The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 17 No. 9 • October 2014


EPIGENETIC MECHANISMS IN CARDIOVASCULAR DISEASE — EXPLOSION OF NEW DATA

Boom! Bang! Blam! Epigenetic Mechanisms Being Uncovered in Many Diseases Explosion of New Data Reveals Important

New Ways to Improve Health and Probably Live Longer

Hot Off the Press — Greater Protection Against Cardiovascular Disease

Blam!! When an idea catches hold in science, you may see something akin to an explosion of important connections to that idea (as if, all of a sudden, “everything” is explained by the new idea) that bring together a huge amount of data, making it more understandable and more useful for doing the heavy lifting of living longer and better.

That is what is happening now in the field of epigenetics, the scientific area that explains how genetic expression can be controlled by regulatory mechanisms (for example methylation of DNA) that change how DNA is transcribed rather than changing the actual DNA code. These epigenetic mechanisms are being connected to a large variety of age-associated diseases and, indeed, to aging itself. It is important to note that, while aging is associated with increased DNA methylation overall (reducing genetic expression), there are areas where there is decreased DNA methylation (which increases genetic expression). Hence, once again this is a balancing act that gets out of kilter with the progression of aging.

Aspirin Reduces Methylation of ABCA1, Gene
Important for Regulating Intracellular Cholesterol

Let’s look at a paper just published this year on epigenetics and disease. In this paper1 researchers have identified DNA demethylation brought about by aspirin (acetylsalicylic acid) that corrects excessive methylation at the ABCA1 gene promoter locus (responsible for regulating intracellular cholesterol content by inducing its efflux). The scientists who published this paper1 published a previous one2 in which they showed that higher DNA methylation at the ABCA1 gene promoter locus was associated with lower levels of cardioprotective HDL-C and a previous history of coronary artery disease in those with familial hypercholesterolemia. Other papers (cited in reference #1) have reported lower expression of ABCA1 with higher DNA methylation levels. Another paper cited in reference #1 was of a Netherlands paper that found aging and prenatal famine exposure are associated with hypermethylation at the ABCA1 gene promoter locus. The researchers1 note the proposal by another group3 that “aspirin use might reduce the methylation rate associated with aging, especially at cancer-related genes.” Hypermethylation at certain DNA locations causes the silencing (suppression of genetic expression) of cancer protective genes, thereby increasing the risk of cancer.

The study1 relating methylation at the ABCA1 gene promoter locus and coronary artery disease susceptibility and the effect of aspirin on DNA methylation at that DNA locus provides evidence for a mechanism that explains at least part of the protective effect of low-dose aspirin against the development of cardiovascular disease. The researchers found that aspirin therapy was associated with a 3.6% lower ABCA1 methylation level, independent of aging or coronary artery disease status.

Another recent paper4 found that ABCA1 in arterial macrophages not only promotes cholesterol removal to apo-lipoprotein A-1, the major protein in HDL, but is also “a direct molecular link between the cardioprotective effects of cholesterol export from arterial macrophages and [via the activation of JAK2/STAT3] suppressed inflammation.”3B This raises the possibility, the authors suggest, that “ABCA1 has a direct anti-inflammatory function in addition to its lipid export activity.” They note further that loss-of-function mutations in ABCA1 results in the acceleration of atherosclerosis.

Natural Demethylating Agents That Affect Epigenetic Processes

As we have written before, natural demthylating agents include EGCG (found at particularly high levels in green tea)5 and curcumin (a component of turmeric root),6 as well as others. Used at safe physiological doses (as would be found in a diet of those drinking green tea and/or eating foods (such as Indian curry dishes) enriched in turmeric spice), these may provide protection against increasing DNA methylation as occurs in aging and some age-associated diseases. The demethylating drug 5-aza-2’-deoxycytidine is currently used in the treatment of myelodysplastic syndromes and related demethylating drugs are in Phase II and III cancer trials. DNA hypermethylation can silence cancer suppressor genes; by restoring their expression, these genes can help combat the cancer.7

IMPORTANT NOTICE: The FDA has now declared the scientific word “anti-inflammatory” to be prohibited if used within sight of a dietary supplement (e.g., on a label or in an advertisement). The word may be used in commercial speech without risk of FDA thuggery (agency legal action against you) only in association with FDA-approved drugs. So much for the many U.S. Supreme Court decisions declaring it unconstitutional for the government to discriminate between different speakers in the communication of the same truthful speech. If it is protected speech for a scientific journal to report on the anti-inflammatory effects of a certain natural product, then it is unconstitutional for the government to prohibit certain other speakers from communicating that same information.

References

  1. Guay, Legare, Houde, et al. Acetylsalicylic acid, aging, and coronary artery disease are associated with ABCA1 DNA methylation in men. Clin Epigenetics. 6:14 (2014).
  2. Guay et al. ABCA1 gene promoter DNA methylation is associated with HDL particle profile and coronary artery disease in familial hypercholesterolemia. Epigenetics. 7:464-72 (2012).
  3. Noreen et al. Modulation of age- and cancer-associated DNA methylation change in the healthy colon by aspirin and lifestyle. J Natl Cancer Inst. 106(7). pii: dju161. doi: 10.1093/jnci/dju161. Print 2014 Jul.
  4. Tang, Liu, Kessler, et al. The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J Biol Chem. 284(47):32336-43 (2009).
  5. Fang, Wang, Ai, et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563-70 (2003).
  6. Liu, Xie, Jones, et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
  7. Du, Xie, Wu, et al. Reactivation of RASSF1A in breast cancer cells by curcumin. Nutr Canc. 64(8):1228-1235 (2012).

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