01
Mar

Q. I am most interested in the glycation theory of aging- whereby because of proteins cross-linking they become impaired etc. I am a 50 year old male who has been tested by BioCLIP™ and found to have hardening of the arteries. I also have mild cataracts and a potential pre-diabetic (type-II) development, (hence my interest in this theory!) Please advise me on any suitable strategies to reduce my glycated blood load.

B.A., Oregon

A. Dear B.A.,

The glycation theory of aging is a modern outgrowth of the venerable cross-linking theory of aging, first proposed by Johan Bjorksten in 1942.1,2 Bjorksten was a chemist from Finland, who earned his Ph.D. degree at the University of Wisconsin in 1937. He went to work for the Ditto Corporation of America, which was the ‘Xerox’ of the day.

Protein cross-linking as cause of aging

While at Ditto Corporation, one of the main problems Bjorksten faced was to develop a way to increase the ability of the Hectograph films to withstand summer temperatures, exposure to water, mechanical stretching and friction, and to prevent their drying out and cracking. The ‘aging’ of hectograph films was due to the cross-linking of protein molecules, which Bjorksten believed was also the cause of aging in humans. This was confirmed in a crude way by comparing the similarity between the shape of the mortality curve for humans (Fig. 1) Fig. 1. Mortality rate plotted against time for white American males.

with a viscosity curve of gelatin during a cross-linking reaction (Fig. 2).3,4 The crosslinkage theory stated that the principal cause of aging was the linking together of two or more large molecules (macromolecules), which progressively linked with other molecules, impairing the functioning of cells, tissues, and organs, resulting in the aging of the organism.

Fig. 2. Rate of progressive cross-linking of gelatin.

Search for cross-linkage inhibitors

Bjorksten focused on a potential means of preventing and breaking up crosslinkages by using chelating agents that attach to metals within the body, enabling them to be excreted. Ethylene-diamine-tetra-acetic acid (EDTA) is a synthetic amino acid that removes metal-based crosslinkages by chelation, thereby “depolymerizing the gerogenic aggregates.” 5 Chelating agents in current clinical practice besides EDTA (approved for use in the treatment of lead poisoning) are deferoxamine (Desferal® for acute iron intoxication), and DMSA (used to treat lead and mercury intoxication). Physician members of the American College for Advancement in Medicine (ACAM) are proponents of intravenous chelation therapy with EDTA as a treatment for many chronic degenerative diseases, like atherosclerosis, hypertension, diabetes, and Alzheimer’s disease.6 Chelation with oral EDTA chelation is also becoming more widely used.

[Ed. – EDTA is available in BCI®Beyond Clean 2® and Beyond Fiber®]

Other natural chelators include garlic, 7 chlorella, 8 lactic acid, citric acid, and malic acid. Bjorksten demonstrated that lithium was also an effective aluminum chelator and crosslinkage inhibitor, stating that “lithium continues to be the most effective electrolyte for aluminum detachment.” 9

[Ed. – Lithium orotate is available from IAS]

Chelators as life-extending substances

A number of studies confirm that chelating agents, particularly, EDTA — may have life-extending properties. Scientists demonstrated the life-extending effects of EDTA on lowly rotifers (small multi-celled animals found in freshwater lakes and ponds).10-14 In the Soviet Union in the 1970s, Dr. T.L. Dubina performed a series of studies with EDTA on the life span of rats. In most of the studies, the mean life span of female rats treated with EDTA was increased by nearly 50%, and in one study the maximum lifespan increased 18-25% over the control animals. 15

Aluminum—a powerful cross-linker

Aluminum is a highly reactive metal that occurs freely in nature, and comprises over 8% of the earth’s crust. Although it also occurs very widely in human nutrition, (most people ingest 10-100 mg of aluminum daily), it does not play a role in any known metabolic process. Aluminum is highly toxic, even in extremely small amounts, and although the neurotoxic effects of aluminum have been known for many years,16 scientists have recently shown that aluminum accumulation may contribute to Parkinson’s disease17 Down’s syndrome18 and Alzheimer’s disease.19

Aluminum uptake increases with age

In 1955, during a talk on gelatin crosslinkages and aging at the Gerontological Society in Baltimore, Bjorksten discussed the relationship of aluminum to crosslinking. One of the attendees, Prof. H.H. Zinsser of Columbia University, was so interested in the concept that he and Bjorksten began a fruitful collaboration that was to last for seven years. Using spectrographic analysis, they examined the aluminum content of 84 persons, ranging in age from 10 to 90 years (Fig. 3).

Aluminum concentration versus increasing age in aortic tissue. Bjorksten, J. The crosslinking reaction in relation to aging, Life Chemistry Reports, 1988, 6:367-385.

They found peak levels at age 40-50, followed by a drop and then leveling off, indicating that those whose aluminum accumulation peaked in middle age most likely did not survive the next ten years. 20 Zinsser’s data were confirmed independently by scientists who demonstrated a progressive increase of aluminum concentrations in the brain (Fig. 4).

Brain aluminum concentrations as a function of age. Bjorksten, J. The role of aluminum and age dependent decline, Environmental Health Perspectives. 1989, 31, 241-242.

21 Bjorksten concluded that the progressive increases of aluminum with age were of great importance, and believed that the aluminum mechanism alone would limit human lifespan to 110-120 years of age even if no other cause of death intervened.22

Preventing aluminum accumulation and crosslinking

Bjorksten and his staff evaluated the ability of chelating agents to remove aluminum-containing stains from the aortas of 5-6 month-old hogs (Fig. 5).

Comparison of the ability of various chelating agents to remove aluminum from hog aorta

23 it can be seen that EDTA was the most effective. Lactic acid, similar to blood concentrations generated by exercise were moderately effective. Of interest was the fact that 0.5 % procaine—the active ingredient of Gerovital® (or GH3, the Romanian antiaging drug)—was also moderately effective in reducing the aluminum. This raises the question whether the metabolites of GH3—DMAE and PABA—might also have some effect in this regard.24 In fact, Drs. Imre Zs.-Nagy and Katalin Nagy demonstrated that both dimethylaminoethanol (DMAE) and centrophenoxine (CPH) are indeed able to diminish the extent of crosslinking in old rats.25

[Ed. – Original Gerovital-H3® and generic GH3-Pro® are available, as is centrophenoxine as Cent-Pro®]

Bjorksten’s team also evaluated the ability of various concentrations of lithium to remove tightly bound aluminum from tanned leather baseball covers.26, 27 Using a 0.05M concentration of lithium citrate, they completely demetalized the leather in approximately three months. Lithium is used clinically to treat manic depressive illness (MDI). Recent studies indicate that it may offer benefit in the prevention and treatment of Alzheimer’s disease, as well. 28 Perhaps long-term treatments with low doses of lithium may be an effective way to displace crosslinked/protein bound aluminum in animals and humans. Lithium orotate as a dietary supplement is the safest, most effective form of lithium available. Bjorksten spent his entire career searching for the cause and cure of crosslinks, which he believed would result in the reversal of aging and maintenance of prolonged youth. He believed that one cause of the crosslinks was heavy metal poisoning, (especially aluminum), which could be prevented and reversed with chelation therapy. He also identified the loss of fluidity of cell membranes as a contributing factor, and supported the use of membrane fluidizers such as centrophenoxine, phosphatidylserine, choline and lecithin.

Advanced Glycation End Products of Aging (AGEs)

In 1965, Dr. H.B. Bensusan proposed that a process known as the Maillard reaction, (the non-enzymatic chemical reactions between proteins and carbohydrates that cause cooked foods to turn brown) was what caused all long-lived proteins in the body to turn brown and become fluorescent, (under UV light), become more cross-linked, less soluble, less elastic, and less digestible by enzymes. In 1985, Monnier, Kohn and Cerami provided further details of the role of the Maillard reaction,1 and further developed the idea that the Maillard reaction causes premature aging and degenerative diseases such as diabetes and heart disease.29 In this regard, many scientists think the human body may be viewed as a ‘low temperature oven’ with a relatively long—approximately 75 year —‘cooking cycle.’30 The Maillard reaction involves a chemical reaction between a sugar with a protein, into a complex known as a Schiff base. With continued exposure to the sugar, the Schiff base undergoes a ‘rearrangement’ known as non-enzymatic glycosylation that results in a more stable, less reversible substance, known as an Amadori product. In the human body, this process reaches equilibrium over several weeks (Fig. 6).

Pathway of advanced glycosylation, from Schiff bases to AGEs over time.

31 The Amadori product further degrades irreversibly into a number of highly reactive carbonyl (C=O) compounds called Advanced Glycation End products, designated by the acronym AGE.32 AGE is a clever pun which reflects the proposed relationship of these reactive substances to aging and age-related diseases. AGEs can further react with other fats, proteins and nucleic acids to form largely indissoluble crosslinks. The age-related accumulation of these AGE products has been demonstrated in many tissues of the body (Fig. 7).

