July 2006 Blog with Durk and Sandy

SPECIAL VITAMIN D ISSUE

No matter if the science is all phony, there are collateral environmental benefits … climate change [provides] the greatest chance to bring about justice and equality in the world.—Christine Stewart, Canadian Environmental MinisterCurrently, there is a federal Whistleblower Protection Act that was enacted into law a number of years ago, that was intended to give whistleblower protection to federal workers. Unfortunately, the First Amendment free speech rights intended by that law have been interpreted away by the administrative courts … [Emphasis added]—From an interview with Dr. David J. Graham, 

Associate Director of the FDA's Office of Drug Safety 
(and whistleblower), published in Fraud, Sept./Oct. 2005Chocolate lovers, rejoice! Mars Inc. is launching a new line of chocolate products called CocoaVia that contain a dark chocolate high in flavanols and with added soy plant sterols. (We'll try it when it comes in sugar-free versions.)—Elko Daily Free Press, Feb. 23, 2006We'd rather do business with 10,000 Arab terrorists than with 1 Jew.—Sign over Goldberg's Funeral Parlor in Baltimore

Modulation of Glucocorticoid Action by Vitamin D on Aging Hippocampal Cells

Glucocorticoids, such as the stress hormone cortisol, can cause deterioration of cells in the hippocampus and decline in cognition with aging in otherwise healthy people.^1,2Hence, one of the things we have long been interested in is modulation of glucocorticoid actions to ameliorate or prevent these deleterious effects. A new paper shows that vitamin D reduced the neurite outgrowth-inhibiting and hippocampal cell apoptosis-inducing effects of dexamethasone (a synthetic corticosteroid) in cell culture.³

Vitamin D-synthesizing machinery has been found in kidney, hypothalamus, cerebellum, substantia nigra (degeneration in this brain area causes Parkinsons disease), retinal neurons, and, of course, skin.³ The vitamin D receptor (VDR) has also been identified in both neuronal and glial cells of the limbic system, as well as the choroid plexus and other brain regions. The authors mention that a recent study showed that oral intake of 4000 IU per day of vitamin D greatly improved the sense of well-being and eased depression in a large group of patients, supporting previous studies which suggested that raising vitamin D blood levels may be useful as an alternative and/or supplementation in treating various affective disorders. Moreover, Vitamin D was demonstrated to be a modulator of key molecular events in the brain related to growth factor signaling, cellular proliferation, and differentiation. (Citations given in the quotes are deleted here.)

The authors used the progenitor cell line HIB5, derived from embryonic rat hippocampus (day 16). The cells were treated with either the glucocorticoid dexamethasone (Dex) or vitamin D or a combination of the two, followed by the addition of the differentiation inducer PDGF (platelet-derived growth factor). "The majority of cells in the control cultures extended neurites of various lengths; the same was observed in cells pretreated with vitamin D alone, whereas treatment with Dex inhibited morphological changes of HIB5 cells and allowed further proliferation. … In contrast, administration of 100-nM vitamin D in addition to Dex prevented, to a significant degree, the inhibitory effects of Dex [on neurite outgrowth] …"

Vitamin D Opposed Inhibition of Glucocorticoids

The authors summarize that, while vitamin D alone produced only a marginal and statistically insignificant increase in neurite outgrowth compared to controls, "when differentiating HIB5 cells were supplemented with vitamin D in addition to Dex, the number of cells that sprouted neurites twice as long as the diameter of their cell body increased 2.5-fold compared with Dex alone (13.5 plus or minus 2.04% vs. 5.38 plus or minus 0.72% in the Dex group), further indicating that application of vitamin D does not on its own significantly impact on neurite outgrowth, but can act against the inhibition of glucocorticoids in the HIB5 model of hippocampal cell differentiation."

Vitamin D Reduced Dex-Induced Cell Death

In another experiment, the researchers pretreated the hippocampal cells (as above) with vitamin D (10^-8 and 10^-9 M, concentrations they report are close to physiological levels) for 24 hours before adding Dex. Vitamin D alone had a small and insignificant effect on cellular viability, but in the hippocampal cultures also exposed to Dex following vitamin D treatment, apoptosis was markedly reduced compared to cultures exposed to Dex and receiving no vitamin D.

Since neurite outgrowth is a major mechanism whereby mature neurons increase their connectedness in enlarging networks importantly related to cognitive abilities, these studies suggest that vitamin D may protect brain cells, at least in part, from the deleterious age- and stress-related effects of glucocorticoids.

Perhaps the emotionally uplifting effects of a good vacation are due, at least in part, to the reduction in stress-induced release of hippocampus-damaging amounts of cortisol and the likelihood of greater solar exposure, with its increased daily production of several thousand IU of protective vitamin D. Tanning-bed use may produce a feeling of well-being for the same reason. Vitamin D supplementation is much safer than UVB exposure!

