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Life Extension Magazine

LE Magazine February 2001

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Lipoic acid, inflammation and skin aging

Dr. Nicholas Perricone is best known as the author of The Wrinkle Cure, a cutting-edge book on reversing skin aging. In the book, he announces, “After years of working with antioxidants, I knew I had finally found the ultimate wrinkle cure.” What is it? Topical lipoic acid in the right concentration. Why does it work so well? Because it's a superb anti-inflammatory.

“Lipoic acid inhibits Nuclear Factor kappa B (NFkB) better than anything else,” Perricone stated. The ability to inhibit NFkB seems a key to anti-inflammatory action, since NFkB is a transcription factor that activates the production of inflammatory cytokines that initiate cellular destruction. And if inflammation plays a central part in skin aging, as Perricone believes, then an effective anti-inflammatory cream makes perfect sense.

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The greatest enemy of youthful skin is probably smoking. "There is a 15 to 20 year difference in appearance between smokers and nonsmokers,"...

Lipoic acid has been found to significantly reduce fine lines and shallow wrinkles. This is far from sensational, since Retin-A, topical vitamin C (Perricone recommends the ascorbyl palmitate form for topical use), CoQ10 and various other antioxidants do the same thing. The surprising discovery made by Dr. Perricone was that lipoic acid can also help heal acne scars. It is generally believed that only aggressive procedures such as laser resurfacing can do anything about acne scars. Needless to say, compared to a laser peel, lipoic acid is much cheaper, not to mention non-traumatic.

How does lipoic acid perform this feat? According to Perricone, lipoic acid activates a transcription factor known as AP-1, which leads to the production of enzymes called metalloproteinases. These enzymes digest the damaged collagen, thus helping erase wrinkles and even scars. At the same time, lipoic acid helps cells produce more energy in the mitochondria, thus making more energy available for healing. Finally, due to its anti-inflammatory effectiveness, lipoic acid makes it easier for patients to tolerate Retin-A. Both Retin-A and lipoic acid inhibit the inflammatory cytokine-induced destruction of normal collagen.

Yet another benefit of topical lipoic acid is diminished puffiness around the eyes. This puffiness, or swelling, is technically called edema, and is one of the visible signs of inflammation (redness is another; since inflammation is pro-aging, beware of products that irritate your skin to the point of redness).

“The effective range for topical lipoic acid is between 3% and 10%. We use mainly 5%. We sell this product to dermatologists,” Perricone explained. The bad part is that Perricone's products sold to the public typically contain only 1% lipoic acid, with 3% available, but for over $100 for a small amount. Fortunately there are compounding pharmacies. You may be surprised how many of them work closely with dermatologists. Many topical products, however, are available to the public without the need for a prescription. This is where having the right knowledge really pays.

Dr. Perricone emphasized that his approach to skin rejuvenation goes far beyond topical anti-inflammatories. “Beauty is the look of health,” he said. Good looks serve as a terrific incentive for patients to eat a low-glycemic, anti-inflammatory diet (high in fish oil and flavonoids—instead of meat, think fish and seafood; instead of cake, think strawberries). Perricone also encourages patients to take supplements, exercise, practice meditation and improve their lifestyle in general.

The greatest enemy of youthful skin is probably smoking. “There is a 15 to 20 year difference in appearance between smokers and nonsmokers,” Perricone asserted. Speaking of sun exposure, Perricone made the interesting point that we need some sun exposure—fifteen minutes a day is probably enough. He also noted that perhaps as much as 50% of skin damage is due to glycation (the damage to proteins caused by simple sugars such as glucose and fructose). The skin of people whose blood sugar is chronically high can look as old and wrinkled as the skin of smokers. While a low-glycemic diet that excludes refined carbohydrates is the main means to reducing glycation, Dr. Perricone noted that lipoic acid also helps reduce glycation.

Our pursuit of the dazzling dermis has never been more relentless—or more expensive. The old saying, “After 40, you have the face you deserve” should be amended to, “After 40, you have the face you can afford.” Fortunately there are some topical antioxidant preparations that are both effective and affordable (at least by comparison with laser surfacing). The first breakthrough was Retin-A, a form of vitamin A. Then came the hydroxy acids (including salicylic acids). Hydroxy acids act not only as exfoliants, but also as antioxidants and anti-inflammatories. Then the power of topical vitamin C to increase collagen production was discovered. Now Dr. Perricone has publicized his discovery of the powerful rejuvenating effects of topical lipoic acid. No doubt more discoveries lie ahead. The future looks beautiful.

