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How the world got lost on
the road to an anti-aging pill
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March 31, 2009: by Bill Sardi
Currently, heart transplantation is the only reliable means of replacing lost muscle tissue following a heart attack but is limited by the number of donors and cost. Because heart muscle cells are not rapidly replaced following a heart attack, researchers have been investigating stem cell technology in hopes of replacing damaged cells. [Transplantation Review (Orlando). 2009 Jan; 23(1):53-68]
Donor cell transplants emerge as a promising strategy to regenerate diseased heart muscle cells (called cardiomyocytes). However, stem cell therapy has produced inconclusive and contradictory results. [Current Opinion Organ Transplantation 2009 Feb;14(1):79-84] There are many drawbacks and hurdles, including high cost, that need to be overcome before stem cell therapy for the heart can be offered in the clinic. [BioDrugs 2008; 22(6):361-74]
Now, for the first time, researchers have demonstrated that heart muscle cells (cardiomyocytes) are slowly replaced over time, about 1% per year, not fast enough to restore healthy function to the heart following a heart attack, but sufficient to demonstrate regenerative potential towards the introduction of molecular medicine.
Living cells in the human body exhibit different cell turnover (renewal) rates. For instance, brain cells do not replace themselves for more than a decade or otherwise memory would be erased. In contrast, cells that line the outer layer of the skin, called epithelial cells, which are subjected to greater physical challenges by solar radiation, heat, cold, etc., need to renew themselves more rapidly. New skin cells are produced daily and the entire skin layer is regenerated about every six weeks.
For decades biologists have believed that cardiomyocytes, heart muscle cells that humans are born with, are there for a lifetime. The number of heart muscle cells declines slowly after birth to the end of life. But now, surprisingly, researchers have found that about 1 percent of the heart muscle cells are replaced every year at age 25, and that the regeneration rate gradually falls to less than half a percent per year by age 75. About 45% of heart muscle cells are replaced over time.
This breakthrough is claimed to be one of the more important discoveries in cardiovascular medicine in years as it may lead to new understandings how to regenerate heart tissues following a heart attack.
In the following chart, the gray area depicts the fraction of cardiomyocytes (heart muscle cells) remaining from birth, and the white area is the contribution of new cells.
The limited recovery of pumping power of the heart after a heart attack is due to the inherently slow replacement of heart muscle cells, as described above. Molecular medicine needs to be applied to regenerate new muscle cells.
Researchers now say “it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.” In other words, instead of stem cell transplantation, cardiomyocyte regeneration! [Science 3 April 2009: 324; 98-101)
This is one example of practical science that got ahead of theoretical research. Towards the objective to regenerating cardiomyocytes, researchers in China experimented with one red wine molecule, resveratrol (rez-vair-ah-trawl), to measure its effects upon the rate of cardiomyocyte cell death, a process called apoptosis. (Apoptosis is a form of cell death in which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area.)
Embryonic cardiomyocytes from rodents were subjected to oxygen-starvation (called hypoxia or ischemia in biological terms) for 24 hours and a notable increase in the rate of apoptosis (cell death) occurred. Recall that a heart attack is when circulation in any of the four coronary arteries is interrupted by a blood clot, plaque eruption or artery narrowing, resulting in lack of blood flow and the provision of oxygen to tissues.
Then researchers add resveratrol to the lab dish and a “greatly decreased rate of apoptosis” was noted. Resveratrol prevents cell death in oxygen-starved conditions!
The comparable cell death (apoptosis) rate was 0.37 for cardiomyocytes under normal oxygen conditions, 11.60 for oxygen-deprived cells and 4.76 for resveratrol-treated cells! [Biochemical and Biophysical Research Communications 378 (2009) 389–393]
Here is how the effect of resveratrol on oxygen-starved heart muscle cells was graphically depicted:
In the past year researchers were also able to measure the effects of resveratrol in live animals subjected to ischemic (oxygen deprived) conditions. Intentional ischemia (oxygen deprivation) was induced for 30 minutes, mimicking a heart attack, followed by 3 hours of recirculation (reperfusion), which resulted in an area of dead tissue (infarct size) of about 40%, with about 25% die-off of the cardiomyocytes. Treatment of animals with the human equivalent of 175 mg of resveratrol (160-lb person) after an intentionally-induced heart attack results in significant reduction of cardiomyocyte cell death and the area size of scar tissue (fibrosis). [Free Radical Biology Medicine 2008 Jan 1; 44(1):82-90] Quercetin, another red wine molecule, has also been shown to protect cardiomyocytes. [Phytotherapy Research 2004 Jul; 18(7):516-21]
The dosage of resveratrol employed determines whether this red wine molecule preserves or rescues oxygen-deprived cardiomyocytes or if it actually induces cell death. Relatively low oral doses of the red wine molecule resveratrol (rez-vair-ah-trawl) send survival signals and protect heart tissues from damage should a heart attack occur, but supra-high doses completely reverse this survival effect and send a cellular death signal that worsens heart damage when a heart attack is intentionally induced in laboratory animals.
Supra-high dose resveratrol supplements (Biotivia, Rev Genetics, Redmedin) were first marketed in 2006 when a mouse study suggested high-dose resveratrol (~1565 milligrams) reverses some of the effects of a high-fat diet. However, this study employed a 60% fat-calorie diet which cannot be applied to humans who consume ~30% fat-calorie diet. [Nature. 2006 Nov 16; 444(7117):337-42] Later it was shown the lifespan of laboratory mice on this dose (1565 mg) was shortened when placed on a standard calorie diet. [Cell Metabolism 2008 Aug; 8(2):157-68]
In the recent University of Connecticut animal study, researchers found the human equivalent of 175 and 350 mg of resveratrol sends cell survival signals, while 1750 and 3500 milligrams for a 160-lb human sends death signals to cells. Supra-high dose resveratrol demonstrably increased the area of dead tissue in the heart after a 30-minute period where the heart was deprived of oxygen, but actually reduced the size of a heart attack in lower doses.
“Consumers were also errantly advised to wait for stronger pills that a pharmaceutical company was developing, a resveratrol-like pill that would activate a particular gene 1000-fold better than plain resveratrol. But subsequent animal studies showed more than 7.5 fold activation of that gene (Sirtuin1) induces heart failure in animals. [Circulation Research 2007; 100:1512]. We now know mega-dose resveratrol may not be beneficial, and appears to be deleterious for healthy adults,” adds Sardi.
More recently, Longevinex® ( www.longevinex.com ) sponsored a mouse study which showed its proprietary and patent-applied for blend of nutriceuticals, which includes 100 mg of resveratrol per capsule, and 250 mg of natural mineral-chelating molecules overall (about the same amount of molecules provided in 3-5 glasses of red wine), favorably influenced 1711 longevity genes in heart tissue, compared to only 225 genes in animals fed 100 mg of plain resveratrol. [Experimental Gerontology 2008 Sep; 43(9):859-66] –
Copyright 2009 Resveratrol Partners LLC, dba Longevinex. Not for posting on other websites.
Extent of damage to animal heart tissue by dosage of resveratrol.
White area in photos below represents scarred tissue.
The equivalent of 2.5 mg per kilogram of body weight of resveratrol
in a 160-lb human = 175 mg; 5.0 mg/kilogram = 350 mg;
25 mg/kilogram = 1750 mg; 50 mg/kilogram = 3500 mg.
Heart cell (cardiomyocyte) death during an induced
heart attack, by dosage of resveratrol. Lower doses reduced
cell death and exhibit protection for heart tissues,
mega-doses increased cell death and increased the area
of scarred tissue in the heart.