Vitamin D Dose

We note that the dose of vitamin D currently recommended by the bureaucrats at the Food and Nutrition Board (400 IU/day) is thought by ourselves and many others to be far too low. According to one recent study,⁴ "Healthy men seem to use 3000-5000 IU cholecalciferol/d, apparently meeting >80% of their winter cholecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. Current recommended vitamin D inputs are inadequate to maintain serum 25-hydroxycholecalciferol concentration in the absence of substantial cutaneous production of vitamin D."

The authors also note that "Evidence available to the FNB [Food and Nutrition Board] with regard to vitamin D toxicity at inputs of the magnitude employed in this study was scant in the extreme. Nevertheless, on the basis of sporadic reports (of uncertain quality) of hypercalcemia and hypercalciuria, the panel settled on a conservative tolerable upper level of 2000 IU/d for vitamin D, recognizing that many persons, especially those who work outdoors in the summer, almost certainly had higher inputs without apparent adverse effect. … As already noted, the data presented here indicate an average daily need perhaps twice that amount. Note that, in our study, 20 wk of supplementation at 5500 and 11,000 IU/d, starting from a status of relative vitamin D repletion, produced no elevation of serum calcium above the upper limits of normal in any subject." (This may not be true for everybody; this was a small study of 67 healthy men; hence, the effects of large doses of vitamin D on serum calcium levels in those with diseases, such as those that affect vitamin D metabolism, cannot be predicted from these data.)

Sandy takes 4000 IU vitamin D per day, while Durk (who is much bigger) takes 9600 IU vitamin D per day. (We provide this information not as a general recommendation but simply to indicate how we are using vitamin D in our own regimen.) Do not take a vitamin D supplement if you have parathyroid disease (not the same as thyroid disease), tuberculosis (because of possible immune system overreaction), sarcoidosis, lymphoma, excessive blood calcium levels, or are pregnant, without the advice of a physician.

References

1. Behl. Effects of glucocorticoids on oxidative stress-induced hippocampal cell death: implications for the pathogenesis of Alzheimer's disease. Exp Gerontol 33(7/8):689-96 (1998).
2. Sapolsky. Glucocorticoids, stress, and their adverse neurological effects: relevance to aging. Exp Gerontol 34:721-32 (1999).
3. Obradovic et al. Cross-talk of vitamin D and glucocorticoids in hippocampal cells. J Neurochem 96:500-9 (2006).
4. Heaney et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204-10 (2003).

 

Potential Antiaging Effects of Vitamin D3 Protection Against Neurotoxic Agents

A paper we recently obtained reports that vitamin D3 attenuates damage induced by 6-hydroxydopamine, a powerful free radical-generating oxidant, both in cell culture of rat midbrain neurons and in rats whose brains were lesioned with 6-hydroxydopamine.¹

The paper reports that vitamin D3 has been shown to be a “potent inducer” of endogenous GDNF (glial-derived neurotrophic factor), which is neuroprotective against the toxicity of 6-hydroxydopamine and MPTP in animal models of Parkinson’s disease. GDNF is upregulated in response to neuronal injury and in cortex after ischemia, as well as in response to the cytotoxic effects of kainate in rats and has also been found to reduce the extent of infarction in cerebral cortex of rats. The authors note that, in addition to inducing GDNF, vitamin D3 also increases nerve growth factor and transforming growth factor beta2 expression in neuroblastoma cells and neurotrophin3/neurotrophin4 mRNA levels in astrocytes. Moreover, the authors note, vitamin D3 (in contrast to GDNF) can pass through the blood-brain barrier, making it possible to take vitamin D3 orally to reach brain tissues.

The researchers found that vitamin D3-pretreated 6-hydroxydopamine-lesioned rats had significantly higher peak locomotor activity as compared to lesioned animals that had received saline pretreatment. Peak mean rest time was significantly lower in D3-pretreated animals. “These results suggest that D3 treatment attenuates the hypokinesia produced by 6-hydroxydopamine lesions.” Vitamin D3 pretreatment also normalized nigral dopamine and dopamine metabolites in the lesioned animals in vivo. The authors conclude, “… since D3 can pass through the blood-brain barrier and elevate GDNF levels, this vitamin may be potentially useful in treatment of Parkinson’s disease and other neurodegenerative disorders.” As dopaminergic neurons are damaged and destroyed in the process of ordinary aging, even in the absence of overt Parkinson’s disease, this paper supports the use of vitamin D3 as a possible antiaging treatment for the brain.

Reference

1. Wang et al. Vitamin D3 attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res 904:67-75 (2001).

 

Glucocorticoids Induce Muscle Wasting: Could Vitamin D Provide Protection?