Increased accumulation of AGEs (carboxymethyllysine [CML]) with age in human lens protein and skin collagen

33 During long-term hyperglycemia (elevated blood sugar), as in diabetics, glycation and AGE formation may be quadrupled! This explains why diabetics suffer the premature onset of a wide range of age-related complications including cataracts, retinopathy, neuropathy, nephropathy, atherosclerosis and osteoporosis.34, 35

Crosslinkage Theory Gets New Life

Bjorksten was a talented petroleum chemist. Had he been a food chemist instead, he may have appreciated this link between the Maillard Reaction and crosslinking much earlier, and made even greater progress in developing preventive and therapeutic approaches to crosslinkage-induced aging. Through their insightful work in understanding this process, scientists like Brownlee, Cerami and Monnier provided renewed impetus and a ‘rebirth’ for the crosslinkage theory. Unfortunately, they did this with little attribution to Bjorksten, who had doggedly pursued this approach to aging for over 50 years.

AGE Breakers (and inhibitors)

There are a number of substances that have been used to delay and reverse glycation-induced crosslinkages (AGEs). Khalifah and his colleagues proposed a schematic of the formation of AGEs, and illustrates a number of specific therapeutic targets (Fig.8).31

Schematic of Maillard Reactions and potential sites of intervention

Metformin (Glucophage®): Metformin is an anti-diabetic biguanide that was derived from the herb, Goat’s rue (Galega officinalis). Biguanide drugs were recognized by Prof. Vladimir Dilman as early as the mid-1970s as the most effective antiaging drugs in existence. Metformin is an insulin receptor sensitizer, capable primarily of lowering blood sugar and insulin. Dilman also demonstrated that biguanides restored cortisol receptor sensitivity. Metformin has many other beneficial properties, including optimizing lipid profile, reducing body fat, maintaining levels of growth hormone, stimulating immunity, and extending the maximum lifespan of experimental animals.36

Aminoguanidine (Pimegedine): Aminoguanidine is a substance that has been known for over 100 years. It is structurally very similar to guanidine, the active ingredient in the herb, Goat’s rue (the herbal prototype for metformin). Aminoguanidine has aroused a great deal of interest in the last twenty years, due to its demonstrated ability to block the formation of AGEs and AGE-induced crosslinkages in both animal and human clinical studies. Aminoguanidine inhibits AGE formation, preventing AGE-induced crosslinks in collagen and other tissues. Fortunately, aminoguanidine does not interfere with the formation of normal collagen crosslinks, which are required for structural integrity. Another mechanism by which aminoguanidine is believed to act is by enhancing the action of nitric oxide (the same mechanism by which Viagra functions).37, 38 Aminoguanidine also reduces the formation of lipofuscin (age pigment) and prevents or reduces cataracts, atherosclerosis, diabetic retinopathy, nephropathy and neuropathy (Fig. 9).

Effect of aminoguanidine on prevention of structural abnormalities of long-term diabetics in the eye (retina) and kidney (glomerulus).

30, 39-41 In a study of diabetic patients, after four weeks of therapy with aminoguanidine, LDL cholesterol decreased almost 30%, and total cholesterol and triglycerides both decreased almost 20%. Hemoglobin-AGE levels, a circulating marker of the degree of glycosylation, also decreased dramatically (13.8 U/mg Hb at the beginning of therapy, to 10.0 U/mg Hb after only four weeks).42 Aminoguanidine is very safe, as indicated by short-term human studies which used the astronomical dose of 1200 mg daily.43 (This is in comparison with a usual human dose of 100-300 mg daily). The dose required to cause death in half the animals (mice) to which it was administered (Lethal Dose 50 [LD50]) was 1800 mg/kg.37 That would be equivalent to a human dose of almost 300 grams!

Pyridoxal-5-Phosphate (P5P): P5P, the active form of vitamin B6, has been found to significantly reduce the non-enzymatic glycosylation (formation of AGEs) of bovine serum albumin (BSA) with radioactive-labeled sugar. Of the substances tested, P5P was exceeded only by aminoguanidine in its ability to inhibit AGE formation (Fig. 10).

. In vitro (“test tube”) test comparing the formation AGEs on bovine serum albumin when exposed to glucose

Combining P5P with metformin or aminoguanidine may enhance their AGE-inhibiting actions even more.44

Vitamin B1 (Thiamine) and Benfotiamine: In their book, Life Extension, Durk Pearson and Sandy Shaw reported that thiamine was an effective crosslink inhibitor.45 They were at that time consuming two grams of thiamine each day in their personal antiaging regimens. Thiamine may ultimately also prove to be an effective crosslinkage breaker as well as inhibitor. Another thiamine derivative is the fat-soluble Benfotiamine. Benfotiamine is very helpful in the treatment of diabetic neuropathy at a dose of 300 mg twice daily.

Carnosine: Dr. Alan Hipkiss of the Division of Biomolecular Sciences, King’s College London, reviewed the antiaging effects of carnosine and aminoguanidine.46 Dr. Hipkiss believes that one of the major mechanisms of the antiaging effects of carnosine is its powerful effects as a crosslink inhibitor and breaker, and that the use of these substances might help to control age-related molecular dysfunction. Carnosine has been used in doses generally ranging from 500-2,000 mg/day.

Sorry for this long answer to your short question—but I believe that Dr. Bjorksten’s often overlooked contributions to the glycation/crosslinking theory need to be remembered and reemphasized.

Ward Dean, M.D.

References:

1. Bjorksten, Johan. Recent developments in protein chemistry, Chem Industries, 1941,48: 746-751.

2. Bjorksten, Johan, and Champion, William J. Mechanical influence upon tanning, J American Chemical Society, 1942, 64: 868-869.

3. Bjorksten, Johan. A common molecular basis for the aging syndrome. J American Geriatrics Society, 1958, 6: 740-747.

4. Bjorksten, Johan, and Andrews, Fred. Fundamentals of aging: A comparison of the mortality curve for humans with a viscosity curve of gelatin during the cross-linking reaction. J American Geriatrics Society, 1960, 8: 632-637.

5. Bjorksten, Johan. Pathways to the decisive extension of the human specific lifespan, J American Geriatrics Soc., 1977 a, 25: 396-399.

6. Chappell, L.T., Stahl, J.P., and Evans, R. EDTA Chelation treatment for vascular disease: A Meta-Analysis using unpublished data. J Adv. Med, 1994,

7: 3, 131-142. 7. Lau, B. Garlic for Health, 1988, Lotus Light Publications, P.O. Box 2, Wilmot, Wisconsin 53192, pp. 31-32.

8. Wilkinson, S. Mercury removal by immobilized algae in batch culture systems, J Applied Phycology, 1990, 2: 223-230.

9. Yaeger, Luther L., and Bjorksten, Johan. Displacement of protein bound aluminum. Rejuvenation, 1984, 12: 12-14.

10. Tyler, A. Longevity of gametes: Histocompatibility, gene loss and neoplasia, in: Aging and Levels of Biochemical Organization, by Bruder, A.M., and Sacher, G.A. (eds), Section II, Part 11, 1965, U Chicago Press, Chicago, 50-86.

11. Tyler, A. Prolongation of life-span of sea urchin spermatozoa and improvement of the fertilization-reaction by treatment of spermatozoa and eggs with metal-chelating agents (amino acids, versene, DEDTC, Oxine, Cupron). Biol Bull, 1953, 104: 224.

12. Sincock, A.M. Calcium and aging in the rotifer Mytilina brevispina var redunca. J Gerontology, 1974, 29, 514-517.

13. Sincock, A.M. Life extension in the rotifer Mytilina brevispina var redunca by the application of chelating agents. J Gerontol, 1975, 30: 289.

14. Neigauz, B.M., and Ravin, V.K. Effect of physiologically active substances on the longevity of the nematode Caenorhabditis elegans. Zh. Obshch Biol, 1983, 44: 6, 835-841.

15. Komarov, L.V., and Bakaev, V.V. Means of the Life Prolongation, Rejuvenation, 1983, XI: 2-3, 46-51.

16. Spira, L. Clinical Aspects of Chronic Poisoning by Aluminum and its Alloys, 1933, Bale and Sons, London.

17. Galle, P. , and Duckett, S. X-ray microanalysis of pallidal arteries in Parkinson Disease, Sixth European Congress on Electron Microscopy, 1976, Jerusalem, 210-211.

18. Crapper, D.R., Kalrik, S., and DeBoni, U. Aluminum and other metals in senile (Alzheimer) dementia, in: Alzheimer’s Disease: Senile Dementia and Related Disorders, by Katzman, R., Terry, R.D., and Bick, K.L. (eds), 1978, Raven Press, New York.

19. Crapper DR, Krishnan SS, Quittkat S. Aluminium, neurofibrillary degeneration and Alzheimer’s disease. Brain. 1976 Mar; 99(1):67-80.

20. Zinsser, H., Bjorksten, I., Bruck, E.M., Baker, R.F., et al. The freezing pool: A unified sequence of the aging process, in: Medical and Clinical Aspects of Aging, by Blumenthal, H. T. (ed.), in: Proc 5th Int Assn Gerontology, 1962, Columbia U Press, 1962, 482-505.

21. Markesbery, W.R., Ehmann, W.D., Alauddin, M., and Nossain, T.I.M. Brain element concentrations in aging. Neurobiology of Aging, 1984,5: 19-28.

22. Bjorksten, Johan, Yaeger, Luther L., and Wallace, Terri. Control of aluminum ingestion and its relation to longevity. Internat J Vit Nutr Res, 1988, 58: 462-465.

