February 2004 Blog with Durk and Sandy

The second half of the [twentieth] century has been incomparably more peaceful than the first, simply by putting power into the hands of those people who wanted peace.— Edward Teller  Ye have made the way from worm to man, and much within you is still worm.— Friedrich Nietzsche. . . the agency [FDA] should avoid using expansive definitions of such words as "model" to bootstrap itself into new realms of administrative and regulatory authority.

In developing regulations, it is important that the Agency not allow rent seekers from one side or another to use the power of the Agency to raise barriers to entry or expansion against new products, companies, or processes.

In the final analysis, the consumer is the supreme regulator, and the Agency must be careful not to restrict the consumer’s access and choices for any reasons short of compelling issues of safety.

— Quotes taken from a letter by Chris Cannon, Member of Congress (3rd District, Utah) to Mark McClellan, the Commissioner of the Food and Drug Administration, concerning the FDA’s proposed new Good Manufacturing Practices for dietary supplements

Once Upon a Time . . . "Absence of Administrative Centralization"

Previously, I distinguished two kinds of centralization; I called one governmental and the other administrative. The first alone exists in America; the second is nearly unknown there. If the power that directs American societies found these two means of government at its disposal, and added the capacity and the habit of executing everything by itself to the right of commanding everything; if, after having established the general principles of government, it entered into the details of application, and after having regulated the great interests of the country it could descend to the limit of individual interests, freedom would soon be banished from the New World. But in the United States, the majority, which often has the tastes and instincts of a despot, still lacks the most perfected instruments of tyranny.— Alexis de Tocqueville, Democracy in America (1831). Far ahead of his time, his predictions of the path of government growth and the loss of individual freedoms were uncanny. The United States now has "perfected" the administrative process, the instrument of tyranny missing in 1831, in the Regulatory State. The FDA is just one example of the results.

Life-Extending Sirtuins Activated by Resveratrol—Living Longer Through Red Wine?

Much has been published recently about life extensions in yeast and nematodes by members of the sirtuin family of NAD+-dependent protein deacetylases. In yeast, Sir2 (which stabilizes repetitive DNA) expression is increased by life-extending caloric restriction, while in nematodes (C. elegans), the SIR-2.1 enzyme regulates lifespan. Humans have a closely related deacetylase, SIRT1, that promotes cell survival by negatively regulating the tumor suppressor gene p53. The authors of a new work¹ have published a paper in which they looked for small-molecule activators of sirtuins.

The researchers show that resveratrol, found in red wine, activated SIRT1 more than any of the other substances examined (by 13.4 ± 1.0 times the control level); it increased cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol was found to mimic caloric restriction by stimulating Sir2, increasing DNA stability, and extending lifespan by 70%.

The authors also report that quercetin and piceatannol, both polyphenols, increased (compared to controls) the SIRT1 stimulation by 4.59 ± 0.47 and 7.90 ± 0.50 times, respectively. They report that both these substances have previously been reported to be protein kinase inhibitors. (On the other hand, a variety of free radical-protective compounds, including antioxidants, chelators, and radical scavengers, failed to stimulate SIRT1. Hence the authors considered it unlikely that these chemical properties explained the stimulative effect of resveratrol and the other effective substances.)

They tested some of these substances on yeast to test their ability to increase replicative lifespan. Three compounds—butein, fisetin, and resveratrol—were reported to increase average lifespan by 31%, 55%, and 70%, respectively. All three significantly increased maximum lifespan. They found that resveratrol doubled the rate of deacetylation by SIRT1 at about 11 µM and was saturated at 100–200 µM. Higher concentrations of resveratrol provided no additional lifespan benefit. Quercetin and piceatannol had no significant effect on lifespan, they reported, suggesting that this might possibly be due to oxidation of the compounds in the medium or insufficient uptake into cells.

Looking further into resveratrol’s effects on yeast lifespan, they found that there was no significant extension of long-lived resveratrol-treated cells when they were also subjected to glucose restriction, a form of caloric restriction in yeast that ordinarily increases lifespan. This may mean that resveratrol acts through the same pathway as caloric restriction in yeast. The authors propose that many of the effects of polyphenols (such as cardioprotection, neuroprotection, and cancer suppression) may be the result of a caloric restriction-mimetic defense effect mediated by sirtuins. By suppressing p53, which might otherwise cause rapid apoptosis of DNA-damaged cells, the cells would have additional time to repair the damage.