Part of the process of sarcopenia (loss of muscle mass with aging) may involve the action of glucocorticoids, which not only enhance muscle protein degradation but also reduce protein synthesis.¹ A study of young (4–5 weeks), adult (10–11 months), and old (21–22 months) rats receiving the synthetic glucocorticoid dexamethasone (Dex) in their drinking water showed that Dex did not alter muscle-protein synthesis stimulation by leucine in young rats, but muscles from adult and old rats became totally resistant to the anabolic effects of leucine.¹ Moreover, the recovery of leucine responsiveness after Dex treatment discontinuation in the old rats was slower than that in younger rats. One of the mechanisms by which glucocorticoids affect muscle protein synthesis is by inducing insulin resistance, the inhibition of muscle response to insulin, an anabolic hormone.

The published data support an association between vitamin D deficiency and reduced insulin sensitivity and pancreatic beta-cell dysfunction (an impairment in insulin secretion).² One paper² studied the relationship between blood levels of vitamin D on plasma glucose concentration and insulin sensitivity in 126 healthy glucose-tolerant (fasting glucose levels below 110 mg/dL) human subjects. The authors found that there was a significant positive correlation of vitamin D concentration with insulin sensitivity and a negative effect of vitamin D deficiency on pancreatic beta-cell function. An oral glucose tolerance test showed that there was “a significant and negative interaction of 25(OH)D [vitamin D metabolite] concentration with 60-, 90-, and 120-minute post-challenge [i.e., following a standard glucose bolus] plasma glucose concentrations.” Subjects with vitamin D deficiency were at increased risk of the metabolic syndrome (as determined by analysis of risk factors) as compared to those with normal vitamin D levels. Here, the authors report that “… serum 25-hydroxyvitamin D explained only 6% of the variation in insulin sensitivity in our study.”³

The researchers also cite studies in which vitamin D supplementation improved insulin secretion in vitamin D-deficient and nondiabetic subjects, as well as in patients with type 2 diabetes. Hence, we suggest that adequate vitamin D levels may help to attenuate the negative effects of glucocorticoids on insulin sensitivity.

While we have no specific information linking vitamin D to muscle-protein synthesis in response to glucocorticoids or leucine stimulation, it is interesting to note that higher vitamin D levels in a population of 4100 ambulatory U.S. adults greater than or equal to 60 were associated with better lower-extremity function.⁴ Vitamin D receptors have been identified in muscle. Cross-sectional studies have shown that elderly persons with higher vitamin D serum levels have increased muscle strength and fewer falls.⁵ A single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49% compared with calcium alone⁵ in a study of 122 elderly women (mean age 85.3 years). The 62 individuals on the vitamin D plus calcium regimen received 1200 mg calcium plus 800 IU cholecalciferol (vitamin D), while the 60 subjects not receiving vitamin D received 1200 mg calcium; treatment lasted 12 weeks.

References

1. Rieu et al. Glucocorticoid excess induces a prolonged leucine resistance on muscle protein synthesis in old rats. Exp Gerontol 39:1315-21 (2004).
2. Chiu et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 79:820-5 (2004).
3. Chiu. Reply to M Manco et al. and to MF McCarty [their letters to the editor commenting on the paper cited in Ref 2 above]. Am J Clin Nutr 80(5):1452-3 (2004).
4. Bischoff-Ferrari et al. Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged greater than or equal to 60 y. Am J Clin Nutr 80:752-8 (2004).
5. Bischoff et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Min Res 18(2):343-51 (2003).

 

Vitamin D Dosage and Cancer Chemoprevention

A new paper¹ in the Journal of the National Cancer Institute performs an analysis of cancer risk in the Health Professionals Follow-Up Study of 51,529 male subjects and multiple sources of vitamin D (including sun exposure, dietary and supplemental vitamin D, skin pigmentation, adiposity (“Higher body mass index or obesity has usually been associated with substantially lower blood concentrations of 25(OH)D, probably as a result of decreased bioavailability of 25(OH)D because of its deposition in body fat compartments”¹), geographic residence (lower sun exposure in northern latitudes), and leisure-time physical activity. The researchers updated nondietary vitamin D exposures every 2 years and dietary information every 4 years from 1986 to 2000.

They found that the absolute annual rate of total cancer was 758 per 100,000 men in the lowest decile (lowest 10%) of predicted vitamin D (estimated from analysis of the above factors) and 674 per 100,000 men in the highest decile. Cancer mortality was 326 per 100,000 in the lowest decile compared to 277 per 100,000 in the highest decile. Digestive-system cancer mortality was reduced from 128 to 78 per 100,000 in the lowest compared to the highest decile. An increment of 25 nmol/L of vitamin D was associated with a 17% reduction in total cancer incidence and a 29% reduction in total cancer mortality, as well as a 45% reduction in digestive-system cancer mortality.

