Healthy Heart with Resveratrol

Low-Dose Resveratrol
Prevents Cardiac Aging

Gene technology indicates extraordinary similarity
between effects of resveratrol and caloric restriction
By Will Block

ave you heard of “kissing chromosomes”? No? Well, here’s how it works. Sometimes a portion of a chromosome’s DNA strand (which is extremely long) can loop out of its normally tightly “woven” structure, like an errant loop of yarn that emerges from the weave of a sweater. If such a DNA loop encounters another DNA loop from an adjacent chromosome, a chemical interaction can occur at the point of contact, called a “kiss” (awww).

These molecular smooches are not just random encounters among promiscuous DNA loops, however. They’re biologically specific events that serve useful purposes—it’s nature’s way of providing for the coordinated activities of genes residing in different chromosomes within the cell’s nucleus.

So—what do kissing chromosomes have to do with the subject of this article? Probably nothing. It was a shameless ploy to “hook” you into the article so we could tell you about a more general phenomenon involving chromosomes—one that is central to the subject. It goes by the humdrum name chromatin remodeling, but don’t let that fool you. Certain proteins that are involved in chromatin remodeling are tied, in apparently fundamental ways, to the molecular basis for aging and, therefore, to the molecular basis for antiaging. You’ll see.

Without getting too technical (we don’t want your eyes to glaze over), chromatin is the name given to the substance—an extremely intricate supramolecular complex of DNA and proteins—that constitutes our chromosomes (of which we have 23 pairs). And chromatin remodeling is a process by which the gross structure of a chromosome is temporarily altered (remodeled, in biospeak) in such a way as to affect the functions of various genes without a change in the gene sequence of the DNA. Certain genes are themselves involved in the process of chromatin remodeling, via the actions of the proteins they code for.

Even at Low Doses, Resveratrol Mimics Caloric Restriction

To see how important this process is to our health and longevity, we turn to a study just published by researchers from the United States and Switzerland.1 Their results demonstrate striking similarities (in mice) between the effects of supplementation with the celebrated longevity compound resveratrol and those of the severe dietary regimen called caloric restriction (CR). The latter strongly protects against the diseases of aging and greatly extends both average and maximum lifespan. (CR is a drastic reduction, by about 30–40%, in daily caloric intake, for life.)

Both resveratrol, which is a polyphenolic compound found mainly in grapes and red wine, and CR are known to improve health and prolong lifespan in a wide variety of organisms. Most remarkably, supplementation with resveratrol appears to mimic, with uncanny precision, the biological effects of CR: it provides the benefits of CR without the need for actual CR! [See “Resveratrol Mimics Caloric Restriction” (April 2008) and “Promoting Survival with Resveratrol” (May 2008).]

The authors of the new study stated,1

Based on the functional analysis of gene-expression profiles in multiple tissues, we postulate that both CR and resveratrol impact pathways that determine chromatin remodeling, perhaps in response to a metabolic stress signal. The ensuing alteration in chromosome architecture and transcription [genetic information transfer from DNA to RNA] may . . . retard some aspects of the aging process in the long term. Understanding the pathways that influence the expression of genes involved in chromatin remodeling and transcription in response to both CR and resveratrol may therefore provide key insights into the molecular basis of aging in mammals. . . . Our studies suggest that dietary consumption of a low dose of resveratrol partially mimics CR and inhibits some aspects of the aging process.

In other words, it appears that: (1) the longevity effects of both resveratrol and CR occur via their effects on chromatin remodeling; (2) the mechanisms in question are at least partially the same; and (3) resveratrol may confer longevity benefits in lower doses than had previously been recognized. That last item is exciting news because most prior research had indicated that resveratrol’s longevity benefits could be achieved only with relatively massive doses, mainly because of its exceptionally poor bioavailability when administered via the digestive tract.

Using Gene Technology to Obtain the Evidence

In a groundbreaking study of resveratrol’s dramatic effect on longevity in obese mice published in late 2006, the largest (and most effective) amount used was 22.4 mg per kg of body weight per day.* Using the standard scaling factor, 0.081, for converting mouse dosages to human equivalent dosages (to reflect the great differences in body surface area and metabolic rate between mice and humans), this figure would be reduced to 1.81 mg/kg per day or, for a 75-kg (165-lb) person, 136 mg/day.