The richest sources of resveratrol include Polygonum cuspidatum, root extracts used extensively in oriental folk medicine, Veratrum gradiflorum and Veratrum formosanum(two species of lily), peanuts and groundnuts, and grapevines. Red wine is also a rich source, with the highest concentration reported in wines prepared from Pinot Noir grapes (averaging 5.13 mg/L). White wines are reported to generally contain 1–5% of the resveratrol content present in most red wines.²

Interestingly, phytoalexins such as resveratrol are not found in vine leaves or berries unless they have been stimulated by ultraviolet light or in response to fungal or microbial infections.²

Anti-inflammatory studies in a rat model of carrageenan-induced paw edema have shown that resveratrol is very effective, with an anti-inflammatory activity greater than that of indomethacin or phenylbutazone. Resveratrol inhibited prostaglandin synthesis via selective inhibition of COX-1 and, in a mouse study, decreased arachidonic acid release and COX-2 induction by the tumor promoter PMA, reactive oxygen intermediates, or lipopolysaccharides (LPS). The resveratrol-mediated decrease in COX-2 activity was confirmed in gene transfer experiments to be due to resveratrol’s inhibitory effect on protein kinase C.²

Other effects of resveratrol that have been reported to occur include, in rats, vasorelaxation and COX-2 inhibition and, in humans, cardiac preconditioning.³

The bottom line is that there may be more to the benefits of drinking red wine than anyone before realized. It would be wonderful if resveratrol also acted as a caloric restriction mimic in humans. Imagine that rather than having to cut your intake of food way back, you might get similar effects simply by consuming red wine regularly (or, possibly, a resveratrol supplement might be required for effective amounts). We await further results (such as a C. elegans, a fruit fly, and then mouse gene expression and lifespan studies with resveratrol) with bated breath!

Final note: The Life Extension Foundation is planning to support a research study (when the funds are available for this expensive work) that compares the changes in gene expression in mice being supplemented with resveratrol with calorically restricted mice. This is just another example of how FDA regulations are hindering the search for practical life extension technology: the Life Extension Foundation can’t fund much research at the moment, as it, like others in the dietary supplement industry, is having to expend its available money to defend itself from the FDA.

1. Howitz et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191-6 (2003).
2. Pervaiz. Resveratrol: from grapevines to mammalian biology. FASEB J 17:1975-85 (2003).
3. Bhat et al. Biological effects of resveratrol. Antiox & Redox Signal 3(6):1041-64 (2001)

Centenarians in Japan

A new study¹ reports that the number of years needed for the population of centenarians (in Japan) to double has been halved in 29 years, after adjusting for the birth cohort numbers. This extraordinary increase in very long-lived individuals is a good example of how the fall in mortality rates has included not just an increase in average lifespan, but also the numbers of people reaching very high lifespans. (Nevertheless, the authors report, the increase did not involve a strong reduction in the dispersion of individual lifespan around average values, and the survival curves do not appear much more rectangular than 20 years ago.) The authors suggest that it is the emergence of a very old sector of the population (95 years and older) that is allowing the lifespan to continue increasing. The researchers report that the ratio of centenarians per 10,000 births has increased from 3.5 for the 1873 cohort (1.4 for men, 5.6 for women) to 49.6 for the 1902 cohort (16.3 for men, 84.5 for women). In September 2002, it is reported that 23 supercentenarians (110 and older) were living in Japan (17 women and 6 men). The number of those aged 105 and older had reached 850 by the same date (127 men, 723 women).

The mortality rates calculated for women from the population of those aged 100–104 show a decrease from 43% in 1973 to 30% in 1999. For men 100–104, the mortality rate decreased from 48% in 1973 to 35% in 1999. The data also suggest a continuing decrease in female death rates at age 105 and over, but death rates for men 105 and over seem to increase. However, the number of people, especially men, 105 and over is small.

