Can Nitric Oxide Increase Lifespan?

Can Nitric Oxide Increase Lifespan?
This vital molecule plays a key role in caloric
restriction, the only known way to increase lifespan
By Will Block

Every man desires to live long, but no man would be old.
— Jonathan Swift

id you ever notice that aging is a rare phenomenon? Probably not, because you’re a human being surrounded by other human beings (and perhaps a dog or cat or some other cuddly critter that you dearly love). And they all age, don’t they? Heck, it could even happen to you if you don’t watch out.

We’re so wrapped up in our own concerns and the concerns of those around us that it’s easy to overlook a startling fact: by and large, animals in the wild do not age (nor do perennial plants). They do get older, to be sure, but they don’t age in the usual sense—a long, slow deterioration of the body’s structure and function, leading often (but thankfully not always) to a prolonged state of decrepitude, and always, eventually, to death.

It’s vital to realize, though, that aging in the usual sense is not inevitable. In humans, it’s generally the result of poor lifestyle choices (improper diet, inadequate exercise, substance abuse, excessive stress, etc.), whose cumulative effect is to erode our health silently and insidiously while we’re too busy to notice. Granted, some people live long and remain remarkably healthy to the end despite having broken all the rules, but they’re statistical flukes. By and large, the people who accomplish this feat are those who have taken exceptionally good care of themselves throughout their lives. Good genes play an important role too, so choose your parents wisely.

Why Animals Don’t Age

But let’s get back to plants and animals—especially animals, because they’re our next of kin. What accounts for the apparent paradox mentioned above? In the wild, animals seldom live long enough to age, because they’re taken out by one of four factors: starvation, predation, infectious disease, or an environmental calamity such as fire, flood, drought, or intolerable extremes of temperature.

“Nature, red in tooth and claw,” in the evocative words of Alfred, Lord Tennyson, exacts a terrible price on the unfit, the unwary, and the just plain unlucky. Simply getting old is a major accomplishment out there, and getting old enough to age is almost unheard of. Our pets age, though, because they live in a bubble of safety, comfort, and TLC that their wild brethren could never imagine. Zoo animals also age, but farm animals tend not to, for an obvious reason: their usual destiny is the abattoir.

Aging in Humans—A New Phenomenon . . .

That leaves us humans, and believe it or not, aging—on a broad scale, anyway—is a new phenomenon in the history of our species. Although there have always been a few people who lived to be extremely old (about 120 at most), the sad truth is that for most folks throughout history, life was relatively brutish and short. For starters, there was the high rate of infant mortality, as well as the high perinatal mortality of mothers. Then there was the appalling toll taken on young men by the more or less permanent state of warfare that has existed, in one way or another, throughout recorded history.

For those who survived these trials, life tended to be cut short by injury, famine, or infectious disease (pneumonia, influenza, tuberculosis, plague, etc.) long before the chronic degenerative diseases, such as heart disease, cancer, arthritis, diabetes, and dementia could take hold. For all practical purposes, such diseases were unknown to most of humanity until the twentieth century; now they’re extremely common.* Meanwhile, thanks to antibiotics, immunization, improved sanitation, etc., the major infectious diseases have been largely tamed—in the developed world—except for the occasional flu pandemic. (For more on this, see the sidebar “Will Longevity Ever Get Longer?”)

*Although not a disease, the condition of postmenopause is also a twentieth-century “innovation,” which most women of the past never lived long enough to experience.

Will Longevity Ever Get Longer?

The prospects for cheating death and living indefinitely are strictly in the realm of science fiction, but open minds cannot rule out the possibility of future “miracles” for which the present state of scientific knowledge is still totally unprepared. It’s a sobering fact that the maximum human lifespan of about 120 years has remained unchanged since humans began recording their ages thousands of years ago. The fantastic advances in science and medicine throughout human history have had no effect whatever on this seemingly immutable figure.

Thus it seems obvious that we were (note the past tense) destined by our genome—the sum total of all our genes—to live no more than about 120 years, no matter what. But we have recently entered the age of genetic engineering, and that may change everything. We are slowly learning how to tinker with our own genome so as to improve some aspects of our health and, perhaps, to extend our maximum lifespan. Some scientists are determined to overcome the 120-year barrier to longer life—and perhaps, someday, they will. Will they be able to extend the “deadline” to 125? 150? 200? No one knows, so our advice is to stay alive long enough to see how this pans out.

Meanwhile, we can rejoice in the fact that the average human lifespan has risen dramatically during the past century. In 1900, the life expectancy of a newborn child in the United States was 47 years; now it is 74 for men and 80 for women, and there is every reason to think that these figures will continue to increase until … what? Again, no one knows—we’ll just have to wait and see.