23. Schenk, Roy U., Bjorksten, Johan, Lipert, Robert, and Mortell, Molly. Extraction of aluminum from aorta tissues by chelating agents and lactic acid. Rejuvenation, 1981, 9: 4-10.

24. Dean, W. DMAE and PABA — An alternative to Gerovital (GH3), the ‘Romanian Youth Drug,’ Vitamin Research News, 2001, 15: 9, 1-7.

25. Zs.-Nagy, I., and Nagy, K. On the role of cross-linking of cellular proteins in aging. Mech Aging Dev, 14: 245-251, 1980.

26. Yaeger, Luther L. Electrolytic scission of hexadentate aluminum bonds. Rejuvenation, 1983, 11: 76-80.

27. Yaeger, Luther L., and Bjorksten, Johan. Displacement of protein bound aluminum. Rejuvenation, 1984, 12: 12-14.

28. Fugate, L. Potential Role for Lithium in Preventing Alzheimer’s disease. Vitamin Research News, 2002, 16: 2, 1-7.

29. Monnier, V.M., Kohn, R.P., Cerami, A. Proc. Natl. Acad. Sci., 1984, 81: 583-587.

30. Dyer, D.G., Blackledge, J.A., Katz, B.M., Hull, C.J., Adkisson, H.D., Thorpe, S.R., Lyons, T.J., and Baynes, J.W. The Maillard reaction in vivo. Z. Emahrungswiss-enschaft, 1991, 30: 29-45.

31. Khalifah, R.G., Baynes, J.W., and Hudson, B.G. Amadorins: Novel post-Amadori inhibitors of Advanced Glycation Reactions. Biochem. and Biophys. Res Comm., 1999, 257, 251-258.

32. Brownlee, M., Cerami, A., Vlassara, H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N. Engl. J Med, 1988, 318: 1315-1321.

33. Cohen, M., and Van, Y. Age-related changes in non-enzymatic glycosylation of human basement membranes, Exp. Gerontol., 1983 , 18: 6, 461-468.

34. Vlassara, H. Advanced glycation end-products and atherosclerosis. Annals of Medicine, 1996, 28: 419-426.

35. Van Boekel, The role of glycation in aging and diabetes mellitus. Molecular Biology Reports, 1991, 15: 57-64.

36. Dean, W. Aging Matters,

37. Brownlee, M. Non-enzymatic glycosylation of macromolecules—Prospects of pharmacologic modulation, Diabetes, 1992, 41: Suppl. 2, 57-60.

38. Friedman, E.A. Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. Diabetes Care, 1999, 22: Supplement 2, B65-B71.

39. Mruthint, S., Green, K., and Abraham, E. Inhibition of cataracts in moderately diabetic rats by aminoguanidine. Exp. Eye Res, 1996, 62: 505-510.

40. Forbes, J., Soulis, T., Thallas, V., Panagiotopoulos, S., Long, D., Vasan, et al. Reno-protective effects of a novel inhibitor of advanced glycation. Diabetalogia, 2001, 44: 1, 108-114.

41. Brownlee, M. Glycation products and the pathogenesis of diabetic complications, Diabetes Care, 1992, 15: 12, 1835-1843.

42. Makita, Z., Vlassara, H., Rayfield, E., et al. Hemoglobin-AGE. A circulating marker of advanced glycosylation Science, 1992, 258: 651-653.

43. Sell, D.R., Monnier, V.M. [pentosidine] J Biol. Chem., 1989, 264: 21597-21602.

44. Khatami, M., Suldan, Z., David, I., Li, W., and Rockey, H. Inhibitory effects of pyridoxal phosphate, ascorbate and aminoguanidine on non-enzymatic glycosylation, Life Sciences, 43: 1725-1731.

45. Pearson, D., and Shaw, S. Life Extension—A Practical, Scientific Approach. Warner Books, New York, 1983.

46. Hipkiss, A., Brownson, C. A possible new role for the antiaging peptide. , 2000, 57(5): 747-53.

47. Dean, W. Carnosine: Multipurpose Anti-Aging Nutrient. Vitamin Research News, 2004, 18(9), 1-12.

Q.Two days ago I was diagnosed with Essential Tremor (ET). I am 37 years old and in good shape but struggle with tremors in my hands and at times in my feet. I also have anxiety from time to time.
I am looking for a line-up of supplements that I could try synergistically to possibly help restore cognitive health or at the very least stop any progression. Currently I am taking magnesium, idebenone, CoQ10 and creatine. I also am taking a prescription (today is my first day) of primidone…only half a pill to help control tremors. I avoid caffeine, as anything that “excites” the brain seems to make the symptoms worse. Please let me know what recommendations you have for me. I am willing to experiment with different things in an effort to find something that works.
Thanks, B.B., USA

A. Dear B.B.,

Why this condition is called essential is a mystery to me. The same with “essential hypertension.” There is nothing “essential” about either of these conditions. I guess it’s our way of admitting we don’t know the cause. Unfortunately, just as we don’t know the cause, there is also no universally effective treatment–although many substances have been tried. Some people respond better to one treatment than another. Consequently, a trial-and-error approach is used, to try to find something that will work with minimum side effects. Currently, Primidone (Mysoline®, Elan Pharma)—that you are taking–is a first-line choice. Primidone is an anti-epileptic structural analog of phenobarbital. In early studies of primidone in ET patients, beneficial responses were noted in 60%.

Another drug to consider is Propranolol (Inderal®, Wyeth Pharmaceuticals). Propranolol is a beta-blocker, and was the first medication shown to be efficacious for ET. Propranolol may be administered on either an as-needed (PRN) or a constant-use basis. Propranolol is beneficial in approximately 50% to 70% of patients with ET.

Primidone and propranolol may also be used in combination if either one alone has not sufficiently controlled the tremor. In addition, when appropriate, low dose benzodiazepines, such as lorazepam or clonazepam can be added to primidone and/or propranolol. As is the case with propranolol, benzodiazepines may be used in small doses on a PRN basis about 30 minutes to 1 hour before an important event.

Topiramate (Topamax®, Ortho-McNeil), used for migraine headaches, may also be tried for ET. Topiramate treatment improves tremor scores by approximately 29%, at an average dose of 300 mg.

The anticonvulsant gabapentin (Neurontin, Pfizer) has also been used in ET. Gabapentin monotherapy is comparable to propranolol in reducing tremors, and may have fewer side effects than many of the other anti-ET substances.

Calcium Channel Blockers like nicardipine (Cardene®, Roche) and nimodipine (Nimotop®, Bayer) have shown some promise in attenuating ET. However, these agents generally are less effective than propranolol.

For most ET patients, alcohol consumption may temporarily attenuate tremors. Therefore, a small amount of alcohol ingested before an important event may provide transient symptomatic relief.

Other substances that have been used with limited success in ET include low-dose amantadine (Symmetrel®, Endo Pharmaceuticals), clonidine (Catapres®, Boehringer Ingelheim), trazodone (Desyrel®, Bristol-Myers Squibb), thymoxamine, and linoleic acid.

Finally, you might investigate pulsed electromagnetic frequency (PEMF) for essential tremor. I’ve seen a number of unconfirmed reports of PEMF’s benefits for ET.

I know you asked for supplements that might help, and I gave you mostly a list of drugs. Hopefully, you may find something in this assortment that will control your tremors, without causing bothersome side-effects. In keeping with your objective to control your symptoms and restore cognitive health, my top two suggestions are to try Gabapentin, starting with 600 mg as a night-time dose, and PEMF.

Ward Dean, M.D.

Q. In the last few years my skin has developed ‘liver spots.’ Additionally, I have a diagnosis of Hepatitis C or B. Apparently there are often false positives in the testing. While my liver enzymes are slightly elevated they are not in the range of someone with the hepatitis C virus. The enzyme levels decrease with major autohemotherapy (using ozone). I have had several glutathione IVs, and I regularly do a gall bladder flush. What other therapies are available for liver health?

Thanks a lot, J.M., United States

A. Dear J.M.,

Firstly, ‘liver spots’ don’t have anything to do with liver disease. They are also known as ‘age spots,’ and are due to the deposition of ‘aging pigment’ (lipofuscin).  Lipofuscin is a fluorescent, highly cross-linked lipoprotein pigment resulting from the inefficient metabolism of polyunsaturated fatty acids. Lipofuscin accumulates in our cells with age, and ‘liver spots’ in the skin are thought to be an indicator of the concentration of lipofuscin elsewhere in the body. Dr. Kalidas Nandy, of the Department of Anatomy and Neurology, Boston University School of Medicine, stated that; “One of the most consistent cytological changes in aging mammals, is the deposition of lipofuscin” (age pigment).1 Researchers in Italy emphasize that; “lipofuscin pigments are well known biomarkers of the aging process.”2

I believe that ‘liver spots’ are an indicator of the degree of lipofuscin accumulation in other parts of the body (brain, heart, muscles). Although there is no evidence that lipofuscin is in any way harmful, it can be considered as ‘intracellular garbage,’ and may in some way impair cellular function. Fortunately, there are a number of substances that can eliminate these pigments—and you can watch your skin changes as an indicator of the degree of their removal. Centrophenoxine, DMAE, and Hydergine, have all been demonstrated to reduce lipofuscin deposits in experimental animals1. I know several patients who have used these substances to rid themselves of their ‘age spots,’ over 3-6 months

I’m puzzled that you have a diagnosis of “hepatitis A or B.” With tests available today, very specific, accurate diagnoses can be made. If you really do have hepatitis, the type of hepatitis can accurately be made—and if you have hepatitis C, a ‘viral load’ (using PCR) will provide an indication of the severity of the disease. Liver enzyme tests are an indicator of liver abnormalities, but may be caused by other factors such as statins, acetaminophen (Tylenol®) or other drugs. I’d ask your physician to re-check, or find another doctor.

