create an adverse reaction.
The author does not have nor has ever had any business relationship with any company that packages or markets any dietary supplement.