Nutraceuticals and nootropics for anti-aging

My father-in-law is showing signs of Alzheimer’s Disease, and his doctor has told him that even the most effective drugs available won’t do much for him. He has my father-in-law on galantamine; and, as predicted, it seems to be almost worthless. So I’m looking for alternatives. In July 2006 Dr. Zarkov wrote an article for LifeLink that discussed curcumin supplements and their activity against this disease. Would it be possible to get an update on this and other anti-Alzheimer’s substances?

This is a good time for an update because there has been an upsurge in curcumin research during the past year. I’ll discuss curcumin and several other substances, each of which affects Alzheimer’s Disease in a different way. Together they have a potential for acting synergistically, which would give the combination a greater impact than would be expected from their individual actions.

Curcumin and ferulic acid

A very exciting paper appeared last month in the Journal of Neurochemistry, in which the authors described experiments on mice with a genetic propensity to develop Alzheimer’s Disease. The brains of these mice accumulate the plaques of misfolded beta-amyloid protein which characterize Alzheimer’s Disease. The researchers report that “systemic treatment of mice with curcumin for 7 days clears and reduces existing plaques, as monitored with longitudinal imaging, suggesting a potent disaggregation effect.”¹ In other words, curcumin treatment not only halted the progression of the disease, it reversed it.

It has also been reported that ferulic acid, a supplement closely related to curcumin, has the ability to disrupt amyloid deposits in vitro.^2,3 Ferulic acid has a higher solubility in water than curcumin, is probably more bioavailable, and may have somewhat different disruptive effects on amyloid deposits than curcurmin has.

Another study explored the molecular interaction between curcumin and beta-amyloid protein.⁴ It appears that curcumin binds to specific regions of the amyloid surfaces, interferring with the tendency of the amyloid layers to stick to each other. This interference prevents plaque formation and disrupts the structure of already-formed plaques. Think of it as analogous to inserting pieces of waxed paper between slices of cheese, thereby preventing the cheese slices from clinging to each other so tightly. The looser amyloid layers are more accessible to processes that chop them up and dispose of them.

Other mechanisms that have been explored in some depth are curcumin’s ability to alter signalling pathways between cells,⁵ and to alter the activity of specific genes.⁶ These processes have far-reaching effects on the life, death, and functioning of cells, including nerve cells.

A recent review of curcumin treatment for Alzheimer’s states that clinical trials are (at long last!) in progress.⁷

What dosages of curcumin and ferulic acid would be likely to have an anti-Alzheimer’s benefit? This depends upon the formulation. Curcumin by itself has a low bioavailability, and could require multiple grams per day for any effect at all. Curcumin formulas like LifeLink’s Primeric™, on the other hand, contain bioavailability enhancers that reduce the required dosage many-fold. I myself take two Primeric capsules per day (666 mg of curcumin) as part of my own anti-aging, anti-Alzheimer’s regimen. After reading the research papers mentioned in this article, I’m considering upping this to three capsules per day. I have also started taking three capsules of ferulic acid per day (250 mg/capsule).

Lithium

Lithium salts have been used for more than a century to treat mania. During the first half of the 20th Century, however, lithium therapy fell out of fashion and was not rediscovered until 1949. Since then, it has become one of the mainstays in the treatment of ‘bipolar disorder’ (the current euphemism for manic-depression).⁸

The problem with most lithium salts is that the therapeutic dose is nearly as large as the toxic dosage. This makes these substances risky to use without the supervision of a medical specialist. There is one lithium salt, however, that is effective at dosages far lower than the toxic dosage: lithium orotate, a so-called ‘organic salt’ of lithium.

With a non-toxic form of lithium available, there is an incentive to explore other medical applications of lithium besides the traditional one: mania. In my opinion, the most exciting of these other applications is neuroprotection.

As is discussed in LifeLink’s monograph on lithium orotate, lithium interferes with a key process in the brain that damages nerve cells in Alzheimer’s disease. As researchers investigated this phenomenon, they realized that lithium is a potentially important treatment for other neurologically damaging conditions, including stroke, Huntington’s, ALS, Parkinson’s, and less well-known ailments.