Of dwarf mice and growth hormone: does growth hormone replacement shorten life expectancy?


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"Every male cardiovascular patient should be on testosterone," ... furthermore, testosterone builds muscles and bones, decreases exercise-induced stress, reduces abdominal fat, protects joints, helps prevent cognitive decline and Alzheimer's disease, and is a wonderful antidepressant.

The lectures and workshops on hormone replacement showed a remarkable consensus on two points: testosterone and growth hormone have extraordinary health benefits. But while a few years ago the safety of testosterone replacement was being questioned, now the controversy is directed to the impact of growth hormone replacement on longevity.

The news about testosterone couldn't be better. According to the latest findings, testosterone lowers LDL cholesterol and triglycerides, increases insulin sensitivity, strengthens the heart muscle and increases cardiac output, dilates the coronary arteries and alleviates angina.

“Every male cardiovascular patient should be on testosterone,” Dr. Neal Rouzier declared. This is a revolutionary reversal of the old dogma that held that testosterone was bad for the heart. Not one person in the audience contested Rouzier's assertion.

Furthermore, testosterone builds muscles and bones, decreases exercise-induced stress, reduces abdominal fat, protects joints, helps prevent cognitive decline and Alzheimer's disease, and is a wonderful antidepressant. One conference participant commented, “Testosterone is a wonderful everything.” “I think testosterone is fabulous,” another physician concurred.

As for the danger of prostate cancer, the new thinking is that the main culprit is estrogen. Consequently we now see a lot of interest in aromatase inhibitors, compounds that decrease the conversion of testosterone to estradiol. Chrysin, a flavonoid, has become particularly popular.

Interestingly, dihydrotestosterone (DHT), once maligned, is now in greater favor, since it can't be converted to estradiol. A DHT patch is in use in Europe, and so far no increase in prostate cancer has been found.

Rouzier favors testosterone for women as well, though of course in gender-appropriate doses. The addition of testosterone appears to further enhance bone density. It also increases a woman's libido and her sense of energy and well-being.

What kind of testosterone replacement is best? The news is that the gel appears to be more effective than the patch (not to mention the fact that if you order testosterone gel or cream from a compounding pharmacy, you are getting a terrific bargain).

Rouzier observed that Prozac and similar drugs work poorly at best. The real improvement in mood and energy comes from increasing the levels of hormones such as testosterone, growth hormone and thyroid. By the way, Rouzier pointed out the little known finding that T3, the most active of the thyroid hormones, enhances cardiac performance; he warned that Synthroid (thyroxine, or T4) may not raise T3.

As for the anti-hormone stance of many conservative mainstream physicians, Rouzier remarked, “Someone out there doesn't want you to feel good.” The old attitude is that only specific diseases are to be treated, but not aging as such. The new attitude, represented by Rouzier and many other holistic physicians, is that we should begin safe hormone replacement relatively early in life, before the development of pathological changes (such as insulin resistance, atherosclerosis or cognitive decline) that are related to “natural” hormone deficiencies that progress as we age. Again, there was no disagreement with this still revolutionary notion.

The high drama of the conference began with the first presentation on growth hormone. Actually all three main speakers were in agreement that growth hormone replacement (or enhancement) should be universal, and started as early as mid-thirties. “Everyone over the age of 35 is growth hormone-deficient,” Rouzier stated, arguing that we shouldn't wait for symptoms of “somatopause” such as atherosclerosis and osteoporosis before beginning replacement with multiple hormones, definitely including growth hormone. Rouzier stressed that he doesn't believe that “reversing aging” is possible. We can, however, slow down aging by various means, including maintaining hormones at youthful levels and in youthful ratios. Hence the urgency about starting hormone therapy early.

If we are serious about anti-aging medicine, sooner or later we have to face the thorny issue of “growth hormone for everyone over 35.” Very likely, growth hormone is the most potent rejuvenating therapy currently available. No other hormone can decrease body fat so dramatically while building muscle. No other hormone can actually cause a regrowth of organs such as the kidneys back to their youthful size. Patients on correct (low-dose) growth hormone replacement appear extremely satisfied with it: their “spare tire” disappears, together with the flab under the chin; their skin thickens and smooths out, their energy, zest for life and libido increase.