*For a discussion of this study, see “Revolutionary Antiaging Discovery with Resveratrol” (January 2007). In another groundbreaking study, this one pertaining to resveratrol’s dramatic effects on physical strength and endurance in normal, healthy mice, the amount used was much higher: 400 mg/kg per day. See “Resveratrol Boosts Strength and Endurance in Mice” (February 2007).


To obtain that amount of resveratrol from red wine, you would have to drink about 136 bottles of wine daily, because red wine contains, on average, about 1 mg of resveratrol per bottle. Fortunately, resveratrol can be taken as a supplement instead. In the American/Swiss study profiled in this article, the amount used in the mice was 4.9 mg/kg per day, which converts to a human equivalent, for a 75-kg person, of only 30 mg/day (that’s only 30 bottles of wine per day—now we’re talking!).

It’s important to note, though, that most of the evidence for the benefits attributed to resveratrol at this lower dosage was not obtained directly in the mice, but indirectly via a sophisticated laboratory technique called gene expression profiling, in which all the genes in an organism’s genome (its full complement of genes) can be tested simultaneously on a “gene chip” (aka DNA chip or biochip or microarray) for activity under a given set of circumstances.*


*For an explanation of this amazing technique, see “Vitamin E Combats Alzheimer’s Disease” in the July 2005 issue. See also the illustration on page 19.


Resveratrol—A “Robust Intervention” for Heart Health

In this case, the researchers tested for gene activity in three types of tissue—heart, skeletal muscle, and brain (neocortex)—taken from young and old mice, with and without resveratrol supplementation and with and without caloric restriction during the 16-month duration (age 14 to 30 months in the mice) of the study. Their objective was to discover changes in gene activity that are related to aging alone and to the effects of resveratrol and caloric restriction.

In the heart, there were 1029 genes whose expression (level of activity) changed significantly with age. With CR, the changes (called transcriptional alterations) were reduced in 921 (90%) of these genes, indicating a broad antiaging effect of CR. With resveratrol, the changes were reduced in 947 (92%) of the genes—essentially the same. The authors stated,1

Thus, resveratrol at doses that can be readily achieved through dietary supplementation in humans is as effective as CR in opposing the majority of age-related transcriptional alterations in the aging heart. Because the collection of such alterations in gene expression is a biomarker of aging, our results imply that, similar to CR, middle-age-onset resveratrol supplementation at low doses is likely a robust intervention in the retardation of cardiac aging.

In skeletal muscle, there were 515 genes whose expression changed significantly with age. Here both CR and resveratrol reduced the changes in only 26% of the genes—a much more limited effect than in the heart, but again striking in its being the same figure for both interventions. Finally, in the brain’s neocortex, the number of age-altered genes was 505; here the changes were reduced in 19% of the genes with CR and in 13% of the genes with resveratrol.

Resveratrol and CR Take Genes in the Same Direction

Next the researchers used gene expression profiling to examine those gene activities that are not altered by aging but that are altered by both CR and resveratrol. In their words, “Such changes in gene expression represent shifts induced by the dietary interventions and can provide clues to mechanisms of action and the degree and nature of CR mimicry by resveratrol.”

The numbers of non-aging-related genes whose activities were changed by both CR and resveratrol were 747 for the heart, 1164 for skeletal muscle, and 1134 for the brain. In any given case, the change could be in one direction of gene activity or the other, i.e., it could be either upregulation or downregulation. This raises a vital question: were the changes induced by CR and resveratrol in any given case always in the same direction, meaning that they would tend to have the same effects? The answer is: virtually always.

For heart, skeletal muscle, and brain, the changes in gene activity occurred in the same direction for 99.7%, 100%, and 99.6% of the genes, respectively. In rather an understatement, the authors said, “Clearly, resveratrol can mimic a large component of the transcriptional profile of CR in all tissues examined.” (A reminder: transcription is the process by which genetic information is transferred from DNA to RNA; it’s the first step in the synthesis of proteins, whose structures are encoded in our genes.)

