Let Resveratrol Go to Your Head

Resveratrol Boosts
Energy Metabolism

Mimicking the effects of caloric restriction, it provides
neuroprotection by producing more mitochondria
By Will Block

hen was the last time you thought about your mitochondria? No, really, when? . . . Oh, that long ago? Well, admittedly, it is hard to think about things like that when there are so many vital issues dominating the news, such as Paris Hilton and Paris Hilton and, oh yes, Paris Hilton. Of course, Miss Hilton has mitochondria of her own, and she probably spent a good deal of time thinking about them while she was in jail . . . well, maybe not.

Mitochondria are the key players in the production of chemical energy in your cells. If you want to know the source of your “life energy,” it’s your mitochondria (a single one of which, by the way, is called a mitochondrion). They are the tiny cellular “power plants” in which the slow oxidative combustion of your body’s principal fuels—glucose and fatty acids—converts the fuels’ chemical energy to a form that can be used to drive life’s biochemical processes. Reduced mitochondrial function is associated with age-related degenerative diseases and a shortened lifespan, and it may contribute substantially to the high risk for cardiovascular disease associated with obesity and the metabolic syndrome.1*


*In 1972, Dr. Denham Harman, of the University of Nebraska College of Medicine, proposed what is now called the mitochondrial theory of aging, as an extension and refinement of his earlier (1956) free radical theory of aging. The theory, which involves the role of mitochondrial function and dysfunction in aging and longevity, is supported by much circumstantial evidence.


It’s Your Mitochondrial ATP that Keeps You Going

The form of chemical energy alluded to above is a molecule called ATP (adenosine triphosphate), an incredibly versatile little dynamo. In enzyme-catalyzed reactions with a great variety of other substances, ATP readily gives up the energy in one of its chemical bonds. When that “high-energy phosphate bond” is broken, donating its energy for the making or breaking of a chemical bond in some other molecule, ATP becomes ADP (adenosine diphosphate) and an inorganic phosphate group. ADP can be further broken down to AMP (adenosine monophosphate). With the input of energy from the combustion of more nutrient fuel, however, AMP and phosphate can be made to recombine to ADP, and ADP and phosphate can be made to recombine to ATP. The cycle then begins anew.

The overall process of cellular energy metabolism, also called cellular respiration, produces and consumes vast amounts of ATP daily—as much as your entire body weight if you’re a very physically active person—and it never ends for as long as you live. That, in a nutshell, is what keeps you going, and going, and going, like the Energizer bunny. And, like the bunny, you do want to outlive the “competition,” right? If you’re serious about that, you should think about your mitochondria and what you can do for them so that they can keep on going for you for a very long time. One word that should come up in this regard is resveratrol, the celebrated red-wine compound whose biological activities in terms of health and longevity are unprecedented—and spectacular.

Resveratrol—A Key to Longevity

In an article in the January 2007 issue ( “Revolutionary Antiaging Discovery with Resveratrol”), we discussed the five keys to longevity as we see them. They are: (1) maintaining general good health; (2) providing antioxidant protection; (3) practicing caloric restriction; (4) promoting upregulation of the SIRT1 gene (more on that below); and (5) taking resveratrol. The fact that a single chemical compound could make it into such a list is stunning—it could not have been foreseen just a few years ago.

In the article cited, we showed how resveratrol (pronounced rez·VEER·ah·troll) ties in with the other four factors to achieve its status as a true “longevity molecule,” one that has greatly extended both the average lifespans and the maximum lifespans of a variety of organisms, in studies published over the last few years. Those organisms range from lowly yeasts (fungi) to less lowly roundworms (nematodes) to fruit flies (insects) to fish (vertebrates) to mice (mammals!) to . . . well, there the story is interrupted, but by no means ended. There is good reason to believe that similar results will eventually be found in primates, our closest living relatives on earth.

Resveratrol Provides Many Health Benefits

Meanwhile, evidence continues to mount regarding resveratrol’s myriad health benefits and the mechanisms by which they are achieved. These benefits include strong protective effects against cardiovascular disease, cancer, diabetes, and neurodegenerative diseases. A recent paper by scientists at the Washington University School of Medicine in St. Louis focuses on the last of these categories.2 The authors point out that resveratrol has important protective effects on the nervous system.

In experiments with nematodes, for example, it blocks the accumulation of abnormal (mutant) protein aggregates associated with Parkinson’s and Huntington’s diseases and increases the organisms’ survival rates. In the very short-lived turquoise killifish (Nothobranchius furzeri), it reduces the neurofibrillary degeneration associated with normal aging and, probably not coincidentally, delays the age-dependent decline in memory function; it also delays the age-dependent decline in locomotor capacity, i.e., the ability to move around (in this case, by swimming).