So, although we do not see (at least in Japan) a discernibly more rectangular curve of survival versus time, the oldest (100 and over) people are becoming greater in number at an astonishing rate. How much of this is due to genetic factors, nutritional state, medical treatments, etc., remains to be determined.

1. Robine et al. The emergence of extremely old people: the case of Japan. Exp Gerontol 38:735-9 (2003).

FDA Update 
FDA "Clarifies" Its Position on Health Claims: It Is Illegal to Say that Vitamin C Can Treat Scurvy

In our (Dr. Julian Whitaker, American Longevity, Durk Pearson & Sandy Shaw, and Pure Encapsulations, Inc.) latest suit against the FDA (Whitaker v. Thompson), we seek a health claim that saw palmetto can reduce the symptoms of mild benign prostatic hypertrophy. The claim is truthful and nonmisleading. The FDA, however, has refused to evaluate the evidence for the claim, saying that this is a drug claim, since saw palmetto (a dietary supplement) is said to be able to treat or cure disease. The FDA claims that health claims are allowed only for prevention of disease, not treatment.

Our two most important arguments against the FDA are that the congressional statute (DSHEA) allowing for health claims specified that they could apply to the relationship between a nutrient and any health-related condition, the clear language of which includes treatment claims. Second, even if the statute did not allow for treatment claims, the FDA cannot prohibit truthful, nonmisleading speech on dietary supplement labels (First Amendment, U.S. Constitution; Pearson v. Shalala, Court of Appeals for the District of Columbia, Jan. 19, 1999).

As we have noted before, the outcome of this suit will be of immense importance. If we win, there will be a parallel system of medicine in which less regulated and usually inexpensive dietary supplements can compete directly with prescription drugs. On Nov. 10, 2003, oral arguments took place before the U.S. Court of Appeals for the District of Columbia Circuit in the case of Whitaker v. Thompson (No. 03-5020). After the oral arguments had taken place and in violation of court rules, the FDA sent a letter to the court, attempting to "clarify" something they’d said at oral argument. (This shows that the FDA is seriously concerned about the outcome of the oral arguments.) In the letter, the FDA said, "Consistent with the position in our brief, under Section 321(g)(1)(B) and the penultimate sentence in section 343(r)(6), a claim regarding the treatment, mitigation, or cure of a nutrient deficiency disease, like any other disease, remains a drug claim."

What the FDA is saying here is that it would be illegal (and would require a New Drug Application) for a manufacturer or distributor of supplemental vitamin C to say that vitamin C can treat or cure scurvy! They did this, we believe, because they felt they had to be consistent in their drive to reserve all treatment and cure claims to prescription drugs. They couldn’t allow an exception without weakening their restriction. The requirement for consistency led them to make the unbelievably incredible statement to the court, namely, that one could not say that a vitamin C dietary supplement can treat or cure scurvy.

We do not believe that FDA could find a single scientist who would not agree that vitamin C effectively treats and cures scurvy. This is clearly a truthful and nonmisleading statement. The FDA’s other strategy is to claim that they are not stopping you from saying vitamin C cures scurvy, but that in order to say it, you have to file a New Drug Application and get it approved. The response to that is that you are denied your First Amendment rights if you cannot come up with the $250,000 needed to make such an application and the $50,000,000 or so needed to get it approved. Moreover, the vitamin C is the same whether you call it a drug or a dietary supplement—only the speech used with it is different—thus, the FDA is regulating speech and this case is a pure First Amendment issue.

Lycopene May Not Provide All the Benefits of Tomatoes in Preventing Prostate Cancer

A new study¹ shows that when foods contain a number of potentially beneficial compounds, studies based on just one of them may give you a false picture of that food’s health-promoting qualities. This study compared the effects of tomato powder, lycopene, and caloric restriction in preventing the development of prostate cancer in rats fed N-methyl-N-nitrosourea and testosterone to induce that cancer.