The authors conclude that “Low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive-system cancers. The vitamin D supplementation necessary to achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day.” [Emphasis added]

In the editorial accompanying the above paper,² the authors state that “… the present recommended allowance for vitamin D—400 IU—for individuals aged 50–70 years is inadequate even to maintain skeletal health and is probably too low for meaningful anticancer effects. A dose of 400 IU of vitamin D3 will raise serum levels of 25(OH)D3only modestly, by about 7 nmol/L or less than 3 ng/mL. The use of this low dose, in conjunction with the relatively short duration of the trial, may explain the recent failure of vitamin D to reduce the incidence of colorectal cancer in the Women’s Health Initiative.”

References

1. Giovannucci et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 98(7):451-9 (2006).
2. Schwartz and Blot. Vitamin D status and cancer incidence and mortality: something new under the sun. J Natl Cancer Inst 98(7):428-9 (2006).

 

Vitamin D Supplementation as a Possible Treatment for Heart Failure

“Despite evidence-based advances in the treatment of CHF [congestive heart failure] over the past 15 years, large observational studies have shown no substantial changes in the prognosis of patients with heart failure. Survival rates 5 years after a first diagnosis of CHF are still only 35–40%.¹ [Citations deleted from quote]

For this reason, the findings in a new study¹ of the effects of vitamin D supplementation on patients with congestive heart failure are very encouraging. The researchers first note that patients with CHF have considerably lower concentrations of the vitamin D metabolite 25-hydroxyvitamin D [25(OH)D] and calcitriol than do age-matched healthy controls, and a significant percentage of CHF patients have biochemical signs of hyperparathyroidism. The parathyroid hormone is regulated by vitamin D. Too much parathyroid hormone results in resorption (loss) of bone in order to get calcium. (Resorption of bone is one reason that deficiency in vitamin D is associated with periodontal disease.)

Sixty-one subjects were given 2000 IU of vitamin D plus 500 mg of calcium each day for 9 months, while the “placebo” group (62 subjects) received just the 500 mg of calcium daily for the same period. Ninety-three patients completed the study. The results showed that, compared with baseline levels, parathyroid hormone was significantly lower and the important anti-inflammatory cytokine interleukin 10 was significantly higher in the vitamin D-supplemented group after 9 months. Moreover, the proinflammatory cytokine TNF-alpha (tumor necrosis factor-alpha) increased in the group not receiving vitamin D, while TNF-alpha levels remained constant in the vitamin D-supplemented group. However, the survival rate did not differ significantly between the study groups (vitamin D + calcium or calcium alone) during the 15-month follow-up period.

The editorial accompanying this paper² added some interesting points. The authors note that there were two clinical trials in CHF patients assessing the effect of vitamin D supplementation prior to the current study. “The study by Witte and Clark used vitamin D at 10 :g/d (400 IU/day), and this dose did not affect cytokine concentrations. Another study by Mahon et al. produced modest responses [presumably effects on cytokines] with 25 :g vitamin D/d (1000 IU/d).” Hence, as the editorial discusses, this new paper indicates that higher doses of vitamin D were needed than used in the earlier studies to achieve desired effects on cytokines in CHF. We suggest that, as there is no reason to believe that 2000 IU/d is optimized for effects on inflammatory processes (and the cytokines that promote or attenuate them), it would be reasonable to try a dose of 4000 IU/d in CHF patients; perhaps that dose would even provide a survival advantage.

Once again, we find potential treatment effects for a dietary supplement. The FDA’s stranglehold over information on treatment effects for vitamins and other natural products, and the obvious benefits to drug companies of maintaining their monopoly on treatment claims for anything, must be broken! Please help by going to stopfdacensorship.org and signing the petition supporting the passage of the Health Freedom Act (H.R. 4282), currently cosponsored by 20 Congresscritters; your support will be automatically e-mailed to your Congresscritter.

References

1. Schleithoff et al. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 83:754-9 (2006).
2. Vieth and Kimball. Vitamin D in congestive heart failure. Am J Clin Nutr 83:731-2 (2006).

 

Effects of Acetic Acid (Vinegar) on Glycemic and Insulinemic Response to Food: Inhibitory Effects on Digestive and Other Enzymes

Acetic acid (as found in vinegar) is a very interesting food, as it has been reported in a number of studies to reduce glycemic and insulinemic responses to foods such as a starchy meal, possibly by delaying gastric emptying.¹ One study² reported finding that a vinegar supplement [20 g apple-cider vinegar, 40 g water, and 1 tsp saccharin (diluted) sweetener] significantly improved postprandial glucose and insulin sensitivity in insulin-resistant subjects as compared to those who received a placebo. As a constituent of many types of foods, such as pickled cucumbers, salad dressings, and soups, vinegar is easy to incorporate into a diet.