When mammalian neurons are injured, resveratrol delays the degeneration of their axons (an axon is the long, slender portion of a nerve cell that usually conducts impulses away from the main body of the cell). It also blocks the accumulation (in vitro, i.e., in laboratory experiments) of amyloid-beta, the destructive protein that is a hallmark of Alzheimer’s disease. And in both adult and newborn rodents, it provides protection from brain damage caused by cerebral ischemia, or inadequate blood flow (which can lead to hypoxia, or oxygen deficiency).

Resveratrol Promotes Mitochondrial Biogenesis

Because of these promising neuroprotective effects, resveratrol is currently being evaluated in human clinical trials of patients with Alzheimer’s disease. The great majority of studies with resveratrol thus far have been done in vitro or with experimental animals, so human trials are a welcome step up to what ultimately matters: answering the question, does it work in humans or not?

Assuming that it does, there is still the question of mechanism, i.e., how does resveratrol work? The Washington University researchers mentioned a number of possible mechanisms that others have suggested, including alteration of the expression of various enzymes that affect different aspects of our metabolism and neuronal function. Another possibility is that resveratrol promotes mitochondrial biogenesis (the increased creation of mitochondria in our cells). Having more mitochondria can make our cells more efficient in terms of energy production.


“Interestingly, many of the activities
of resveratrol are similar to the
beneficial effects offered by
caloric restriction (CR), including
slowed aging and delaying the
onset of chronic diseases.”


Resveratrol Mimics Caloric Restriction

The researchers stated, “Interestingly, many of the activities of resveratrol are similar to the beneficial effects offered by caloric restriction (CR), including slowed aging and delaying the onset of chronic diseases.” CR, a drastic (30–40%) reduction in daily caloric intake, ideally for the remainder of the organism’s life, is still the only known method of increasing maximum lifespan in all organisms, up to and including primates (the earlier in adulthood that CR is begun, the greater the chance of life extension).* As we saw above, this claim cannot be made for resveratrol, because resveratrol’s longevity effect has not yet been adequately tested in primates. The fact, however, that resveratrol’s effects mimic those of CR (which also promotes mitochondrial biogenesis) is remarkable and suggests that the two phenomena are connected at some deep level in organisms throughout the animal kingdom.


*For more on caloric restriction and its connection with mitochondrial biogenesis, see “Can Nitric Oxide Increase Lifespan?” in the January 2006 issue. And for the rapid progress in our knowledge of resveratrol, see “Resveratrol and Quercetin—Puzzling Gifts of Nature” (July 2005), “Resveratrol Fights Brain Plaque” (November 2005), “Can Resveratrol Help Prevent Alzheimer’s?” (February 2006), “Resveratrol Prolongs Life in a Vertebrate!” (April 2006), “Resveratrol—Star Molecule Against Disease and Aging” (August 2006), “Resveratrol Instead of Aspirin for Heart Health” (November 2006), “Revolutionary Antiaging Discovery with Resveratrol” (January 2007), and “Resveratrol Boosts Strength and Endurance in Mice” (February 2007).


Both resveratrol and caloric restriction provide improved efficiency of energy utilization through mitochondrial biogenesis—and so does an enzyme called AMPK (AMP-activated kinase), which senses changes in cellular energy levels by monitoring the ratio of AMP to ATP.2 AMPK is itself activated by a variety of pathological stressors, such as ischemia, hypoxia, oxidative stress, and glucose deprivation, as well as by exercise and dietary hormones. It provides a measure of protection against such stresses, particularly ischemia, where it decreases the size of infarcts (areas of necrosis, or tissue death). And it’s activated in hypothalamic neurons under diet-restricted conditions.

Many of Resveratrol’s Effects Depend on AMPK

Having noticed that some of the metabolic changes induced by resveratrol mimic those observed in response to AMPK activation, the Washington University researchers investigated whether resveratrol’s actions in neurons (including those of the brain) are mediated to some degree by its activation of AMPK. In experiments with both neuronal cell cultures and live mice, they found that this was indeed the case. It appears that many of resveratrol’s effects, including the stimulation of mitochondrial biogenesis, depend on AMPK.*


*If you’re thinking, why not take AMPK as a supplement, forget it. Kinases are enzymes, and enzymes are proteins, which cannot survive the digestive tract—they’re broken down to their constituent amino acids, which are then absorbed into the bloodstream.