194 rats treated with the carcinogen and testosterone were divided into groups receiving whole tomato powder (containing 13 mg lycopene/kg of diet), lycopene beadlets (161 mg lycopene/kg of diet*) or control beadlets. The rats in each group were then subdivided randomly into groups receiving ad libitum feeding or 20% dietary restriction. The results showed that the risk of death with prostate cancer was lower for rats fed the tomato powder than for the rats fed control beadlets and the rats fed the lycopene beadlets (even though the lycopene-fed rats had greater plasma concentrations of total lycopene than the rats fed the tomato powder). The mortality from prostate cancer was similar between the control and lycopene-beadlet-fed rats.

*This is far above the level attainable with a tomato-rich diet, and at this level the lycopene may have altered liver metabolism of the carcinogen or may act as a pro-oxidant.

Not surprisingly, 79% of the ad libitum-fed rats died with prostate cancer, while only 65% of the restricted-fed rats did so.

As mentioned in the paper, tomatoes contain many compounds besides lycopene that may have been involved in the tomato-powder protection, including all-trans-beta-carotene, 9-cis-beta-carotene, polyphenolic compounds such as quercetin, other phenolics, vitamin C, and folate, to name a few. The authors do not rule out that lycopene may have been a contributor to the total effects of tomato powder, but they note that since 82% of lycopene intake is obtained by American men from just one source, tomatoes, epidemiological studies cannot differentiate which of the many substances in tomato are responsible for its protection against prostate cancer.

The editorial² that commented on this paper also notes that Americans consume an average of 91 pounds of tomatoes per capita per year, second only to potatoes among all fruits and vegetables. In other words, the fact that men with elevated plasma lycopene levels³ or who consumed more tomato products and therefore had higher lycopene intake⁴ have been shown to have a lower prostate cancer risk is undoubtedly (at this point) due to their higher consumption of tomatoes rather than of lycopene supplements.

Another paper⁷ that had results consistent with the above was an epidemiological study of the effects of dietary lycopene, consumption of tomato products, and cardiovascular disease in women. The study group was 39,876 middle-aged and older women initially free of CVD and cancer. While dietary lycopene was not found to be strongly associated with the risk of CVD, there was a possible inverse association between CVD and consumption of higher levels of tomato products (at least 2 servings/week each of tomato sauce and of pizza).

Other work, such as the effect of lycopene on prostate cancer cells in culture⁵ or the chemical properties of lycopene,⁶ suggests that lycopene itself may have protective effects. Only more research can sort this out. In the meantime, we are both† continuing to take our lycopene supplements as well as consuming tomatoes and tomato products.

†Sandy, of course, has no prostate, but breast cancer is very similar to prostate cancer.

1. Boileau et al. Prostate carcinogenesis in N-methyl-N- nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst 95(21):1578-86 (2003).
2. Gann, Khachik. Tomatoes or lycopene versus prostate cancer: is evolution anti-reductionist? J Natl Cancer Inst 95(21):1563-65 (2003).
3. Gann et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 59:1225-30 (1999).
4. Giovannucci et al. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 94(5):391-8 (2002).
5. Kim et al. Effect of lycopene on prostate LNCaP cancer cells in culture. J Med Food 5(4):181-7. (Lycopene significantly decreased the growth of cells in a dose-dependent manner.)
6. Di Mascio et al. Lycopene as singlet oxygen quencher. Arch Biochem Biophys274(2):532-8 (1989).
7. Sesso et al. Dietary lycopene, tomato-based food products, and cardiovascular disease in women. J Nutr 133:2336-41 (2003)

Super-Delicious Tomato Recipe: Tomato-Lentil Salad

Now that we are growing tomatoes (the easy way, with self-watering pots), we have lots of delicious fresh tomatoes to eat. This is a wonderful salad (although this one contains no meat, we are not vegetarians or vegans), easy to make and full of healthful ingredients. About 4 servings.