Nevertheless, to answer your specific question regarding substances that you can add to your ‘liver support’ program, I suggest vitamin B-12, N-Acetyl Cysteine (NAC), glutathione, carnitine, taurine and methionine, and the herbs milk thistle and turmeric.

Metformin, which is now recognized as the treatment of choice for Type 2 diabetes, and which I have long-recommended as a premier antiaging substance, has also recently been reported to be of benefit for those with hepatitis C and diabetes. In a study of 100 diabetics with hepatitis C, 26 of whom were treated with metformin, it was found that metformin use resulted in an 81% reduction in the risk of hepatocellular carcinoma and a 78% reduction in liver-related death or need for liver transplantation.3

Ward Dean, M.D.

[Ed- Curcumin is the extract of turmeric available in slow release form as CurcuminSR™ from IAS].

  1. Nandy, K., Mostofsky, D.I., Idrobo, F., Blatt, L. and Nandy, S.  Experimental manip[ulations of lipofuscin formation in aging mammals. In:  Lipofuscin—1987:  State of the Art.  I. Zs. Nagy, Editor, pp. 289-304, Elsevier Science Publishers, Amsterdam, 1988.
  2. Del Roso, A., De Tata, V., and Bergamini, E.  Regional distribution of the age pigment accumulation across the free wall of the left ventricle of rat heart.  In:  Lipofuscin—1987:  State of the Art.  I. Zs. Nagy, Editor, pp. 441-442, Elsevier Science Publishers, Amsterdam, 1988.
  3.  Nkontchou, G., Casson, E., Aout, M., et al.  Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients.  J Clin Endocr Metab, 96:  2601-2608, 2011.

Q.  Hi, Dr. Dean, First I want to say, you are amazing. I love reading everything you have written on this site. I have Hashimoto’s. I live in Argentina, and Armour® thyroid is not available. I want to switch to Armour, as I have heard so many good things about it, and traditional medications are not helping me. My current combination is 100 mcg of Levetiroxina (T4) and 40 mcg of T3. How would you recommend I start with Armour? Thank you so much.

D.B., Argentina

A. Dear D.B.,

One grain (60 mg) of Armour® thyroid is roughly equivalent to 100 mcg of Synthroid® (Levetiroxina). Armour is comprised of a natural balance of T4, T3, and T2. Therefore, one grain would be a good ‘starting dose.’ Generally I suggest advancing the dose of thyroid by about ½ grain each month, until desired results are achieved. Although blood tests provide additional information, I adjust the dose primarily based on how the patient feels, body temperature, and most important, the heart rate. Shoot for a heart rate of 65-75, and try to maintain the resting heart rate in that range. If the heart rate begins to increase into the 80s, and especially the 90s, reduce the dosage to that where you feel well, but have a normal heart rate.

In your case, with Hashimoto’s, I’d also add anti-inflammatory herbs like turmeric, boswellia and berberine. Also, consider 2-8 drops per day of Lugol’s solution, (potassium Iodide).

Ward Dean, M.D.

[Ed- Curcumin is the extract of turmeric available in slow release form as CurcuminSR™ from IAS].

Q. Dear Dr. Dean,

I have been suffering from adrenal fatigue for several years, and took a round of the peptide bioregulator for the adrenal gland. I am perimenopausal and on bio-identical hormones. About 2-3 weeks after taking the bioregulators, I started having a period and my breasts were extremely tender. Is it possible that the adrenal surge also increased estrogen production in that short amount of time? I will have my blood tested in September for my hormone levels, but in the meantime my naturopath (hormone specialist) lowered my estrogen prescription by half, just based on my external symptoms.

What do you think?

M.B., United States

A.  Dear M.B.,

Firstly, the Russian peptides are a learning curve for us all at present, although they’re based on very good science. They are a direct extension of the work of my Russian mentor, Prof. Vladimir Dilman, and many of his students.1 Dilman believed that a principle cause of aging was the progressive loss of central and peripheral hormone (and neurotransmitter) receptor sensitivity to negative feedback inhibition.  Consequently, he proposed his revolutionary and underappreciated approach to antiaging therapeutics—i.e., to identify drugs and neuropeptides that are capable of restoring this altered receptor sensitivity to a more youthful state. He believed that metformin and phenformin, (a pharmaceutical predecessor to metformin) were the prototypes of these ‘metabolic rejuvenators.’

We’ve already received numerous positive testimonials of the actions of these biopeptides over very short periods of time, and in cases like yours, in very low doses. It appears that the Russian research is being borne out in patient reality. We recommend, (as you have done) that anyone on any type of hormonal therapy monitor themselves closely–especially while taking the peptide bio-regulators. Adaptation to one hormone can naturally affect others, too. Dilman demonstrated long ago that phenformin not only restored insulin receptor sensitivity, but that of cortisol, as well (see figure one).2

I believe that metformin also restores sex steroid receptor sensitivity, although this is merely my clinical impression.

It is not yet possible to say definitively whether adrenal changes due to the adrenal bio-regulators made this impact on your estrogen levels, (or the sensitivity of your estrogen receptors), but it is certainly likely that they did. It would be of value to know your before and after levels of your adrenal hormones (including DHEA), and their changes over 24 hours, as well as estrogen and progesterone. It is clearly a favorable sign that you are improving clinically while simultaneously lowering your estrogen prescription.

Ward Dean, M.D.

  1. Dilman, V., and Dean, W.  The Neuroendocrine Theory of Aging and Degenerative Disease, Center for Bio-Gerontology, 1992.
  2. Ostroumova, M.N.  Age-associated decrease in hypothalamic-pituitary complex sensitivity to dexamethasone suppression test.  The effect of stress, epithalamin and phenformin.  Probl Endokrinol, 1978, 24:  59-64.

Restoration of hypothalamic sensitivity

Figure One: Restoration of hypothalamic sensitivity to suppression by dexamethasone by pineal polypeptide extract, (epithalamion) and phenformin in rats. PPE was injected subcutaneously for 5 days, and Phenformin was injected intraperitoneally for 5 days. The results show that both PPE and phenformin restore hypothalamo-pituitary complex sensitivity to inhibition by dexamethasone (i.e., synthetic cortisol) (Dilman and Dean, 1992).

Q. Dear Dr. Dean,
I have had issues with foggy thinking since my mid-40s. The rebalancing of my hormones has fixed about 50% of the fogginess. Also, I tried modafinil, and was amazed that I was able to think like I was in my 20s (I’m in my early 50s). Unfortunately, I developed hives pretty badly, and assume it was from the modafinil. So I ordered adrafinil from the IAS site. Do you know if it has the same sulfonamide profile as modafinil? I have sensitivity to sulfonamides, which is likely what brought on the rash.
P.H., Canada

A.  Dear P.H.,

Unfortunately, you appear to have experienced an uncommon but potentially severe side effect of modafinil in those who are allergic to it- a profound rash (see figure two).

 

skin rash
Figure two: A rare, but potential side effect of the Eugeroic drugs is a skin rash.
As you can see, the structures of adrafinil and modafinil are quite similar (see figure three). Consequently, you should avoid both of these medications.

 

The structure of adrafinil
Figure three: The structure of adrafinil is shown on the left, the structure of modafinil is shown on the right; the close similarity between the two can be clearly seen.
Suggestions to replace these drugs include combinations of desmopressin or vasopressin nasal spraypiracetam (Nootropil®)phosphatidylserine, acetyl-L-carnitine, and Vinpocetine which should all be beneficial, but will unfortunately not give you the ‘instant’ alerting effects of modafinil or adrafinil.

Ward Dean, M.D

[Ed- Acetyl-L-carnitine is available in ATP-Boost™ from IAS].

Q. I am very interested in using the Can-C™ eye-drops to help fight my cataract – but how soon might I see positive results and what may I do in addition to speed things along?

R.M.F., Scotland

A. In my experience, 3-6 months is the minimum time to see improvement with Can-C™, although I have known people who have persisted, and did not see improvement until over one year had elapsed. Of course, the time required depends on the person’s diligence with the drops, and the degree of progression of the cataract at the time the treatment, (2-drops twice a day) was begun. The formulators of Can-C™ eye-drops also designed Can-C Plus capsules, as an oral adjunct to the eye-drops. Note: Dr. Babizhayev, the principal Can-C™ researcher, doesn’t recommend lutein (found in many ‘eye’ formulas), as lutein competes with same receptors as N-acetyl carnosine, and could down-regulate efficacy of the drops.

An alternative to Can-C™ capsules, would be to take L-carnosine itself, one of the principal (and I believe, most active) ingredients in Can-C™ Plus capsules.