The mechanism by which lithium protects nerve cells is still not understood, despite decades of effort. Lithium may, somehow, reduce the excitability of these cells, thereby preventing them from being damaged by overactivity. This would be consistent with the fact that lithium treatments can suppress neurological ailments that involve hyperactivity in regions of the brain — ailments like mania, impulsive aggressiveness, uncontrollable anger, epilepsy, disruptive behavior, anxiety, etc.

What dosage of lithium orotate would make a suitable treatment for Alzheimer’s? You won’t find the answer in the medical literature because no clinical trials have been conducted to find out. Pharmaceutical companies could conduct such studies if they wanted to, but they don’t want to — there isn’t enough profit in an unpatentable substance. The supplement industry would benefit from conducting an Alzheimer’s/lithium study, but government agencies would prevent it. So we are left to guess at the proper dosage. My guess would be 3 tablets/day at 135 mg per tablet, as part of a combination regimen that includes some of the other supplements discussed below. This would supply about 17 mg/day of elemental lithium.

Acetyl-L-carnitine

ALC was first identified as a treatment for Alzheimer’s Disease in the 1980s. A clinical trial was conducted and reported on in 1983,⁹ and a flurry of clinical trials took place in the early 1990s^{10,11,12,13,30,31,16} and a few more in the late 1990s^17,18,19 — all of which concluded that ALC slows the development of Alzheimer’s symptoms.

Then, around the year 2000, researchers changed the methods of assessment for Alzheimer’s treatments. Several studies using the new assessment tools produced null results,^20,21,22 causing many in the medical establishment to turn their backs on ALC as a treatment. Very little work on ALC has been done since 2003 in the context of Alzheimer’s Disease.

What are we to make of this? Should we believe, as the medical establishment does, that the clinical studies of ALC done prior to 2000 were done incompetently, using untrustworthy assessment tools, and that the benefits seen by the researchers and the patients were illusions? If so, shouldn’t all the Alzheimer’s clinical studies using other treatments besides ALC, including those that tested prescription drugs, be similarly disregarded and their conclusions considered worthless? But they aren’t — the older studies of prescription drugs are still regarded as valid, whereas positive conclusions about dietary supplements are regarded as invalid. I believe that the medical profession is hopelessly biased against dietary supplements and cannot be trusted to come to rational conclusions about them.

My own inclination is to accept as valid the studies that showed a benefit of ALC as an Alzheimer’s treatment, and to assume that something is wrong with the newer assessment methods. The newer methods make use of very complex statistical manipulations that tend to conceal the fact that subjective interpretations do take place when data is prepared for analysis. There is a subjective component in the older methods, too, but it is more visible than in the newer ones.

What dosage of ALC should be used with Alzheimer’s patients? A typical dosage used in the studies in which benefits were reported was 1 gram taken 3 times per day. The half-life of ALC in the body is about 4.2 hours.²³ Therefore, once-per-day dosing would result in large fluctuations of ALC levels over a 24 hour period.

ALC is usually taken with alpha-lipoic acid in order to suppress the extra free radicals generated when energy production becomes more efficient.

Huperzine-A

The product description for LifeLink’s huperzine-A product, Knoitol™, provides a good, short summary of why huperzine is now considered to be a valuable part of an anti-Alzheimer’s regimen. The essence of the matter is as follows:

Huperzine-A (HupA) is a substance found in the club moss Huperzia serrata. The Chinese Academy of Sciences took an interest in HupA in the 1980s and developed it as a treatment for dementia, particularly the dementia of Alzheimer’s Disease. In 2003 it was approved by China’s State Pharmaceutical Administration as a treatment for Alzheimer’s.