1 cup lentils, picked over and rinsed 
1/4 cup extra virgin olive oil 
1/4 cup red wine vinegar 
4 garlic cloves, minced 
1/2 tsp ground cumin 
Salt and pepper to taste 
1 small red onion, diced 
1/2 medium yellow bell pepper, diced 
1/2 medium red bell pepper, diced 
1/4 cup chopped fresh mint 
2 cups cherry, grape, or plum tomatoes, halved 
6 oz cheese of your choice, crumbled or grated, for garnish 
18 olives of your choice for garnish

Place lentils in largish saucepan and cover with water to about 2" above level of lentils. Bring to a boil, reduce heat, and simmer uncovered for 20–30 minutes, until tender or to desired texture. Drain and cool. In a small bowl, whisk together the olive oil, vinegar, garlic, and cumin. Add salt and pepper. Then, in a large bowl, combine the lentils, onion, bell peppers, 1/2 tsp salt and pepper to taste. Dump the ingredients in the small bowl into the large bowl, and toss to mix. Let sit for 20 minutes. Allow to reach room temperature before serving. Garnish with the cheese and olives. Yum!

This recipe is adapted from the recipe on page 92 of You Say Tomato by Joanne Weir, Broadway Books, 1998.

Second Opinions Available from Major Hospitals

An article in Internet Medicine¹ reports on the availability of online second opinions from some highly respected hospitals, including Massachusetts General Hospital (source of the difficult diagnostic puzzles analyzed in most issues of The New England Journal of Medicine), Cleveland Clinic, Brigham and Women’s Hospitals, and Johns Hopkins. The Wall Street Journal says, according to the article, that the second opinions are "surprisingly comprehensive and provide patients with alternative treatment recommendations." The cost is around $600 per opinion. You need to supply pertinent medical records, including diagnostic images and test results. The article gives the address only for the Cleveland Clinic online second opinions (www.eclevelandclinic.org); you can contact the other hospitals directly for further information.

1. Major hospitals offer virtual second opinions; physicians still skeptical about online consulting. Internet Med, pp 1-3, October 2003.

Serum Insulin Concentrations are Lower in Daily Drinkers Compared with Abstainers

A new report¹ examining 883 randomly selected Hispanic and non-Hispanic white men and women aged 65 and over (The New Mexico Elder Health Survey) was published recently. The researchers found that the participants who consumed alcohol daily had significantly lower fasting and 2-hour postglucose serum insulin concentrations compared with those who abstained from alcohol, after adjusting for serum glucose concentration, gender, ethnicity, age, and body mass index. They conclude, "Abstainers with their relative hyperinsulinemia appear to be more insulin-resistant than daily moderate drinkers. This difference in insulin sensitivity may explain the lower prevalence of diabetes in drinkers compared with abstainers observed in various epidemiological studies."

1. Kenkre et al. Serum insulin concentrations in daily drinkers compared with abstainers in The New Mexico Elder Health Survey. J Gerontol (Med Sci)58A(10):960-3 (2003).

Reversal of Cognitive Aging in Old Mice and Cognitive Dysfunction from Alcohol in Young Mice

There is much similarity between mice and men; in fact, there is about an 85% sharing of genes between the two species. Models of cognitive aging include aged mice and alcohol-intoxicated young mice; in both of these models, memory is impaired. A new study¹ reports that the flavonoid quercetin administered chronically at doses of 10, 25, and 50 mg/kg for 30 days or coadministered with alcohol (15% w/v, 2 g/kg per day orally) for 24 days significantly reversed the age-related or chronic ethanol-induced retention deficits in two paradigms (one-trail step-down passive avoidance and elevated-plus maze).

Chronic administration of quercetin for 30 days also reversed age-associated increases in TBARS (caused by lipid peroxidation) and decline in forebrain total glutathione (GSH), superoxide dismutase (SOD), and catalase levels. Chronic alcohol administration in the young mice caused increased TBARS and reduction in forebrain GSH, SOD, and catalase, significantly reversed by coadministration of quercetin (10, 25, and 50 mg/kg). The authors propose that these effects are due to the antioxidant properties of quercetin.

Quercetin also has many effects on signaling pathways, though we do not know which ones might have been involved in these cognition-enhancing effects. For example, quercetin glucuronide (a metabolite of quercetin) prevented hypertrophy of vascular smooth muscle cells (part of the atherosclerotic process) caused by angiotensin II by inhibiting c-Jun N-terminal kinase (JNK) and AP-1 (activator protein-1).² Quercetin also protected human lung cells from cooking-oil fumes by inhibiting cyclooxygenase-2 (COX-2) expression by altering the NF-kappaB pathway.³ Good dietary sources of quercetin include onions, green tea, and bilberry; there are many others. It is also available in the form of supplements.

