Modulation of Glucocorticoid Action by Vitamin D on Aging Hippocampal Cells

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 9 No. 2 • April 2006


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 Minister

Currently, 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. 2005

Chocolate 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, 2006

We'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.1,2 Hence, 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).

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