HupA appears to affect multiple biochemical pathways in the brain, several of which are involved in Alzheimer’s Disease. One such pathway involves the production and breakdown of the neurotransmitter acetylcholine. In Alzheimer’s Disease, there is a shortage of acetylcholine, and consequently an impaired ability for nerve cells to carry information. HupA inhibits one of the enzymes that break down acetylcholine, thereby causing acetylcholine to accumulate, and permitting higher levels of nerve activity to occur.

Huperzine’s raising of acetylcholine levels are just one of several ways that it affects Alzheimer’s. It also:

• protects nerve cells from free radicals generated by the ‘beta-amyloid’ protein plaques found in Alzheimer’s brain tissue.^24,25,26,27
• interferes with the formation of these destructive beta-amyloid plaques.^24,27
• interferes with the ‘suicide’ programming that causes nerve cells to die when they receive spurious ‘time-to-die’ signals, as they do under Alzheimer’s conditions.^24,25,27
• increases the brain’s production of nerve growth factor (NGF) — a substance involved in generating replacements for lost cells.^24,27
• increases the brain’s production of NGF receptors — cell-surface proteins that are required for NGF activity.²⁷

How much huperzine-A do Alzheimer’s patients use? Chinese research has led to the conclusion that 400–800 mg/day is the proper dosage range.²⁸

Excitatory mechanism?

A very recent article by researchers in California suggests that the cognitive deficits seen in Alzheimer’s Disease might be caused by seizure-like activity caused by amyloid deposits.²⁹ If this idea proves to be valid, then treatments that reduce feedback overstimulation of neurons should be added to the Alzheimer’s regimen. In the realm of supplements, piperine (Bioperine®) would be a candidate.

Regimen summary

The anti-Alzheimer’s regimen I now favor consists of:

• 333 mg curcumin 3 times per day
• 250 mg ferulic acid 3 times per day
• 135 mg lithium orotate 3 times per day
• 1 g acetyl-L-carnitine 3 times per day
• 250 mg alpha-lipoic acid (or 100 mg R-alpha-lipoic acid) 3 times per day
• 200 mcg huperzine-A 3 times per day

This is a lot of pills to take each day. But this regimen serves also as an anti-aging regimen. While it isn’t clear that I’m at high risk for Alzheimer’s, it is quite clear that I’m at high risk for aging — so I figure that it’s worth the trouble and expense of taking all these pills since my efforts are countering two major threats, one of them hypothetical and the other definite.

— Dr. Alexis Zarkov, Ph.D.

You can contact Dr. Zarkov at AskDrZarkov@yahoo.com.

Last modified 2007.Sep.26

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References

[1]  Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem. 2007 Aug; 102(4):1095-104 Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ

[2]  Redox regulation of cellular stress response in neurodegenerative disorders. Ital J Biochem. 2006 Sep-Dec; 55(3-4):263-82 Calabrese V, Guagliano E, Sapienza M, Mancuso C, Butterfield DA, Stella AM

[3]  Ferulic acid destabilizes preformed beta-amyloid fibrils in vitro. Biochem Biophys Res Commun. 2005 Oct 21; 336(2):444-9 Ono K, Hirohata M, Yamada M

[4]  Structure-activity Relationships of Amyloid Beta-aggregation Inhibitors Based on Curcumin: Influence of Linker Length and Flexibility. Chem Biol Drug Des. 2007 Sep; 70(3):206-15 Reinke AA, Gestwicki JE

[5]  Curcumin in Cell Death Processes: A Challenge for CAM of Age-Related Pathologies. Evid Based Complement Alternat Med. 2007 Jun; 4(2):181-190 Salvioli S, Sikora E, Cooper EL, Franceschi C

[6]  Modulation of transcription factors by curcumin. Adv Exp Med Biol. 2007; 595:127-48 Shishodia S, Singh T, Chaturvedi MM

[7]  Neuroprotective effects of curcumin. Adv Exp Med Biol. 2007; 595:197-212 Cole GM, Teter B, Frautschy SA

[8]  Wikipedia website Lithium pharmacology

[9]  [The use of 1-acetylcarnitine in (presenile and senile) Alzheimer’s disease. Preliminary results] Clin Ter. 1983 Apr 30; 105(2):135-45 Acierno G