1. Singh et al. Reversal of aging and chronic ethanol-induced cognitive dysfunction by quercetin, a bioflavonoid. Free Rad Res 37(11):1245-52 (2003).
2. Yoshizumi et al. Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II via the inhibition of JNK and AP-1 signaling pathways. Biochem Biophys Res Comm 293:1458-65 (2002).
3. Lin et al. Protection by quercetin against cooking oil fumes-induced DNA damage in human lung adenocarcinoma CL-3 cells: role of COX-2. Nutr Cancer44(1):95-101 (2002).

Thiol Antioxidants Reduce Bone Loss in Estrogen-Deficient Female Mice

There may be a number of mechanisms explaining the protective effect of estrogens on increasing or maintaining bone mass in female mammals. The hormones have direct effects on osteoclasts (bone cells that dismantle bone under the control of signals from osteoblasts, the bone-building cells). Also, inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, have been implicated in bone loss; the effects of these cytokines on bone are opposed by estrogens.

Estrogens act as powerful antioxidants. Since bone loss is stimulated by increased oxidative stress (by, for example, stimulating the secretion of TNF-alpha and other cytokines), this is a very plausible mechanism for estrogenic bone protection. The authors of a new paper¹ investigated the effects of estrogen on antioxidant defenses in bone. They report finding substantial decreases in glutathione and thioredoxin, and in the enzymes that regenerate the reduced forms of these protective thiol antioxidants in ovariectomized rodent bone marrow, that were reversed by estrogen administration. They also found that administration of the thiol antioxidant and glutathione precursor N-acetylcysteine suppressed TNF-alpha expression in osteoclasts, thus reducing bone loss. The N-acetylcysteine was administered to the mice at 100 mg/kg•day intraperitoneally twice per day for 14 days.

The authors note that, "Although [the experiments] suggest that 17-beta-estradiol maintains bone quantity through induction of thiol antioxidants, [the experiments] do not distinguish between central and local mechanisms for this effect on bone, nor, if the action is local, do they identify the target cell in bone. We therefore tested the effects of 17-beta-estradiol on the thiol antioxidant system in osteoblastic and osteoclastic cells. We found that neither glutathione reductase nor total glutathione were [sic] influenced by incubation in 17-beta-estradiol [in osteoblasts]. . . . In contrast, 17-beta-estradiol strongly stimulated glutathione and thioredoxin reductases in osteoclast-like cells in vitro. . . . This was completely reversed by ICI 182,780 [an estrogen inhibitor]. . . . The 17-beta-estradiol also strongly stimulated glutathione levels in osteoclasts. . . ."

The authors reasoned that, if estrogen regulates osteoclasts through thiol antioxidants, they would expect 17-beta-estradiol and thiol-modulating agents to influence reactive oxygen species (ROS)-sensitive signals in osteoclastic cells. They note that the best-studied signaling target for ROS is NF-kappaB, activated by ROS, which controls apoptosis, among other things. They found that BSO (which depletes glutathione) augmented, while N-acetylcysteine suppressed, the level of activated NF-kappaB. Since TNF-alpha is a target cytokine for NF-kappaB, they tested the effects of the antioxidants and estrogen on TNF-alpha and found that both 17-beta-estradiol and N-acetylcysteinesuppressed expression of the mRNA for TNF-alpha in osteoclasts.

These experiments suggest that thiol antioxidants, such as N-acetylcysteine, may be able to prevent bone loss by modulating, at least in part, signaling pathways used by estrogen to prevent bone loss. It is not clear from this paper what the appropriate dose for women would be. We therefore recommend the use of the dietary amino acid cysteine (N-acetylcysteine is rapidly broken down into cysteine in the GI tract) at amounts that could be found in a reasonably egg-rich diet (about 250 mg of cysteine is found in one egg).

1. Lean et al. A crucial role for thiol antioxidants in estrogen-deficiency bone mass. J Clin Invest 112:915-23 (2003).