Additionally, you might consider the AGE-breaking aminoguanidine. Several Japanese research teams have demonstrated the ability of aminoguanidine to inhibit or completely prevent the development of cataracts in two diabetes-prone rat strains. The first team used the Shumiya cataract rat (SCR). SCR is a hereditary cataract model in which lens opacity appears spontaneously in the nuclear and perinuclear portions at 11-12 weeks of age. The researchers found that oral administration of aminoguanidine (AG) strongly inhibited the development of lens opacification in SCR rats.

In another very recent study, the researchers used another strain, Spontaneously Diabetic Torii (SDT) rats. SDT rats have marked hyperglycemia and severe ocular complications. They evaluated the effect of the anti-AGE agent, aminoguanidine, on the development of diabetic retinopathy (DR) and cataract. Five SDT rats were treated with aminoguanidine (0.5 g/L in drinking water). During the duration of the study, ALL of the control rats developed cataracts, whereas NONE of the aminoguanidine-treated rats developed cataracts. These results were dramatically illustrated in the accompanying photographs (Figure 1). The researchers concluded that aminoguanidine had a strong inhibitory effect on diabetic ocular complications in SDT rats.

Although I have unfortunately not found any human studies to corroborate these findings in rats, aminoguanidine has been shown to be safe and effective in humans for a number of conditions, and I would expect it to have the same cataract-inhibiting effect in humans as it has in rats.

1. Mitsushi Inomata, Masami Hayashi, Seigo Shumiya, Seiichi Kawashima and Yoshimasa Ito. Aminoguanidine-Treatment Results in the Inhibition of Lens Opacification and Calpain-Mediated Proteolysis in Shumiya Cataract Rats (SCR). The Journal of Biochemistry, 2000 Volume 128, Issue 5, Pp. 771-776.

2. Fumihiko Toyoda, Akihiro Kakehashi, Ayumi Ota, Nozomi Kinoshita, Chiho Kambara, Hiroko Yamagami, Hiroyuki Tamemoto, Hiroto Ueba, Prevention of Proliferative Diabetic Retinopathy and Cataract in SDT Rats with Aminoguanidine, an Anti-Advanced Glycation End Product Agent. The Open Diabetes Journal, 2011, 4, 108-113

Figure 1: the Effect of aminoguanidine on diabetic cataract and retinopathyFigure 1 right: the Effect of aminoguanidine on diabetic cataract and retinopathy

Figure 1, the Effect of aminoguanidine on diabetic cataract and retinopathy. The top row shows the slit-lamp findings in the lens. The untreated control rat has mature diabetic cataracts, whereas the aminoguanidine-treated SDT rat has minimal lens opacity. The bottom row shows the fluorescein angiomicroscopy findings. The untreated control rat has extensive fluorescein leakage and narrowing of the capillaries around the optic disc. The aminoguanidine-treated SDT rat has no abnormalities.

Q. Dear Dr Dean, I enjoyed reading your interview in Issue 4, 2012 of the Aging Matters™ magazine regarding the use of smart drugs and nutrients. Indeed, I have your books at home! I have some confusion over one of the smart drugs that I personally like to use, and that is Vasopressin. It seems to now be available as both the synthetic version called desmopressin and the original porcine version of vasopressin. I was wondering if you could please tell me the difference between the two nasal sprays and if they may have any different uses / actions and which one you prefer?

S.B.J., California

A. Desmopressin (1-desamino-8-d-arginine vasopressin) is the synthetic version of the posterior pituitary hormone, vasopressin. Desmopressin is considered to be longer acting, and perhaps more potent than its natural analog, but the clinical results with each are variable. I don’t think there’s much difference in the two – i.e., those who respond favorably to one will probably have a similar response to the other. IAS has both versions available. Desmopressin nasal provides 5 mcg per spray, the usual dose is 20 mcg per day, whereas the vasopressin provides 10 IU per spray, the usual dose is 20-25 IU per day. The effective dose is highly individualized, and may be slightly more or less than those cited.

[Ed.- IAS provides desmopressin / Minurin® in 2.5ml = 25 sprays and vasopressin / Vaso-Pro™ in 5 ml = 50 sprays].

Q. Dear Sir, I have high triglycerides, high homocysteine, and a low metabolism. I find myself rather lethargic and gaining weight. Could you please suggest any products that you feel may benefit me in my situation?

A.P.M., Great Britain

A. The safest, cheapest and most effective substance to normalize one’s lipid profile is nicotinic acid (niacin, vitamin B3). Niacin has the optimal effect on the lipid profile. It lowers total cholesterol, triglycerides, and LDL, and raises HDL (the so-called ‘good’ cholesterol). Most people will only require 1500-2000 mg of niacin per day, although I’ve used doses up to 6 grams per day.

[Ed.- IAS provides niacin in Beyond Chelation Improved® and Xan-Pro™ which is the most potent form of niacin called xanthinol nicotinate].

Another substance that normalizes triglycerides is the anti-diabetic drug, metformin. I’ve written on the antiaging benefits of metformin (a ‘metabolic rejuvenator’), as well as its weight-normalizing effects. As a key component of my often-prescribed weight loss protocol, my patients invariably report that after taking metformin, they feel better, have more energy, and lose their carbohydrate cravings. Also, they often are surprised to find that their clothes fit better, even before they note any loss in body weight. This is because metformin seems to cause a shift in body morphology—i.e., loss of body fat, and increase in lean body mass (bone and muscle). Bone and muscle are heavier than fat, resulting in a seemingly paradoxical increase in weight, despite significant fat loss.

[Ed.- IAS provides metformin as Metforal® in 500 mg tablets or Dianben® in 850 mg tablets].

Another frequent cause of the symptoms that you describe – fatigue and weight gain – is overt or sub-clinical hypothyroidism. Thyroid hormone is a natural substance that belongs in your body. I pay very little attention to thyroid blood tests. In most cases, I believe they are a ‘waste of blood.’ I prefer to treat my patients’ symptoms. If my patients exhibit a spectrum of hypothyroid symptoms, (i.e., cold hands and feet, low body temperature, depression, constipation, fatigue, or difficult weight loss), I start them on a low dose of thyroid (i.e., ½ to 1 grain of Armour® Thyroid), and gradually increase the dose every month or so, based on one’s clinical response. As long as the heart rate remains in the normal range (60-75 beats per minute), and the patient feels well, I believe there is very little chance of excessive thyroid being consumed.

The single best treatment for elevated homocysteine is anhydrous betaine (trimethylglycine – TMG), in a daily dose of 3,000-5,000 mg. Another advantage of TMG (besides lowering homocysteine) is that it converts to the antidepressant, SAMe. While SAMe is fairly expensive, TMG is amazingly cheap. Besides, TMG tastes good, and can be added to virtually any beverage (milk, juice, coffee, etc).

[Ed.- IAS provides betaine / TMG in the Bio En-R ‘Gy C® powder drink].

Q. I’m currently using 2400 mg of Nootropil® / piracetam daily to help me in my studies. Some days I get very focused clarity, but other days I don’t seem to achieve as much as I’d like to. I was wondering why this might be – do I need to adjust my dose or might I be better off on another piracetam related supplement? I would appreciate any advice.

S.P., New York

A. Frankly, I haven’t noted much difference between the various Nootropics (piracetam, aniracetam, pramiracetam, etc.) when taken in equipotent dosages. Therefore, I don’t think further increase in your dosage of Nootropil® / piracetam, or switching to one of the other piracetam analogs would result in further improvement. Instead, I would add one or more cognitive enhancers that act via different mechanisms, such as vinpocetine, which increases cerebral oxygen uptake and glucose metabolism, centrophenoxine (Lucidril), or the relatively fast-acting desmopressin nasal spray [Ed.- as mentioned above]. Another ‘wake up’ antidepressant cognitive enhancer is deprenyl / selegiline – especially, the fast-acting sublingual drops.

[Ed.- IAS provides piracetam / Nootropil® 800 mg tablets, plus in liquid form, aniracetam / Ampamet® in 750 mg tablets and a generic Ani-Pro™ in 750 mg capsules, pramiracetam in 300 mg capsules, vinpocetine/ Intelectol® in 5 mg tablets, centrophenoxine in 250 mg tablets and deprenyl (Dep-Pro™) in 20 ml/ 300 mg liquid with 1 drop = 1 mg].

Q. Dr Dean, I have your book the GHB, the Natural Mood Enhancer, which is a great resource for anyone who wants to learn about this remarkable substance – but which has sadly been banned in many parts of the world. When it was legal, I was able to use it very successfully for helping me sleep. I am not ‘officially’ an insomniac, but consider myself borderline. Is there anything similar to GHB that I could try, (legally of course) that you can suggest that will help me get better sleep at night?

A.B., Australia

A. Neurontin (gabapentin) is a GHB analog, which is approved by the FDA as an anti-seizure medication, and also for fibromyalgia, restless legs, and nerve pain due to diabetic neuropathy and shingles. The most common ‘side effect’ of Neurontin® is ‘somnolence’ (i.e., it will induce sleep, in appropriate doses). It is a very safe drug, used in doses as high as 3.4 grams/day. Usually, restful sleep will result from doses ranging from 600-1800 mg about an hour before bedtime.