No one at the conference questioned the well-documented benefits of growth hormone in terms of its ability to restore a more youthful physiology and enhance the quality of life. The controversy centered on the possibility that maintaining youthful growth hormone levels may actually be harmful in the long run, shortening life span. The conference participants seemed surprisingly familiar with the research on the extraordinary longevity of dwarf mice, which are deficient in growth hormone and IGF-1. IGF-1 stands for insulin-like growth factor 1, and is regarded as the most important metabolite of growth hormone, an anabolic hormone that promotes tissue growth. IGF-1 has a structure similar to insulin, and many of its effects overlap those of insulin. The mainstream view is that growth hormone is “translated” in the liver into IGF-1, and expresses its activity through IGF-1—even though it has been documented that low levels of IGF-1 are not a reliable indicator of growth hormone deficiency.

The uproar began when Dr. Rashid Buttar, who discussed trans-D-tropin (a validated prescription-only growth hormone releaser) announced that his study found that as growth hormone levels go up, IGF-1 levels go down. The mainstream belief is that growth hormone always raises the levels of IGF-1. “The literature is wrong,” Buttar flatly stated. He himself was surprised to find this inverse correlation, but it made sense in the light of his other data: he found that aged, sedentary, obese subjects had very high levels of IGF-1 (250-300), while young athletes had levels as low as 88. The highest IGF-1 in the sedentary group was 304, while the highest IGF-1 among athletes was 196. According to literature, IGF-1 levels below 150 may be a marker of growth hormone deficiency. Buttar reminded the audience that young athletes typically have low insulin, but higher testosterone and higher growth hormone than older, sedentary individuals.

Young athletes differ from obese, sedentary, elderly people in many ways, but levels of insulin and cortisol may be of special importance in regard to IGF-1. We know that high cortisol reduces growth hormone release, but increases somatostatin and IGF-1. Excess insulin likewise inhibits the release of growth hormone, though its effects on the levels of IGF-1 may be a more complex story. Somewhat surpringly, Buttar's emphasis was on cortisol more so than insulin. “Adrenal stress is a big factor in insulin resistance, high IGF-1 and low growth hormone,” he stated. It is also well known that cortisol rises with age, while the release of growth hormone keeps on declining. IGF-1 levels correlate with stress, while they do not reliably correlate with growth hormone levels. There is also some inverse correlation with amount of exercise. An increase in exercise results in lower IGF-1 levels.

In fact under certain conditions high levels of growth hormone are accompanied by low levels of IGF-1. For instance, when humans or other primates significantly reduce their food intake (thus causing a dramatic decline in the levels of blood sugar and insulin), the levels of growth hormone go up while the levels of IGF-1 drop. On the other hand, type II diabetics, known to have excess insulin and insufficient growth hormone, show high levels of IGF-1. Incidentally, Buttar found diabetics to be nonresponsive to trans-D-tropin. Their growth hormone levels did not go up. Interestingly, however, their glucose levels went down in the course of trans-D-tropin treatment.

Obviously, there are still many things we need to learn about growth hormone and its metabolites. Sex steroids such as estradiol and testosterone, as well as cortisol, insulin and thyroid hormones all interact with growth hormone. Growth hormone in turn affects the release of many other hormones. The more we study these interactions, the more complex everything looks.

The assertion that growth hormone can actually lower IGF-1 upset Dr. Rouzier, who said that his IGF-1 doubled when he started taking growth hormone shots. Rouzier did admit that IGF-1 is not a reliable measure of growth hormone activity, and its levels fluctuate considerably. Asked, “Why test for IGF-1 if it's unreliable?” Rouzier replied, “Because it's a simple test.”

We must note that Dr. Rouzier used growth hormone injections, while Dr. Buttar used a growth hormone releaser, obtaining a more physiological release of growth hormone. Buttar's argument is confined to growth hormone secretagogues. Enhancing growth hormone release with secretagogues is regarded as a more physiological method, less likely to produce side effects. We know that the effects of hormones are extremely dose-dependent. There is no question that high doses of growth hormone are dangerous. The ideal is the physiological pulse.

Richard Walker, PhD, was a more formidable figure, being regarded as being at the top of his field. He too had trouble with the idea of an inverse correlation between growth hormone and IGF-1, but appeared open-minded toward new evidence. Since women on oral estrogens have also been found to have higher growth hormone levels but lower IGF-1 levels, clinicians have assumed that they need to give women higher doses of injectable growth hormone to produce the same levels of IGF-1 as are seen in men. Walker explained that estradiol actually enhances sensitivity to growth hormone, and that women preserve much better growth hormone levels than men until menopause—and this may be a big factor in women's greater longevity. As for IGF-1, Walker admitted that we simply do not know what the optimal range is for either sex.