[10]  Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer’s dementia. Curr Med Res Opin. 1990; 11(10):638-47 Rai G, Wright G, Scott L, Beston B, Rest J, Exton-Smith AN

[11]  Acetyl-L-carnitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res. 1990; 10(1-2):75-9 Passeri M, Cucinotta D, Bonati PA, Iannuccelli M, Parnetti L, Senin U

[12]  Selegiline versus L-acetylcarnitine in the treatment of Alzheimer-type dementia. Clin Ther. 1990 Jul-Aug; 12(4):306-14 Campi N, Todeschini GP, Scarzella L

[13]  Acetyl-L-carnitine: a drug able to slow the progress of Alzheimer’s disease? Ann N Y Acad Sci. 1991; 640:228-32 Carta A, Calvani M

[16]  Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimer’s type. Drugs Aging. 1993 Mar-Apr; 3(2):159-64 Parnetti L, Abate G, Bartorelli L, Cucinotta D, Cuzzupoli M, Maggioni M, Villardita C, Senin U

[17]  Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer’s disease. Neurobiol Aging. 1995 Jan-Feb; 16(1):1-4 Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ

[18]  A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer’s disease. Neurology. 1996 Sep; 47(3):705-11 Thal LJ, Carta A, Clarke WR, Ferris SH, Friedland RP, Petersen RC, Pettegrew JW, Pfeiffer E, Raskind MA, Sano M, Tuszynski MH, Woolson RF

[19]  Acetyl L-carnitine slows decline in younger patients with Alzheimer’s disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach. Int Psychogeriatr. 1998 Jun; 10(2):193-203 Brooks JO, Yesavage JA, Carta A, Bravi D

[20]  A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology. 2000 Sep 26; 55(6):805-10 Thal LJ, Calvani M, Amato A, Carta A

[21]  Acetyl-L-carnitine for dementia. Cochrane Database Syst Rev. 2003; (2):CD003158 Hudson S, Tabet N

[22]  Effects of acetyl-L-carnitine in Alzheimer’s disease patients unresponsive to acetylcholinesterase inhibitors. Curr Med Res Opin. 2003; 19(4):350-3 Bianchetti A, Rozzini R, Trabucchi M

[23]  HPLC determination and pharmacokinetics of endogenous acetyl-L-carnitine (ALC) in human volunteers orally administered a single dose of ALC. Arch Pharm Res. 2004 Jun; 27(6):676-81 Kwon OS, Chung YB

[24]  Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci. 2006 Dec; 27(12):619-25 Zhang HY, Tang XC

[25]  Huperzine A attenuates amyloid beta-peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. J Neurosci Res. 2002 Jan 1; 67(1):30-6 Xiao XQ, Zhang HY, Tang XC

[26]  Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Zhongguo Yao Li Xue Bao. 1999 Jun; 20(6):486-90 Xu SS, Cai ZY, Qu ZW, Yang RM, Cai YL, Wang GQ, Su XQ, Zhong XS, Cheng RY, Xu WA, Li JX, Feng B

[27]  Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin. 2006 Jan; 27(1):1-26 Wang R, Yan H, Tang XC

[28]  Huperzine A in Alzheimer's Disease ClinicalTrials.gov website

[29]  Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron. 2007 Sep 6; 55(5):697-711 Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L

[30]  Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology. 1991 Nov; 41(11):1726-32 Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, Frattura L, Tiraboschi P, Comelli M

[31]  Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer’s disease. Arch Neurol. 1992 Nov; 49(11):1137-41 Sano M, Bell K, Cote L, Dooneief G, Lawton A, Legler L, Marder K, Naini A, Stern Y, Mayeux R

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Disclaimer: The information provided in this “Ask Dr. Zarkov” article contains no medical advice whatsoever — it contains biological information. Nothing in the article constitutes an effort to persuade readers to use, or not to use, this biological information as a basis for action.