Another related substance is GABOB (gamma amino hydroxy butyric acid), available in 500 mg tablets as Gamibetal®. Gamma amino hydroxy butyric acid is also in Gamalate (at 37 mg) along with GABA (75 mg), magnesium and B6. IAS also stocks 5HTP (50 mg capsules), L-tryptophan (500 mg capsules) and melatonin tablets (3 mg), which also may help restore your sleep to normal.

Q. I would like to know if there are supplements particularly good at helping mild forms of depression. I don’t have anything to be depressed about, but some days I don’t feel like getting out of bed.

D.R., Florida

A. Taking your question at face value, without considering the myriad of potential causes, I’m guessing that your sleep is not as restful as it possibly could be. Tryptophan (1500-2,000 mg) or 5HTP (150-200 mg) at bedtime have sleep-inducing and antidepressant effects. IAS carries both of these nutrients. Also, melatonin (3-6 mg) can be taken along with tryptophan (or 5HTP). Neurontin® / gabapentin, as mentioned above, is an excellent sleep-inducer when used in appropriate doses—and GHB (of which Neurontin® is a chemically-related analog) is a superior antidepressant. When taken in appropriate doses, Neurontin® results in very restful sleep, and enables one to awaken refreshed, and literally ‘bounce out of bed’ (similar to the sleep-wake profile of GHB). Hypothyroidism can also be a cause of low energy and depression so please see my response to the question above.

Q. I have been diagnosed with angina. What can I do to alleviate this situation?

C.K., England

A. First, for acute (immediate) relief, I recommend a combination of IAS’s Nitric Pro™ and Neo40®. This combination will maximize the release of Nitric Oxide, essential for vasodilation and enhancement of blood flow to the heart and other organs. Also, I recommend one aspirin per day.

For long-term improvement, I recommend 1,500 mg of Niacin (vitamin B3) to normalize your lipid levels. Niacin is the safest, cheapest, most effective lipid-lowering agent there is. Also, 500mg of Turmeric (Ed. – or approximately 125mg curcumin) to normalize your fibrinogen levels, which is perhaps one of the most important markers of cardiovascular risk. I also suggest adding Dr. Garry Gordon’s Beyond Chelation Improved®, which contains EDTA. In addition you can consider 100 mg of CoQ10SR™ and IAS’s unique formula for cardiac support, Cardio-Pro™. Let me know how you do.

Q. I am very interested in the mitochondrial theory of aging and understand that healthy mitochondria will generate good internal energy levels and repair systems. Could you please recommend any products that may help my mitochondria perform better?

J.J., New Jersey

A. There are two approaches to enhance mitochondrial energy production.

First, is to optimize the mitochondrial energy producing intermediates such as D-Ribose (5 grams per day), Creatine (5 grams per day), CoQ10SR™ (100 mg per day), NADH and IAS’s ATP-Boost™ (which is principally a combination of Acetyl-L-Carnitine, Alpha Lipoic Acid and Adenosine Triphosphate). The unique cognitive-enhancing drug, Hydergine, has also been shown to restore mitochondrial function of old animals to that of more youthful counterparts.

The other approach to enhanced mitochondrial function is to increase the number of mitochondria. Studies have shown that youthful organisms respond to exercise by increasing the number of small, efficient, energy-producing mitochondria. With increasing age, mitochondria have fewer tendencies to increase in number; rather they increase in size, but are less efficient energy-producers. Recently, a new substance, (PQQ) has been shown to regenerate small, efficient mitochondria — essentially as in youthful organisms.

Thus, the ideal mitochondrial restoration formula would seem to be a balanced combination of mitochondrial energy producing intermediates, PLUS the new mitochondrial regenerating supplement, PQQ-Pro™.

(Ed. – Please note that 2 grams of D-Ribose are contained in each rounded teaspoon of Bio-En’R-Gy C®).

Q. My rising from bed temperature seems to be regularly below 36° C (96.8° F). I can recognize signs ofhypothyroidism in myself. Can you please advise what dose of thyroid I should use to raise my morning temperature with either a T3 or natural thyroid supplement?

B.D., Switzerland

A. I usually recommend Armour® Natural Thyroid, rather than pure T3. Armour contains the naturally-occurring range of thyroid hormones—T2, T3, and T4—and seems to have more beneficial effects than the commonly used T3 (Synthroid®).

Temperature is important—but even more important is your heart rate. I like to maintain the resting heart rate in the 65-75 beats per minute range. I usually start my patients on no more than 1 grain (60 mg) of Armour® thyroid. If needed, I adjust the dose up or down depending on the response. Response to the dosage used is more important than the results of any thyroid function blood tests—which in most cases are a ‘waste of blood.’ If the pulse rate and temperature remain normal, and the patient feels well, there is very little likelihood of overdosing on thyroid. I try to treat the patient—not the blood test.

Q. My doctor has prescribed a statin (Lipitor®) to lower my cholesterol level. Friends have told me that I should also take CoQ10; I would like to know your opinion.

G.P.R., Texas

A. I believe that statin drugs such as Lipitor® are not a preferable solution to hyperlipidemia. Statins are literally toxic to the muscles, and result in weakness, fatigue, cramps, and in worst cases, destruction of the muscle (rhabdomyolysis). These side effects are well known to most cardiologists. As you suggested, statins also impede the actions / reduce body concentrations of CoQ10. Consequently, CoQ10 has been suggested to be taken whenever statins are given.

So yes, I agree with your friends who recommend CoQ10—IF you feel you must take statins.

However, as I said above, the safest, most non-toxic, cheapest lipid lowering substance known is NIACIN (vitamin B3). Niacin lowers total cholesterol, triglycerides and LDL and RAISES HDL.

Recently, there has been a negative report about niacin — however what is NEVER mentioned is that the negative report involved NIA-SPAN® — a prescription form of timed-release niacin. Timed-release niacin is known to be toxic. Therefore I recommend the cheaper health-food store variety of Nicotinic Acid, or the non-flushing Inositol Hexanicotinate or Xanthinol Nicotinate forms.

[Ed. – IAS provides niacin in Beyond Chelation Improved® and Xan-Pro™ which is the most potent form of niacin called xanthinol nicotinate].

Q. I appear to have reoccurring bouts of gout which has now become more painful and uncomfortable. I would very much like to know how I can rid myself of this problem.

E.M., Colorado

A. Of course, you should avoid foods that trigger your attacks, such as red meat, shellfish and alcohol. Colchicine is the time-honored treatment for acute flares of gout, but due to FDA interference, has now been made a frightfully expensive prescription drug in the U.S.

Fortunately, IAS has located an affordable version of colchicine in 1 mg tablets. Take 1 tablet at the first sign of a gout flare, then 1 more 2 hours later if still symptomatic. Wait 12 hours before taking a third dose, if it is needed.

Unfortunately, gout is a genetic illness, so there is no way to ‘rid yourself of the problem.’ However, with proper diet and judicious use of colchicine, the discomfort can be prevented or greatly alleviated.

Q. I have recently been given a urine challenge test and discovered that I am ‘high’ in cadmium and ‘moderately high’ in mercury. What might be the best types of chelation (oral and IV) that I can use to excrete these toxic heavy metals and how long may I have to do so?

R.K., Georgia

A. Intravenous EDTA is an excellent chelator of cadmium, and fairly good chelator of mercury. A minimum of ten treatments will be required, although more will undoubtedly be better. If intravenous EDTA is not available in your area, oral treatment will also help—and is also a useful adjunct if IV treatment is used. One alternative is Dr. Gordon’s Beyond Chelation Improved®. Another oral treatment, (perhaps the best chelator of mercury) is DMSA (dimercapto succinic acid). I recommend a conservative protocol of 300 mg of DMSA orally every other day.

Zeolite is another very interesting chelator worthy of consideration.

Unfortunately, heavy metals are usually lodged in the bones and the brain. Chelation therapy detoxification is a prolonged process, as the chelating agents normally bind with the heavy metals in the blood, lowering the blood levels of these substances, which then re-equilibrate from the bones and brain to restore the levels in the blood. Thus, repeated treatments are required to ultimately deplete the ‘stores’ in the bones and brain. Dr. Gordon believes this should be a lifelong process.

(Ed. – DMSA can be found in Detox-Pro™ at 100 mg per capsule. High quality Zeolite is available in liquid mouth spray and dissolvable in water capsule – see Advanced Cellular Zeolite® and ZeoGold® for details).

Q. I am a 48 year old male and over the last couple of years have noticed that my erections are becoming weaker, to the point where, although not diagnosed, I am sure that I have erectile dysfunction. I don’t really want to become reliant on taking a Viagra® pill every time my wife and I have sex, what can you recommend Dr. Dean and what may address the cause of this problem rather than just the symptoms?

S.S.K., Canada

A. First, I suggest that you ask your physician to check your testosterone levels. If they are in the low or low-normal range, you might ask him to prescribe testosterone. I prefer injectable testosterone (cypionate or enanthate) usually 200 mg injected intramuscularly every 2-3 weeks. Alternatively, the topical creams or gels may also help, although I believe topical testosterone is not as effective as the injectable route. That may solve your problem.