Resveratrol Enhances Erections

The title got your attention, didn’t it? In fact, you’re probably reading this first, which is fine. (But please do read the article too—it’s not chopped liver.) Without good erections, life would be . . . well, there wouldn’t be any life, would there? The same goes for male fertility. So the quest for enhancement, particularly in the former domain, is endless, particularly as the common causes of impotence—hypertension, obesity, diabetes, smoking, and aging—are so prevalent in our society. And the age-related decline in testosterone levels and the associated decline in sperm function are major causes of male reproductive dysfunction and infertility.

Enter resveratrol. A team of researchers in veterinary medicine in Korea has discovered that this amazing red-wine compound, already renowned for a host of disease-preventing and life-extending benefits, can add another couple of notches to its belt.1 In laboratory experiments with corpus cavernosum tissue taken from rabbit penises (rabbits—a good choice!), they chemically induced a contracted state of the tissue, which is bad for erections, because it doesn’t allow the penis to become engorged with blood.

They then tried to reverse this condition to a relaxed state—which is good for erections—with resveratrol. It worked very well, albeit at a concentration about 6000 times greater than that required for sildenafil (Viagra®). Resveratrol was already well known for its beneficial effects on the cardiovascular system, mediated in part by the same mechanism—enhancement of nitric oxide (NO) release—that underlies the physiology of erections.* It is believed that resveratrol enhances NO synthesis through its estrogenic activity: it stimulates the estrogen receptors on cell walls, and that upregulates endothelial nitric oxide synthase, the enzyme upon which NO synthesis depends.


*For more on the cardiovascular benefits, see “Resveratrol and Arterial Health—Dual-Mode Benefits” in the June 2008 issue.


In separate experiments with live mice, the researchers administered resveratrol at 50 mg per kg of body weight per day for 28 days, to determine its effects on serum testosterone levels, sperm count, and sperm motility (which is an indicator of sperm quality). They found improvements by 52%, 16%, and 23%, respectively. Ironically, resveratrol’s effectiveness here too may have been due to its estrogenic activity (even sperm cells contain estrogen receptors). Anything having to do with the sex hormones tends to be very complicated.

The authors concluded,1

Taken together, our findings demonstrate that resveratrol treatment enhances male reproductive function through dual mechanisms including the relaxing effect on corpus cavernosum tissue induced by direct estrogenic activity of resveratrol, which triggers and maintains a penile erection, and the enhancement of serum testosterone levels as well as sperm counts and motility. Hence, the results suggest that resveratrol may be a candidate for the improvement of male reproductive function, as a nutraceutical.

Reference

  1. Shin S, Jeon JH, Park D, Jang MJ, Choi JH, Choi BH, Joo SS, Nahm SS, Kim JC, Kim YB. trans-Resveratrol relaxes the corpus cavernosum ex vivo and enhances testosterone levels and sperm quality in vivo. Arch Pharm Res 2008;31:83-7.

Resveratrol and CR Prevent Declining Cardiac Function

The researchers also measured various aspects of heart function in the calorically restricted and resveratrol-treated mice. From their data, they computed the myocardial performance index, a number that provides an overall assessment of cardiac function. The number increases with declining function, so it tends to increase with age—as it did in the control mice in this study. Both CR and resveratrol supplementation, however, almost completely prevented this effect. The authors stated, “Thus, resveratrol mimics the effects of CR to prevent cardiac aging at both the transcriptional and functional levels.” Think about that.

A Series of Sobering Surprises

Additional experiments were aimed at evaluating insulin sensitivity and glucose (blood sugar) metabolism in the mice, because prior research had shown that both CR and resveratrol supplementation improve these functions. (See “Resveratrol Increases Insulin Sensitivity” in the December 2007 issue.) Here the results showed appreciable benefits from CR but not from resveratrol (with one exception in a measurement on skeletal muscle), and they indicated that the mechanisms of action of these two interventions in this domain are different.

The lack of an effect with resveratrol with the low dose (4.9 mg/kg per day) used in this study is all the more surprising because a previous study (discussed in the December 2007 article cited above) had shown a significant improvement in insulin sensitivity with a much lower dose (2.5 mg/kg per day) of resveratrol. The mechanism of resveratrol’s action in that study (as in most other studies of resveratrol) was strongly dependent on a protein called SIRT1, which is encoded by the longevity gene SIRT1. This protein appears to play a pivotal role in the longevity mechanisms associated with resveratrol and caloric restriction, both of which increase its levels and activity.

