Professor Imre Zs.-Nagy, Ph.D., D.Sc., is a world-renowned gerontologist. He is the Director of the Fritz Verzar International Laboratory for Experimental Gerontology, University Medical School in Debrecen, Hungary, and is the founding editor of the internationally acclaimed scientific journal, Archives of Gerontology and Geriatrics. In addition to training under the venerable Professor Verzar himself at his Laboratory for Experimental Gerontology in Basel, Switzerland, Zs.-Nagy has also been a distinguished invited scientist at the Laboratory for Experimental Gerontology in Ancona, Italy, and the Tokyo Metropolitan Institute of Gerontology in Japan. A key focus of his research has been to develop his free radical-related Membrane Theory of Aging.1,2 Another objective was to identify anti-aging substances for use in humans, based on his theory.3
We are proud that Prof. Zs.-Nagy accepted our invitation to be a featured speaker at the VRP/IAS-sponsored Anti-Aging Conference in Monaco last June, and he has been invited for a return visit to the Second Monaco Conference to be held in June, 2001.
I met Prof. Zs.-Nagy at the International Gerontological Association meeting in New York in 1985. I next encountered him at the International Congress of Gerontology and Geriatrics in Acapulco, Mexico, in 1989. I knew of him because he had made major contributions in developing the lipofuscin (age pigment) dissolving, anti-aging drug,
centrophenoxine.4,5
Centrophenoxine is one of the few substances that has demonstrated the capability to extend maximum lifespan in experimental animals (Fig. 1).6 After working extensively with centrophenoxine, Zs.-Nagy developed an advanced analog—BCE-001—which he believes is as an even more effective life extension substance than centrophenoxine.7 Unfortunately, although patented in the U.D., BCE-001 has yet to be manufactured in commercial quantities.
Through a combination of diplomacy and science, Zs.-Nagy also played a key role in developing yet another highly effective life extension substance—Idebenone.
Idebenone
Idebenone is an analog of CoQ10 (Fig. 2). I learned about it at the meeting in Acapulco at a conference sponsored by Takeda Chemical Industries, Ltd.8 Takeda had been marketing Idebenone in Japan, under the trade name Avan since 1986. John Morgenthaler and I included a chapter about it in our book, Smart Drugs & Nutrients. Although we rated Idebenone quite highly at that time, we reluctantly reported that it was available only in Japan (by prescription) and that it was prohibitively expensive.
Prior to 1990, the majority of the world literature on Idebenone had been published in Japanese—largely unavailable to scientists in the West. Zs.-Nagy, through his contacts in the Japanese research community, encouraged the translation of many of these studies, and was an active participant in much of the research. He published three special issues of his journal, each of which focused entirely on Idebenone.
The first two—May, 1989 and November/December, 1990—contained articles on the in vivo and in vitro effects of Idebenone on experimental animals.9,10 Zs.-Nagy himself authored or co-authored twelve of the articles.
While in Italy at the Laboratory for Experimental Gerontology, Zs.-Nagy encouraged his colleagues there to investigate the clinical effects of Idebenone. These studies resulted in his third special issue, which was devoted exclusively to human clinical trials.11
Idebenone’s numerous benefits were attributed to its antioxidant properties and protective effect against damage to mitochondrial membranes. This results in enhanced formation of ATP (the body’s principal energy molecule), increased glucose metabolism, and reduced tissue oxygen requirements. These properties are the basis for Idebenone’s powerful effects on cellular energy metabolism and utilization.12
Protection Against Hypertension and Strokes
Idebenone was found to (1) protect experimental animals against neurological damage caused by [induced] strokes; (2) prevent the development of hypertension and strokes in a breed of rat that typically develops hypertension, resulting in strokes (Spontaneously Hypertensive Stroke Prone rats—SHRsp); and (3) prolong survival of mice subjected to hypoxia (reduced oxygen). Idebenone protects against brain damage by improving cerebral energy metabolism in both normal rats and SHRsp. Idebenone also enhances the formation of cyclic AMP, and increases serotonin (5-HT) turnover.12
Chronic Cerebrovascular Disease
Idebenone also protects experimental animals and humans from the devastating effects on memory and cognition caused by hypoxia and other causes. One of the first human studies outside Japan was performed in Italy at the University of Pavia.13 This study involved a total of 75 hospitalized men and women who suffered from mild to moderate cognitive impairment. Idebenone was administered in doses of 90 or 180 mg daily. Results of the study are in Figs. 3 and 4. As can be seen, the patients treated with Idebenone improved significantly—particularly in cognitive performance (Fig. 3) and general behavior (Fig. 4).