Another approach, in this regard, is IAS’s new Andro-Pro™. It is designed to naturally raise testosterone levels, although I have not had any clinical experience with it yet. However, there are several nutritional alternatives to Viagra® and the other phosphodiesterase (PDE-5)-inhibiting drugs like Cialis® and Levitra®, all of which are designed to increase the production of endothelium-derived nitric oxide (NO), one of the most important signaling molecules in our bodies. Nitric oxide was designated ‘Molecule of the Year’ by the journal, Science, in 1992, and a Nobel Prize in Physiology or Medicine was awarded in 1998 for its discovery. Unfortunately as we age, we lose our ability to produce NO. This puts us at risk for a host of conditions, including hypertensionatherosclerosis, myocardial infarction (i.e., heart attacks), strokeAlzheimer’s disease, anderectile dysfunction.

One way to increase NO is to consume the nitric oxide-producing amino acid, arginine. The effect of oral arginine intake to improve erectile response was first investigated in animal models. Older rats supplemented with arginine resulted in increased nitric oxide synthase activity and increased nitric oxide levels, which caused improved erectile response. The authors of the study suggested that dietary supplementation with arginine might lead to improved sexual performance in humans, as well.

The first evidence that oral supplementation with arginine might lead to improvement in human sexual function came from a short-term study in 1994. The study showed a positive correlation between arginine supplementation and sexual performance and satisfaction.

These intriguing findings were supported by a more recent, larger study conducted at the Department of Urology and Nephrology at Tel Aviv University in Israel. Fifty men with confirmed erectile dysfunction were administered either a placebo or 5 g/day arginine for six weeks. Thirty-one percent of the subjects receiving arginine reported improvement and satisfaction in their sexual performance. In the placebo group, only 12% of the men noted improvement in sexual function. Importantly, at the 5 gram daily dose, no significant side effects occurred in any of the patients throughout the entire duration of the study. The percentage of patients reporting improved performance (31%) may not sound like an impressive number, but keep in mind that up to 50% of Viagra® users report no benefit from taking this prescription medication.

As a source of arginine, IAS offers Nitric-Pro™ powder, which contains a hefty 3500 mg of L-arginine plus magnesium (to help relax the smooth muscle layer of the endothelium), per serving.

Unfortunately, the intestinal enzyme, arginase reduces the effectiveness of the conversion of oral arginine to NO by metabolizing arginine, reducing the amount that is available for conversion to NO. Citrulline may offer a solution. Citrulline is a semi-essential amino acid that is not found in the diet- it is synthesized in the body via a mechanism called the urea cycle. In this metabolic pathway, arginine is catalyzed by the enzyme arginase to urea and ornithine. Ornithine, in turn, is converted to citrulline, which is converted to argininosuccinate, which is converted back to arginine, completing the cycle. It has recently been shown that oral citrulline supplementation increases the plasma arginine concentration and augments NO-dependent signaling in a dose-dependent manner. This provides the rationale for using oral citrulline supplementation as a donor for the arginine/NO pathway in those with ED.

An article in Urology described a pilot trial aimed to determine whether oral citrulline supplementation could improve erection hardness in patients with mild ED. In the Urology study, 24 men (mean age of 56.5 ± 9.8 years) with mild ED (erection hardness score [EHS] of 3) received a placebo for 1 month. They were then given citrulline, 1.5 g/day split into two doses, for another month. At the end of the study, the erection hardness score, number of intercourses per month, treatment satisfaction, and adverse events were recorded.

The improvement in the EHS from 3 (mild ED) to 4 (normal erectile function) occurred in 2 (8.3%) of the 24 men when taking placebo during the first half of the study. But when the subjects were switched to citrulline, 12 (50%) of the 24 men reported achieving an EHS of 4. An EHS of 3 is considered “hard enough for penetration but not completely hard,” while an EHS 4 is “completely hard and fully rigid.” citrulline increased hardness by 50%. At the same time, the mean number of intercourses per month increased from 1.37 at baseline to 1.53 at the end of the placebo phase (about 12% greater frequency) and 2.3 at the end of the treatment phase (about a 68% increase) for citrulline. Citrulline increased successful intercourse connects by 56% more than placebo, and all patients reporting an EHS improvement from 3 to 4 reported being very satisfied.

Perhaps the most effective way to increase nitric oxide has recently become available. It is a patent-pending combination of natural products, developed at the University of Texas Health Science Center, called Neo40®. Neo40® is primarily a combination of nitrate-rich beet root, and nitrate reductase activity-enhancing Hawthorn Berry extract, plus a relatively small amount of citrulline.

Preliminary clinical studies at the Houston Institute for Clinical Research indicate that Neo40® has demonstrated clinically relevant increases in NO and serum nitrate concentration, improvement in triglyceride levels, and normalization of blood pressure in hypertensive patients. Anecdotal reports from my patients who have used Neo40® also include rapid relief fromangina attacks, and Viagra-like enhancement of sexual performance.

Another approach to improving erectile dysfunction is the time-honored multi-purpose herb, Ginkgo biloba extract (GBE). In a 1991 study, fifty patients with proven arterial erectile impotence were treated with 240 mg of GBE daily for nine months. The patients were divided into two groups. The first group had achieved sufficient erections with intracavernous papaverine injections before beginning treatment with GBE. The second group had not achieved sufficient erections with high-dose papaverine injections.

In the first group (n = 20), all patients regained spontaneous and sufficient erections after six months of oral GBE treatment. Arterial flow rates were actually improved after three months and continued to improve at six months. Rigidities at the penile tip and base were significantly improved after six months and remained constant during the nine month duration of the study. In the second group (n = 30) (this was the group that did not respond to high-dose papaverine injections—i.e., a very severe state of ED), improved arterial penile flow rates and rigidities were noted at six and nine months. Nineteen patients, responded to intracavernous PGE1 following GBE treatment. Of these 19 patients, 9 required a minimal dose of 5 mcg PGE1, while the other 11 required a maximal dose of 20 mcg. The remaining 11 patients remained impotent. Thus, it appears that Ginkgo biloba extract at a dose of 240 mg per day may also greatly assist those with ED.

In summary, I recommend evaluation of testosterone levels, and replacement, if appropriate, or using Andro-Pro™, arginine (3-5 grams per day) or the arginine-containing Nitric-Pro™, citrulline (1.5 grams per day), Neo40® (1 tab twice daily), and Ginkgo biloba (240 mg per day). I don’t recommend starting everything at one time—rather, begin with one nutrient at a time, and add other nutrients in sequence so you can tell what is (and is not) working.

1. Moody JA, Vernet D, Laidlaw S, Rajfer J, Gonzalez-Cadavid NF. Effects of long-term oral administration of L-arginine on the rat erectile response. J Urol 1997;158: 942-¬7.

2. Zorgniotti AW, Lizza EF. Effect of large doses of the nitric oxide precursor, L-arginine, on erectile dysfunction. Intl J Impot Res 1994;6:33-¬5.

3. Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double blind, randomized, placebo-controlled study. BJU Int 1999;83: 269¬-73.

4. Cormio L, De Siati M, Lorusso F, Selvaggio O, Mirabella L, Sanguedolce F, Carrieri G. Oral citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology 2011 Jan;77(1):119-22.

5. Janet Zand, Frank Lanza, Harsha K. Garg, and Nathan S. Bryan.  All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans. Nutrition Research, 31 (2011) 262-269.

6. M. Sohn M and R. Sikora.  Ginkgo biloba extract in the therapy of erectile dysfunction. J Sex Educ Ther (1991) 17: 53-61.

Q. I am so pleased to be asking a world expert this question! Dr. Dean I would say that my memory and cognition as a 60-year old female is quite good and I take care to exercise my brain and use some of the nutrients that you recommended in your Smart Drug books. My main problem seems to be the speed of my recall; my recent conversations have too many ums and errs in them, much to my embarrassment, especially since I give a lot of presentations to my board. Please recommend something that might be able to help me.

M.R., Illinois

A. Not knowing what you are already taking makes this somewhat of a ‘guessing game,’ as I’m not sure what you are taking that isn’t working. Nevertheless, it sounds as if you’re looking for something that will offer a rapid effect that you will notice. If this is the case, I suggest alerting agents such as adrafinil or modafinil. Another cognitive-enhancing substance that has a rapid onset is vasopressin, available as either desmopressin (Minirin®) or Vaso-Pro™. These products are administered as nasal sprays, with rapid absorption through the nasal mucosa.

Vinpocetine, which acts to increase glucose uptake and oxygen utilization in the brain, also seems to cause rapid subjective improvements, sometimes perceived as brighter colors and improved hearing.

Centrophenoxine is another mild cerebral stimulant, although I usually think of it as being of long-term benefit for its ability to remove the cell-clogging lipofuscin, or aging pigment. Also, not to be overlooked, are the nootropics, of which Nootropil® (piracetam) is the prototype. This class of cognitive enhancers is known for improving communication between the cerebral hemispheres.

Have you considered the possibility of sub-clinical hypothyroidism? This may sometimes manifest in the symptoms that you describe. I suggest discussing this with a knowledgeable physician, who may recommend thyroid hormone for its cognition-normalizing effects.

I’m sure I may have recommended some substances that you may already be using, but hopefully you’ll find something within these recommendations that will restore your fluency.