Moreover, as reported by another study,³ vinegar decreases the activities of a number of intestinal glucose transporters and disaccharidases (digestive enzymes that break down disaccharides into their two constituent sugars; sucrose, for example, is broken down into fructose and glucose by sucrase, a disaccharidase) in Caco-2 colon-cell culture. They report that earlier studies suggest that when food containing 10–150 mmol/L of acetic acid is eaten, the concentration may reach the millimolar level in the small intestine (where the acetic acid is absorbed). Cells were cultured for 15 days in a medium containing acetic acid in the range of 0 to 5 mmol/L.

Findings: Acetic acid inhibited sucrase activity in a dose-dependent manner. Even 1 mmol/L of acetic acid inhibited sucrase activity by 30%. Exposure to 5 mmol/L of acetic acid (about 1 tsp of vinegar per quart) for 15 days decreased sucrase activity by approximately 50% compared to the control culture, while other organic acids, including citric, succinic, L-maric, L-lactic, L-tartaric, and itaconic acids, did not. This means that it was not merely a pH effect. In addition, the 15 days of 5 mmol/L of acetic acid resulted in about a 40% decrease in maltase and almost a complete inhibition of trehalase and lactase (perhaps a problem for those with mild lactose intolerance). Moreover (and this is particularly interesting), the activity of angiotensin-converting enzyme (ACE) was reduced to 30% of the control. ACE inhibitors have been shown to have anti-inflammatory effects, and numerous studies have found results in animals and humans indicating that treatment with ACE inhibitors may reduce age-related declines in physical performance, possibly due to a reduction in body-fat mass.^4,5,6 ACE inhibitors also protect the kidneys from age-related functional decline.

References

1. Liljeberg et al. Delayed gastric emptying rate may explain improved glycaemia in healthy subjects to a starchy meal with added vinegar. Eur J Clin Nutr 52:368-71 (1998).
2. Johnston et al. Vinegar improves insulin sensitivity to a high-carbohydrate meal in subjects with insulin resistance or type 2 diabetes. Diabetes Care 27(1):281-2 (2004).
3. Ogawa et al. Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of Caco-2 cells. J Nutr 130:507-13 (2000).
4. Carter et al. Angiotensin-converting enzyme inhibition, body composition, and physical performance in aged rats. J Gerontol: Biol Sci 59A(5):416-23 (2004).
5. Onder et al. Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study. Lancet 359:926-30 (2002).
6. Carter, Onder, et al. Angiotensin-converting enzyme inhibition intervention in elderly persons: effects on body composition and physical performance. J Gerontol: Med Sci 60A(11):1437-46 (2005).

 

Not Just for the Heart! Changes Mediated by Inflammation in the Aging Brain Reversed by Treatment with EPA

Inflammation is now well recognized as a major factor in atherosclerosis, cancer, and aging. In the brain, interleukin-1beta (IL-1beta) increases with aging and is associated with deterioration in cell function.^1,2 In a recent study,¹ four markers of apoptotic cell death [cytochrome c translocation, caspase-3 activation, poly-(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end staining] were found to be increased in the aged rat brain cortex as well as the hippocampus, in association with increased IL-1beta concentration and p38 activation. Moreover, these changes were accompanied by age-related deficits in long-term potentiation, a process vital to learning. The 4- and 22-month-old rats were divided into two groups: those that received a diet enriched in eicosapentaenoic acid (EPA), 10 mg/rat·day for 3 weeks and 20 mg/rat·day for 5 weeks, and those that received standard lab chow for 8 weeks.

While the IL-1beta and p38 activity were both significantly increased in cortical tissue from aged rats fed the control diet as compared to young rats on either diet, EPA supplementation prevented these age-related increases in IL-1beta concentration and p38 activity. The LTP values for the EPA-supplemented aged rats were similar to those for the young rats on either diet, whereas the aged rats on the control diet were LTP-impaired.

If you want to teach an old dog new tricks, give him EPA supplements.

References

1. Martin et al. Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J Biol Chem 277(37):34239-46 (2002).
2. Dinarello. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83(Suppl):447S-55S (2006).

 

A Low-Enough LDL May Reduce Cardiovascular Risk to Nearly Nonexistent

A number of studies suggest that excess LDL plays a major role in the endothelial dysfunction found in patients with coronary artery disease (CAD). For example, one recent study,¹ looking at 188 patients (135 males, 53 females) found that, in comparison with 51 healthy controls (22 males, 29 females), the relaxation in response to calcium ionophore of saphenous veins (removed during varicose vein surgery) was decreased. Total superoxide production was increased, and LDL-cholesterol was “a major determinant of endothelial dysfunction and oxidative stress in these patients.”