Resveratrol’s activation of AMPK is, however, independent of a protein called SIRT1. And why is that significant? Because SIRT1 is the protein coded for by the longevity gene SIRT1 (genes are italicized, by the way; proteins are not), which is upregulated by resveratrol (and by caloric restriction). The SIRT1 protein (which is one of a family of seven) protects organisms from the effects of stress and aging. Knowing that resveratrol’s effects involve mechanisms other than upregulation of SIRT1 (which produces more SIRT1) is useful to scientists because it gives them new avenues to explore in seeking to understand how resveratrol does what it does.

Based on a variety of experimental evidence, the authors suggested that:2

. . . many, if not all, SIRT1-independent CR-mimetic actions of resveratrol depend on the AMPK cascade. Indeed, the multiple beneficial effects of resveratrol may be due to its ability to alter the activity of multiple proteins involved in the cellular response to stress (i.e., SIRT1 and AMPK).

Here “cascade” refers to a sequence of biochemical reactions that are initiated by some agent (such as AMPK) and that cumulatively constitute a physiological process. Noting that AMPK function appears to play a crucial role in neuronal energy metabolism at both the organismal level and the cellular level, the authors went on to say:

Here, we show that resveratrol . . . produces dramatic effects on neuronal function and that these effects are mediated by AMPK activation. . . . Because both SIRT proteins and AMPK are involved in the cellular response to metabolic stress, it will be interesting to determine whether there are additional interactions between these two protein families in neurons and other cells.

How High Can You Count?

Here’s a clue as to how important our mitochondria are: they’re found mainly in metabolically active cells, such as those of the heart, brain, liver, kidneys, and muscles, each of which may have hundreds or thousands of them. It is estimated that we have about 10 quadrillion (10 million billion) of them, and they constitute about 10% of our body weight.3 That’s something to think about.

Which reminds us, unfortunately, of Paris Hilton, who is famous for being famous and especially, of course, for being famous in jail. Resveratrol, on the other hand, is a molecular celebrity for doing useful things, such as . . . oh yes, improving our health and prolonging our life.

References

  1. Nisoli E, Clementi E, Carruba MO, Moncada S. Defective mitochondrial biogenesis: a hallmark of the high cardiovascular risk in the metabolic syndrome? Circ Res 2007;100:795-806.
  2. Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 2007;104(17):7217-22.
  3. Nisoli E, Carruba MO. Nitric oxide and mitochondrial biogenesis. J Cell Sci 2006;119:2855-62.

Purple Corn Color Lowers Rats’ Blood Pressure


© iStockphoto.com/Tamara Bauer
When people quit the rat race to join the human race, their hypertension (high blood pressure) often has something to do with it. We humans are very susceptible to that disease, unfortunately, and therein lies a small paradox: most real rats are not susceptible. Some rats do get it, however, and scientists call them spontaneously hypertensive rats. This strain of rodents is very useful to researchers, for obvious reasons. If you can lower their blood pressure significantly, chances are you can do the same for their human counterparts.

Enter purple corn color, an anthocyanin pigment that turns a certain strain of corn purple.* This pigment has been demonstrated to prevent weight gain in mice that were fed a high-fat diet (30% lard by weight). By inhibiting the action of an enzyme complex called fatty acid synthase, it prevented the accumulation of adipose tissue (fat). That, in turn, provided protection against insulin resistance and type 2 diabetes. (See “Purple Corn Color May Help Prevent Obesity” in the June 2007 issue.)


*Red and purple grapes, as well as red, blue, and purple berries, also get their skin color from anthocyanins, which are one of the major classes of flavonoids.


Now researchers in Japan have found that three plant pigments—all of them anthocyanins—are effective in lowering the blood pressure of young, spontaneously hypertensive rats (SHRs).1 The three pigments they tested were purple corn color (PCC), purple sweet potato color (PSC), and red radish color (RRC).

After adding these colors to the rats’ daily chow (1% by weight of their normal diet) for 15 weeks, the researchers found that their blood pressure—both systolic pressure and mean pressure—dropped significantly compared with that of the control group. The PSC and RRC were more effective in this regard than the PCC, perhaps because the PCC was present in a lower concentration than the other two. In the commercial preparations used in this experiment, the concentrations of PCC, PSC, and RRC were 26%, 38%, and 33%, respectively.

The anthocyanins also lowered the rats’ heart rate compared with the controls, but here there were no significant differences among the three preparations. Finally, the anthocyanins had no effect on the rats’ total food intake or weight gain—they all gained weight equally throughout the 15-week period. (Recall that the dramatic suppression of weight gain mentioned above occurred with a high-fat diet, not a normal diet.)

Reference

  1. Shindo M, Kasai T, Abe A, Kondo Y. Effects of dietary administration of plant-derived anthocyanin-rich colors to spontaneously hypertensive rats. J Nutr Sci Vitaminol 2007;53:90-3.


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

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