Zs.-Nagy’s third special issue on Idebenone reported on further human studies conducted in Italy. Combined, the studies reported on 422 patients with dementia of varying causes, half of whom were given placebo. Patients in all studies were given 45 mg of Idebenone twice daily for periods varying from three to six months. The results were overwhelmingly positive in most of the standard rating scales used. In particular, the authors consistently reported overall improvements in memory, attention, cognition, and behavior. Measurable improvement was frequently noted after one month, with continued improvement as the treatment lengthened, up to about six months (the maximum duration of the study). In addition, benefits tended to persist for at least a month after cessation of treatment. There were no side effects that could be attributed to Idebenone in any study.
A Safe, Effective Anti-Depressant?
Scientists induced low serotonin levels in rats by feeding them tryptophan-free diets (tryptophan is a precursor of the neurotransmitter serotonin). When these rats were given Idebenone, the serotonin-deficient rats performed as well on a discrimination test as did rats with normal serotonin levels.14
Low serotonin levels in humans are associated with impulsiveness, bad temper and violent behavior. Some studies of violent people have found low levels of serotonin metabolites, indicating low serotonin levels. Because of this ability to stimulate the release of serotonin and norepinephrine, Idebenone has been shown to be a very safe, effective anti-depressant.
Conclusion
Idebenone appears to be another in the growing armamentarium of safe, effective anti-aging substances. The major limitations to its use—availability and affordability—have now been largely resolved. Thanks to the Dietary Supplement Health Education Act (DSHEA), Idebenone qualifies as a dietary supplement. Also, although not cheap by any means, it is now within the price range of many consumers. Hopefully, as demand increases, the increased supply will further reduce the price.
One question will certainly be: In view of the similarity of Idebenone to CoQ10, is one better than the other? Or should we take both? Unfortunately, there are no definitive answers. One reason to consider taking both is that the substances may have slightly varying effects. For example, niacin and niacinamide (both forms of vitamin B3) have very different effects when taken in pharmaceutical doses. Consequently, many people take high doses of both substances. Another example of synergistic action of similar substances is the various forms of vitamin E (i.e., alpha, beta, delta and gamma tocopherols). Also, while there are many studies demonstrating effectiveness of Idebenone in dementing illnesses, there are no such studies of CoQ10 in this regard (likewise, there are no studies that I know of showing benefits of Idebenone in cardiac conditions). I believe that taking various forms of substances can be synergistic, because of slightly different sites and mechanisms of action.
The optimum dosage of Idebenone appears to be 45 mg, twice daily. Improvements in cognition, mood and behavior can usually be noted in about one month, with progressively continuing improvement up to about six months.
References:
1. Zs.-Nagy, I. A membrane hypothesis of aging, J Theor Biol, 1978, 75: 189-196.
2. Zs.-Nagy, I. The role of membrane structure and function in cellular aging: A review, 1979, Mech Age Dev, 1979, 9: 237-246.
3. Zs.-Nagy, I. Editorial, Archives of Gerontology and Geriatrics, 1989, 8: 191.
4. Zs.-Nagy, I., Pieri, C., Giuli, C., and Del Moro, M. Effects of centrophenoxine on the monovalent electrolyte contents of the large brain cortical cells of old rats. Gerontology, 1979, 25: 94-102.
5. Zs.-Nagy, I., and Semsei, I. Centrophenoxine increases the rates of total and mRNA synthesis in the brain cortex of old rats: An explanation of its action in terms of the membrane hypothesis of aging, Exp Gerontol, 1984, 19: 171-178.
6. Hochschild, R. Effect of centrophenoxine on the life span of male swiss webster albino mice. Exp Gerontol, 1973, 8: 177-181.
7. Zs.-Nagy, I., Ohta, M., and Kitani, K. Effect of centrophenoxine and BCE-001 treatment on lateral diffusion of proteins in the hepatocyte plasma membrane as revealed by fluorescence recovery after photobleaching in rat liver smears. Exp Gerontol, 1989, 24: 317-330.
8. The Story of Avan, Marketing Brochure, Takeda Chemical Industries, Ltd., 1989.
9. Archives of Gerontology and Geriatrics, 1989, 8: 3, 191-373.
10. Archives of Gerontology and Geriatrics, 1990, 11: 3, 175-326.
11. Archives of Gerontology and Geriatrics, 1992, 15: 3, 197-294.
12. Zs.-Nagy, I. Chemistry, toxicology, pharmacology and pharmacokinetics of Idebenone: A review. Archives of Gerontology and Geriatrics, 1990, 11: 3,177-186.
13. de Nicola, P. Fundamental and Clinical Assessments of Drugs in Cerebral Circulation and Metabolism in Vascular Dementia. Program and Extended Abstracts, XIVth
World Congress of Gerontology. June 20, 1989, Acupulco.
14. Nomura, M. Effects of idebenone on brightness discrimination learning in rats with central serotonergic dysfunction. Jpn J Psychopharmacol, 1985, 37: 235-244.