Other papers have reported that normal humans with genetic polymorphisms that result in unusually low LDL levels (below 70) rarely have cardiovascular disease. One paper²reports that “the plasma concentration of LDL-cholesterol must exceed 2 mmol/L (80 mg/dL) for atherogenesis, even at sites of high shear stress [such as bifurcation points in arteries].” For avoiding cardiovascular disease, therefore, it would appear to be useful to reduce LDL to 80 or below. For those who do not have the advantageous low-LDL-producing genes, you will need to try a combination of diet modification, exercise, and supplements (such as moderate alcohol consumption, niacin, antioxidant vitamins, fish oils, and policosanol with CoQ10, to name just a few). For those who have high risk or already have cardiovascular disease, you may wish to try a statin to achieve this very low LDL level; be sure also to take a supplement of CoQ10 of at least 30 mg three to four times a day.³ But keep in mind that not all statins, though they all reduce cholesterol and LDL-cholesterol, have actually been shown to reduce all-cause or cardiovascular deaths.⁴ For example, in the IDEAL study (results published in the Nov. 16, 2005 JAMA), 80 mg/d of atorvastatin, compared with 20–40 mg/d of simvastatin, resulted in a 23-mg/dL lower LDL-C (by the 80-mg atorvastatin) with an 11% trend (not statistically significant) in reduction in coronary heart disease death, myocardial infarction, or cardiac arrest.

References

1. Al-Benna et al. Low-density lipoprotein cholesterol determines oxidative stress and endothelial dysfunction in saphenous veins from patients with coronary artery disease. Arterioscler Thromb Vasc Biol 26:218-23 (2006).
2. Williams and Tabas. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 15:551-61 (1995).
3. Lamperti et al. Muscle coenzyme Q10 level in statin-related myopathy. Arch Neurol 62:1709-12 (2005).
4. Cannon. The IDEAL cholesterol. JAMA 294:2492-4 (2005).

 

When Pigs Have Fins: The New Health Snacks—Pork Skins and Bacon?

Pigs may never have fins, but there is already a new genetically modified pig strain that has been given a gene for a fatty acid desaturase that allows the pigs to make large amounts of n-3 fatty acids from n-6 fatty acids.¹ They don’t look like fish and they don’t taste like fish, but you can get the same healthy EPA and DHA from eating them. As the new paper notes, one of the main reasons that livestock have such high levels of n-6 fatty acids in their tissues is because of the large amounts of grain they are fed to fatten them up. [Pasture-fed cattle, such as our own, have far less of these fats and get more of the n-3 alpha-linolenic acid from the fresh grasses they eat, resulting in a more desirable n-3/n-6 fatty acid ratio; however, because they do not have the fatty acid desaturase gene, no cattle (yet) can make the long-chain n-3 EPA and DHA. Actually, fish themselves do not have such a desaturase; they get their EPA and DHA entirely from their diet.]

The new and improved piglets have an n-6/n-3 ratio of 1.69 ± 0.30, as compared to the wild-type (without the added gene) piglets with an 8.52 ± 0.62 ratio. The transgenic animals’ production of EPA was increased by over 15 times, while DHA was increased by slightly less than twofold. Total n-3 fatty acids were increased to 8.59 ± 0.84%, as compared to 2.18 ± 0.25% in the wild-type piglets. Meanwhile, total body content of n-6 fatty acids was decreased in the transgenic piglets as compared to the wild-type, from 18.46 ± 1.41% to 14.28 ± 1.31%.

Normally, pork contains about 40% oleic acid, about 15% n-6 fatty acids, and only about 1% n-3 fatty acids.¹ Some pig producers have increased n-3 fatty acids in their animals by feeding them an n-3 enriched diet, such as flaxseed (a good source of alpha-linolenic acid), fish oil, or fish meal. However, too much of the alpha-linolenic acid alone in pork results in a change in its sensory qualities, while EPA and DHA did not have these effects. Moreover, in the long run, having animals that can make their own n-3 fatty acids from n-6 fatty acids will be much more economical than having to feed them expensive fish oils or fish meal.

It will be interesting to see how long the FDA procrastinates on whether to allow humans to eat genetically engineered n-3-enriched pigs. Will they “protect” us from them by allowing only the much less healthful high-n-6 fatty acid, low-n-3 fatty acid pigs now in the marketplace? We love the taste of bacon but don’t like all the unhealthful fat it contains. It will be much more attractive as a food with a relatively high content of n-3 fatty acids. Now all they have to do is get rid of the excess saturated fats …

Reference

1. Liangxue Lai et al. Generation of cloned transgenic pigs rich in omega-3 fatty acids. Nature Biotech 24(4):435-6 (2006).