Thus it was again surprising, in the new study, when the researchers found that neither CR nor resveratrol had any apparent dependence on SIRT1, at least in the brain and liver; and CR actually decreased the levels of SIRT1 in the heart and skeletal muscles. Nor was there any significant effect by resveratrol (unlike CR) on the important protein PGC-1α, which is activated by SIRT1. These confusing findings serve as a reminder that we rarely understand things as well as we thought we did.

Similarly sobering were the results of experiments to assess the ability of CR and resveratrol to reduce spontaneous oxidative damage in various tissues of the mice. No such ability was observed, and in one experiment, markers of oxidative damage were actually increased somewhat. Here too, the discrepancy with previous studies indicates the need for more research to try to resolve the question.

The Fountain of Youth

Juan Ponce de León was not obese—not that anyone would expect a Spanish conquistador to be “calorically challenged”—it was, after all, a physically demanding job to discover and conquer new worlds, fighting the natives at every turn. It kept a man in shape. Ponce de León sailed with Columbus on the second voyage (1493–1494), and in 1506 he became the governor of Puerto Rico. Upon being removed from that office in 1512, he decided to explore the areas north of Cuba.

In 1513 he discovered Florida, which he thought was a large island. He was said to be the first of the Spanish conquistadors—and the first European since the Vikings five centuries earlier—to set foot on North America. That claim seems a bit suspect, however. According to a historian of the period, Ponce de León encountered at least one Indian in Florida who spoke Spanish. Hmmm. (Of course, the Indian might have been a recent immigrant from one of the Spanish-speaking islands.)

In any case, it is claimed (although the story is probably apocryphal) that Ponce de León saw Florida as a likely site for the legendary Fountain of Youth. He knew, however, that many Indians of the Caribbean favored the Biminis—a group of small islands of the western Bahamas, in the Straits of Florida—to be the magical site.

It’s not surprising that the Indians too believed in the Fountain of Youth, because myths of this kind had long been part of the folklore of many cultures. In Europe, the belief—or at least the legend—dated back at least as far as the Alexander Romance, the collective name for a body of hagiographic literature that had developed around the exploits of Alexander the Great.

Although Ponce de León never found the Fountain of Youth, he lived to be 61, which was very old by the standards of his time. He died not of old age, however, but from a poisoned arrow shot by a Calusa Indian in southwest Florida—final justice, perhaps, for all those whom Ponce de León had killed.

Different Dosages, Different Modes of Action?


This gene chip can analyze the activities of about 40,000 genes simultaneously. The level of activity is measured as the intensity of laser-induced fluorescence in each DNA snippet. The torrent of data is analyzed by a computer.
A careful analysis of all their data from gene expression profiling led the researchers to conclude that both CR and resveratrol have a major impact on the genes that regulate chromatin remodeling (and now we’ve come full circle). The resulting changes in chromosomal structure may facilitate biochemical pathways that maintain the stability of the genome and inhibit some aspects of the aging process.

The surprising absence of a role of SIRT1 or PGC-1α in these findings led the authors to suggest that different mechanisms of action may be involved at different dosage levels of resveratrol and, for that matter, in different tissues of the body at any dosage level. Nothing is simple.

Most frustrating is that there is currently no way of knowing whether the results of this study and the other resveratrol studies conducted with experimental animals are applicable to humans. It seems likely that they are, but there is no hard evidence. And the preliminary results of two long-term studies of the longevity effects of caloric restriction in rhesus monkeys (close relatives of ours) are contradictory: one study appears to show life extension, whereas the other does not. (But the trials still have a long way to go, and there is every reason to believe that the results will be positive.)

No Offense, Florida, but You Didn’t Deliver

Meanwhile, all available evidence points to the likelihood that resveratrol will live up to its already well established reputation as a life-extending elixir, the Holy Grail of antiaging medicine. When Juan Ponce de León was searching Florida for the fabled Fountain of Youth five centuries ago, it surely never occurred to him that what he was looking for was readily available to him in the nearest bottle of red wine. And now it’s available to us in the nearest supplement bottle labeled Resveratrol.

Reference

  1. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 2008 June;3(6):1-10. e2264.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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