Q. My blood pressure seems to be rising, it used to be often 120/80, now it appears to be often around 140/90 – furthermore my resting heart rate can sometimes be around 90 beats per minute. I avoid caffeine and whilst I am overweight I am not obese and do mild exercise regularly. I am a 55 year old man.

F.M., Missouri

A. Although there are several nutrients that may lower blood pressure, the combination of high blood pressure with increased heart rate is best treated with a beta blocking anti-hypertensive medication. Propranolol (Inderal®) is good, although cardio-selective beta blockers like Atenolol®, Labetalol®, Carvedolol® or Metoprolol® are also excellent. These medications act to slow the heart rate, (I prefer a resting rate of 65-75 BPM), while simultaneously normalizing blood pressure. Start with low doses, and gradually increase the dose until the target heart rate is obtained. Naturally, please discuss these recommendations with your physician.

I recommend first normalizing your pressure (and heart rate) with one of these medications. You may also add a combination of potassium and magnesium for longer term use, which may enable you to wean yourself from the medication. I often prescribe magnesium-potassium aspartate as a source for these two minerals. The dose can be gradually titrated up to bowel tolerance (magnesium in high enough doses will cause GI distress and diarrhea)—but before that point is reached, blood pressure will usually return to normal.

In addition to monitoring your blood pressure, another useful parameter to follow is your Arterial Stiffness Index (ASI). ASI is one of the best biomarkers of biological aging, as documented in my book, Biological Aging Measurement—Clinical Applications. At the time the book was published (1988), only the most sophisticated cardiovascular testing labs had the expensive equipment required to conduct this test. In recent years, the folks at IAS discovered a compact, computerized unit that was affordable for Doctors’ offices (Bio-Clip™ $799.99), and have now added a personal unit suitable for home use (Bio-Cuff™ $124.99).

Q. As I have gotten older I find that my sleep quality has appeared to have worsened. Now as a 70-year old woman I find that it’s not just the quality of the sleep but the time also. I am now at the point where I seem to be sleeping on average about 4 hours a night. What procedures can I follow to improve this and are there any sleeping drugs you recommend?

G.M., Australia

A. In Aging Matters™, Issue #1, 2013, I answered a similar question, and suggested the anti-seizure drug, Gabapentin (Neurontin®), as a powerful sleep aid. Gabapentin is an analog of the ‘notorious’ GHB. GHB is actually the safest, most non-toxic, non-habit forming sleep inducing agent there is. It is a natural substance, existing in every cell in our bodies in small amounts. When taken in adequate doses, it induces sound, restful sleep—enhancing all four phases of sleep—and is metabolized into harmless carbon dioxide and water.

My experience with gabapentin as a sleep inducing agent is excellent. Although gabapentin doesn’t work for everyone, most of my patients gratifyingly report that it causes sound, restful sleep, without frequent early-morning awakenings. When taken in an appropriate dose, at the proper time, there is little to no ‘hangover’ effect. If you experience a hangover, take it an hour or so earlier, or reduce the dosage. Dosages of gabapentin must be individualized. Some very sensitive people find as little as 300 mg to be adequate. Usually, however, 600-800 mgs are effective and some highly resistant patients require 900-1200 mg. It is a very safe, non-habit forming medication. IAS now stocks gabapentin.

Q. I am a 40-year old woman, in otherwise good health and fit. But I have recurring skin problems, specifically acne and boils which not only appear on my face, but other parts of my body such as my back. Obviously this is not a pleasant experience for me, I have tried using fiber and vitamin C to help detox myself with some limited success, but I would welcome your advice.

N.M., England

A. Of course, I’m at a disadvantage in not being able to ‘eyeball’ your lesions. Skin lesions as you describe could be due to Rosacea, acne, or even by infectious microbes like staphylococcal bacteria. With that caveat, here are some general suggestions.

Vitamin D is essential for healthy skin, and a healthy immune system. Most of my patients are deficient in this essential vitamin. I like to see levels in the range of 60-70 ng/ml. To reach these levels usually requires supplementation of 5,000-10,000 IU per day. IAS has a very potent form of Vitamin D, D3-Pro, in a dose of 50,000 IU, these capsules should be taken once per week. [Ed- IAS now also stocks D3-5000 which are 5000 IU capsules).

Tetracycline or doxycycline may help. The usual dose of doxycycline is 100 mg twice per day. You may have to continue to take smaller ‘suppressive’ doses on a chronic basis, if you find that this will control your outbreaks.

Another suggestion is to purchase a bottle of ‘hand sanitizer’—basically an ethyl alcohol gel, and apply it topically to the skin several times daily. This will kill bacteria on the skin, and should help to ‘dry up’ your lesions.

If you have acne, you may apply Retin-A® topically, as well—although if you are truly having ‘boils’ (i.e., abscesses), Retin-A® will probably not be effective.

Finally, have you had your hormone levels tested? Excess testosterone (as can occur if you are taking DHEA—women very efficiently convert DHEA to testosterone) is known to cause acne in women. If you are taking DHEA, I’d suggest reducing your dose.


Disclaimer: All educational information is offered under IAS terms and conditions. This information does not replace the advice of your physician and restrictions may apply in some countries. The opinions expressed by the writers may not be those of IAS.

8 Responses to Dr Ward Dean Answers Reader Questions

  1. scott tomlinson

    Hello dr. Dean,

    I am seeking you out to become my primary physician. I believe you were the Doctor who helped me at Dr. GARGS office. He has cancer and no longer can prescribe my medications or treat my illnesses. We spoke in his office and you said you would take me as a patient which made me really like you as a MD. You are very caring and helped me in the office that day. You listened when I explained the gabapentin did not help with my sleep and you were understanding. Instead of saying sorry you allowed me to return to my normal medication that helps me sleep. It tells a lot about you. You understand that not all medications work for everyone and that everyone shouldnt be given the same medication. You understood that if It didnt work that it didnt work. Then you gave me what I knew worked for me. You never once looked down upon me or made me feel like a bad person for needing a medication that you dont normally like to prescribe. You realize that sometimes the benefits outweigh the risks. Regaurdless of personal feelings you still do whats right for your patients when it all boils down to it. I hope to see you again as a actual patient. I appriciate your dedication to your patients.

  2. Ward Dean

    Thanks for your comment. I’ve written a lot about Turmeric elsewhere. I agree that it’s good stuff for many things. I recommend whole Turmeric, rather than Curcumin. There are many other cofactors in Turmeric, besides Curcumin.

    Ward Dean, MD

  3. Jim English

    Thanks for your comment. I’ve written a lot about Turmeric elsewhere. I agree that it’s good stuff for many things. I recommend whole Turmeric, rather than Curcumin. There are many other cofactors in Turmeric, besides Curcumin.

    Ward Dean, MD

  4. J M Bush

    Can you comment on Turmeric or Curcumin? I have read about the health benefits and have been taking 1500mg per day for four years in addition to other supplements. I find it effective for pain management of Rheumatoid Arthritis.

    Sincerely, J Bush

  5. Ward Dean

    Dear Terenz,

    I was aware of some problems with Hydergine. Apparently, several pharmaceutical companies in Europe had discontinued the product. The researchers at IAS have subseqently searched for a replacement product/supplier, and IAS now offers Hy-Pro, 4.5 mg tablets of generic Hydergine. They are also looking into carrying dihydroergocristine, one of the three ergot alkaloids of which Hydergine was comprised. Dihydroergocristine appears to have effects nearly equal to those of Hydergine, and should be available at a slightly lower price.

    Ward Dean, MD

  6. Doctor Dean,
    We met about fifteen years ago. After a lecture you gave in a small auditorium at a Hotel/motel in Santa Clara, CA, I was the one who came up on stage and shook your hand before asking my question. I had already read your 1990 book, Smart Drugs & nutrients and thanked you for the service you had provided me and others. Today I tried to purchase Hydergine with Piracetam as I have for more than a decade from I.A.S. They have discontinued Hydergine, both tablet and liquid. Can you suggest an alternative product with similar purported benefit that I can still order from I.A.S. I am retired and 67 years experienced. The supplements I consume are too many to list but I have tried one at a time beginning after reading Durk and Sandy’s book and then your books too and since 2003 I have taken one 800mg Piracetam daily and one Hydergine on Monday, Wednesday, Friday and Saturday since 2005. The third regular item I have purchased thru I.A.S. (again on the Mon.,Weds,Fri. & Saturday regime) is centrophenoxine. Cost is my limiting factor. Again, thank you so much for all the information you have given to me in books and the three cassette tape sets I purchased from I.A.S. and/or VRP.

  7. Clark & Edith Grady

    Dear Dr. Dean Ward,
    In the latest issue of AGINGMATTERS Issue 3, 2013, you stated “add(ing) a combination of potassium and magnesium for longer term use which may enable you to wean yourself from the (high blood pressure Rx)medication. I often prescribe magnesium-potassium aspartate as a source of these minerals.” My question is how much of the magnesium -mgs.? and the Potassium-mgs? I know one should take twice as much magnesium as potassium. Exactly how many mgs. of magnesium and how many mgs. of potassium would be helpful for high blood pressure improvement? Does IAG have these two mineral supplements available in the amounts you feel are effective; Thank you for any advice;suggestions.
    Sincerely yours, Edith G.

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