 

Pomegranate Juice Improves Myocardial Perfusion in Patients with Coronary Heart Disease

We have written several articles in recent newsletters on the newly discovered health benefits of pomegranate juice, which include (as discussed in our last issue) reducing macrophage cholesterol synthesis by 50% in cell culture and inhibiting the angiotensin-converting enzyme (ACE) activity by 36% and systolic blood pressure by 5% in ten hypertensive patients drinking about 2 oz of pure pomegranate juice per day for 2 weeks. [2 oz of 100% pomegranate juice corresponds to 8 oz/day of the commercially available “Diet” Langers, with 25% juice and reduced sugar (8 g per 8 oz).]

A recent study¹ reports on the results of pomegranate juice consumption by 45 patients with coronary artery disease, half of whom (after randomization) got a placebo drink while the other half drank 240 ml (a little less than 10 ounces) of undiluted pomegranate juice for 3 months. The patients were subject to exercise treadmill testing (for those unable to perform this test, a pharmacologic stress test using adenosine or dipyridamole was performed) to evaluate the induction of myocardial ischemia.

The researchers report that “At baseline, the 2 groups showed similar levels of inducible ischemia (SDS). After 3 months, the extent of stress-induced ischemia decreased in the experimental group but increased in the control group. This benefit was observed without changes in cardiac medications or revascularization in either group. … Angina episodes decreased by 50% in the experimental group (from 0.26 to 0.13) but increased by 38% in the control group (from 0.53 to 0.75), although this difference was not statistically significant.” This was a very small trial (26 subjects drank pomegranate juice while 19 subjects received the placebo drink), so it did not have enough statistical power to be able to determine whether there was a real change in angina episodes as a result of treatment, or just a chance effect. Interestingly, the paper reports that “One patient in each group developed rhabdoid myalgia [muscle damage and pain] after being prescribed statin medications, and these were discontinued.”

The paper further reports that there was “an average improvement of 17% in myocardial perfusion in the experimental group and an average worsening of 18% in the control group (i.e., a 35% relative between-group difference) after only 3 months.” There were no negative effects on lipids, blood glucose, hemoglobin A1c (glycated hemoglobin), body weight, or blood pressure. As the authors note, “neither grape juice nor red wine has been shown to improve ischemia in humans who have CHD.” Of course, these effects will need to be verified in a larger trial.

This is not a cardiovascular preventive effect; it is a potential treatment effect, yet the FDA allows no communication to the general public of information concerning disease treatment (not even in health claims) with foods or dietary supplements (at least by those entities they regulate, which includes those that offer pomegranate juice products in interstate commerce). The FDA considers such information to be drug information, therefore illegal to communicate without spending hundreds of millions of dollars to receive FDA’s approval to sell pomegranate juice as a drug. We consider the FDA’s position to be a threat to the public health and a violation of the First Amendment (“Congress shall make no law … abridging the freedom of speech”) and therefore a usurpation of our constitutional freedoms, and unacceptable in a free society. To have to spend hundreds of millions of dollars to communicate truthful, nonmisleading information is to hold free speech hostage.

Reference

1. Sumner et al. Effects of pomegranate juice consumption on myocardial perfusion in patients with coronary heart disease. Am J Cardiol 96:810-14 (2005).

 

Broker-Importer Sues FDA for Blocking Ephedra Importation

This information comes from a press release from Emord & Associates. For more information on this case, contact Jonathan Emord (202-466-6937). Jonathan Emord is our constitutional attorney, who won the victory in Pearson v. Shalala and other cases in which we participated.

As many of you may know, it has not been possible to import ephedra herb for its use in our traditional Chinese ephedra herbal tea (made from ground whole ephedra herb) since the FDA started illegally blocking the herb’s import for that purpose. Although the FDA had banned ephedra herb and its extracts in the form of capsules and tablets as dietary supplements as being, in the FDA’s judgment, harmful to the public, the Chinese traditional ephedra herb tea (which was never associated with any reported adverse effects of ephedra use) was exempted from this ban. Moreover, the original ephedra ban was later struck down in a suit in which the plaintiff was represented by Emord & Associates, Neutraceutical v. Crawford. In that decision, the court held that the FDA lacked scientific evidence that 10 mg or less of ephedrine alkaloids per day cause any significant or unreasonable risk of injury. The court also held FDA’s final rule banning ephedra a violation of the DSHEA dietary supplement adulteration provision.

Jonathan Emord reports that “FDA has refused to abide by Judge Tena Campbell’s order in Nutraceutical v. Crawford. Although Her Honor held FDA’s rule invalid and specifically determined there to be no proper science to support the conclusion that 10 mg or less of ephedrine alkaloids cause harm, FDA has ignored the order, violating it all across the United States by enforcing the very rule held invalid. This is lawless conduct.” In the new suit against the FDA, EMAX Enterprises Ltd., a Hong Kong-based importer and broker of ephedra products, asks the court to compel the FDA to abide by the rule of law by following the court order.

The Nutraceutical case is currently on appeal before the United States Court of Appeals for the Tenth Circuit. EMAX has moved for a preliminary injunction barring FDA from blocking import of the ephedra shipment now detained by FDA and Customs in Salt Lake City.