Still, it was the specter of those long-lived, growth hormone-deficient dwarf mice that haunted all lectures and workshops on hormone replacement. Could it be that growth hormone per se shortens life expectancy, or is it rather a combination of high insulin and high IGF-1? If the answer turns out to be growth hormone, that most dramatically rejuvenating of all hormones, then we may have on our hands the painful choice between quantity and quality of life. On the other hand, the chief culprits are likely to be excess insulin and excess IGF-1— precisely the type of pathological endocrine profile that we see in obese, sedentary individuals.

A massive National Institute of Aging study singled out low insulin as the best predictor of longevity in men. In other words, men with the lowest insulin had the lowest mortality. Also, this reporter contacted Dr. A. Bartke, one of the chief investigators involved in the dwarf mouse research, for comment on high IGF-1 in relation to longevity. His opinion is that it's high IGF-1 that is likely to be harmful. For instance, we know it's linked to higher risk for various common cancers; this is not surprising, since, like insulin, IGF-1 promotes tissue proliferation. When calorie-restricted monkeys are given IGF-1 injections, they lose their resistance to cancer. Buttar pointed out that initial stages of cancer are accompanied by high levels of IGF-1, while treatments that suppress IGF-1 also inhibit cancer.

Low IGF-1 correlates with longevity, according to Bartke. IGF-1 is “virtually absent” from the serum of the long-lived dwarf mice. Thus, aiming at high IGF-1 levels might not be desirable, both in terms of life expectancy and susceptibility to cancer. Bartke warned, however, that at this point we have trouble separating the effects of growth hormone itself from those of its metabolites, chiefly IGF-1. It is an enormously confusing situation.

It is still too early to make clear practical recommendations as to the optimal form of growth hormone therapy for everyone over 35 or 40. Too many questions remain to be answered. Dr. Walker warned that injectable growth hormone should not be used as a short-term treatment for obesity. Obese patients tend to have high blood sugar and high insulin, and need to be monitored more closely than non-obese patients due to the possibility of extremely serious side effects such as the development of diabetes. In the future, growth hormone replacement or enhancement will probably emerge as a universal anti-aging therapy. Currently, the use of growth hormone releasers (secretagogues) rather than injections appears to be the safest route to obtaining the benefits of increased growth hormone release without the risk of raising IGF-1 to potentially excess levels. Restricting calorie intake is another proven way to raise growth hormone. Drugs that raise dopamine (e.g. deprenyl) also increase growth hormone release. Meditation has been shown to increase growth hormone (possibly because it decreases cortisol). Melatonin also slightly raises growth hormone.

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The deeper the sleep, the greater the release of growth hormone. But how do we counteract the age-related loss of deep sleep?

Finally, there is also a lot of interest in improving the depth of sleep as another means to safely raise growth hormone release. We know that the length of slow-wave sleep starts decreasing in men as early as age thirty. The deeper the sleep, the greater the release of growth hormone. But how do we counteract the age-related loss of deep sleep? According to Dr. Walker, growth hormone-releasing hormone (GHRH) enhances sleep, but giving growth hormone through injection may cause the side effect of sleep shortening. As we age, we appear to lose sensitivity to GHRH. There seems to be no end of complexity the more we look into any issue pertaining to hormone replacement.

For now, the only answer is “We need more research.”

Overall, in spite of the continued controversy over growth hormone therapy, the recent ACAM conference showed the emergence of a growing consensus that alternative medicine is coming of age, and gaining a respectable scientific base. In all presentations dealing with specific diseases there was an effort to get at the root causes, not just treat the symptoms. One of the root causes in the development and/or progression of a chronic disease is often inflammation. Inflammation has also emerged as one of the most important factors in aging. We do have considerable knowledge about inflammation as well as about anti -inflammatory agents. Simple, inexpensive remedies such as ibuprofen, aspirin, fish oil, lipoic acid or bilberry extract have been validated as powerful preventive medicine. The future should bring even more exciting breakthroughs in this area.

References

Bartke A, Ph.D. Personal communication.

Miller P, MD. Personal communication on IGF-1 levels in type II diabetics.

Nelson JE, Harris RE. Inverse association of prostate cancer and NSAIDs: results of a case-control study.
Oncol Rep 2000; 7:169-70.

Sharpe CR et al. Nested case-control study of the effects of NSAIDs on breast cancer risk and stage.
Br J Cancer 2000; 83:112-20.

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