This is typical of the FDA’s behavior. Having been unable to find evidence of harm with which to legally ban traditional Chinese ephedra herbal tea or ephedra-containing products with 10 mg/day or less of ephedrine alkaloids, it simply resorted to preventing its availability in the marketplace by illegally blocking ephedra herb imported for that and other legal purposes. It is also quite typical for the agency simply to ignore court orders. When we won Pearson v. Shalala against the FDA in 1999 after five years of litigation, the FDA simply ignored the court’s order that the FDA’s ban on communication of truthful information concerning four health statements (including the claim that “fish oils may reduce the risk of cardiovascular disease”) was unconstitutional and continued to prohibit these claims. (While all this was going on, about 300,000 Americans per year were dying of sudden-death heart attacks, at least half of which could have been prevented by consumption of fish-oil supplements or eating of fatty coldwater fish.) It took another two years of further litigation and a threat to sue the decision makers at FDA as individuals (because we were able to get a declaration by district court judge Gladys Kessler that the FDA was “willfully violating our constitutional rights”) to finally get the FDA to stop enforcing the ban on the four statements. This is the state of free speech in America under FDA’s stewardship; every time you want both to offer nutritional supplements and to make a truthful, nonmisleading statement to consumers concerning their effects on disease, you have to sue the SOBs.

We look forward to a clear and convincing victory for Emord & Associates and its clients Neutraceutical Corp. and EMAX Enterprises Ltd. in challenging the FDA’s illegal actions in the case of ephedra herb.

 

Moderate Alcohol Consumption Increases Neurogenesis in the Adult Mouse

A new paper reports the exciting news that in mice, moderate levels of voluntarily ingested ethanol (~6 g/kg·day) for ~10 weeks increased the proliferation of cells in the dentate gyrus of the brain, which survived and developed a neural phenotype.¹ (This is about the amount of alcohol contained in 1 to 2 drinks per day for an adult human when calculated on a food-intake basis.) Moreover, the ethanol consumption at this level did not increase apoptosis (programmed cell death) or change differentiation or distribution patterns of the new cells. (It has previously been shown that binge ethanol administration for 1 and 4 days or via food for 6 weeks results in a decrease of neurogenesis in adult rats.¹) After discontinuation of alcohol treatment in this study, it took 3 days for the proliferation rate to return to basal levels. Interestingly, the researchers report that in their study, female mice were investigated because they tend to consume more alcohol and that the mice were also kept one to a cage because group-housed animals do not consume much ethanol. Isolation is a social stress in both mice and humans. The authors suggest that “It is, thus, possible that ethanol had anxiolytic [anti-anxiety] effects in the present experiments, thereby counteracting a stress-induced depression of neurogenesis.”

Studies in alcoholics have found decreases in hippocampal size due to a reduction of white matter and numbers of astrocytes, though not in a reduction of neurons.¹Moderate alcohol consumption is thought to act as a mild stressor that results in upregulation of protective mechanisms, with consequent health benefits. For example, moderate alcohol consumption has been reported to increase cholesterol efflux in humans,² inhibit advanced glycation end-product formation by acetaldehyde in diabetic rats,³ reduce the risk of total and cardiovascular disease mortality in hypertensive men,⁴and increase HDL in men and women and reduce platelet aggregability in humans as well as animals.⁵

There is, in fact, a rather large scientific literature on substances (including ionizing radiation and ozone) that are toxic in large amounts but induce protective mechanisms for beneficial effects at low doses, a process called hormesis. Even caloric restriction is believed by some scientists⁶ to be a low-intensity stressor (hormetic agent) that induces various genetic and regulatory changes that result in life extension.

This study was partly funded by the National Institute on Drug Abuse. The agency must not have been very pleased with the results!

References

1. Aberg et al. Moderate ethanol consumption increases hippocampal cell proliferation and neurogenesis in the adult mouse. Int J Neuropsychopharmacol8:557-67 (2005).
2. Beulens et al. Moderate alcohol consumption increases cholesterol efflux mediated by ABCA1. J Lipid Res 45:1716-23 (2004).
3. Yousef Al-Abed et al. Inhibition of advanced glycation end product formation by acetaldehyde: role in the cardioprotective effect of ethanol. Proc Natl Acad Sci USA 96:2385-90 (1999).
4. Malinski et al. Alcohol consumption and cardiovascular disease mortality in hypertensive men. Arch Int Med 164:623-8 (2004).
5. Renaud and de Lorgeril. Wine, alcohol, platelets, and the French paradox for coronary artery disease. Lancet 339:1523-6 (1992).
6. Masoro. Caloric restriction and aging: controversial issues. J Gerontol: Biol Sci 61A(1):14-9 (2006).