Meanwhile, we try to make the best of our uncertain lot through life enhancement—improving (or at least maintaining) our health so as to improve both the quality and the length of our lives.

. . . For Which Evolution Left Us Unprepared

The irony in our greatly extended lifespan relative to that of just a century ago is that we were grossly unprepared for it by the evolution of our species through natural selection. Mother Nature’s supremely unsentimental design for all living things is centered on just one phenomenon: survival of the species by reproduction. After parents have successfully reproduced and raised their young to a point where the latter can fend for themselves, they are no longer needed, and they soon die—except for us humans, because we’ve figured out ways to beat the system.

Somewhat to our surprise, however, we have been finding out that our physiology was not designed to accommodate an extended lifespan. Biochemical systems that worked efficiently in our younger years can become seriously deficient as we pass through middle age—the stage of our lives when the major chronic degenerative diseases begin their assault on our systems in earnest. Our hormone levels decline dramatically, e.g., as does our ability to absorb and metabolize various nutrients, especially certain vitamins and minerals. Meanwhile, the cumulative effects of oxidative stress (including free radicals) take their toll on our organs and tissues, to a degree that our inborn antioxidant defense mechanisms were never designed to cope with.

Good Nutrition Is Vital, and Includes Supplements

Thus we have slowly come to the realization that the importance of good nutrition (a healthy balance of fruits, vegetables, nuts, grains, fiber, and coldwater fish) becomes greater as we age, because of the declining ability of good nutrition to fulfill our bodies’ changing needs. As vital as it is that we try to eat for good health, it becomes ever more difficult to maintain desirable levels of some nutrients that are required for good health—not to mention optimal health.

All of which leads to two conclusions: (1) if we want to live longer, in better health, we must improve our nutrition (as well as that other great pillar of health, exercise); and (2) if we want to overcome the age-related biochemical obstacles put in our path by an uncaring Mother Nature, we must turn to supplements. As Linus Pauling put it,1

I believe that you can, by taking some simple and inexpensive measures, lead a longer life and extend your years of well-being. My most important recommendation is that you take vitamins every day in optimum amounts to supplement the vitamins that you receive in your food. Those optimum amounts are much larger than the minimum supplemental intake usually recommended by physicians and old-fashioned nutritionists. . . . My advice that you take larger amounts of C and other vitamins is predicated upon new and better understanding of the role of these nutrients—they are not drugs—in the chemical reactions of life.

That’s good advice from one of the greatest scientists who ever lived (Pauling died in 1994 at the age of 93). As time goes on, evidence for the benefits of other nutritional supplements, such as various hormones, amino acids, and herbal extracts, continues to mount. There is, however, no proof of a life-extending effect of any supplement in humans, and it’s unlikely that there ever will be—in the traditional sense—because the requisite studies would be of enormous magnitude and duration (of the order of decades), and there’s no financial incentive to incur such costs. Proof, however, is not necessary where evidence of substantial health benefits is strong.

Caloric Restriction—Effective but Wildly Unpopular

Meanwhile, we do know of one (and only one) sure-fire way to extend maximum lifespan in lower organisms—and probably in humans as well, although humans will never embrace it: caloric restriction. This means eating less—a lot less—than normal, for the rest of your life. Over the last 70 years, studies with a great variety of organisms, from yeasts to roundworms to fruit flies to rodents, have consistently shown that reducing normal caloric intake by about 30% increases lifespan by amounts ranging from about 10% to as much as 50% in some mammals and up to 90% in certain fruit flies.

In mammals, caloric restriction (CR) produces dramatic weight loss and reduces the incidence, or delays the onset, of various age-related degenerative diseases. It also confers protection against infectious diseases, to which aging animals (and humans) are increasingly susceptible owing to declining immune function. Long-term studies on Rhesus macaques (Macaca mulatta) begun in the 1980s have shown that, in addition to providing numerous other substantial health benefits, CR rejuvenates the immune system of these monkeys—an important factor in increased longevity.2

How Does Caloric Restriction Work?

How CR increases longevity has been the subject of much research and debate. Here is one plausible explanation that has had wide currency: because a reduced food intake produces less glucose for energy production in the cells’ mitochondria—the tiny “powerhouses” that generate virtually all of the organism’s chemical energy through oxidative metabolism—the rate of oxidative metabolism should be reduced. This, in turn, should reduce the levels of oxidative stress in the cells. And since oxidative stress is strongly implicated in many degenerative diseases, and in the aging process itself, the organism should remain healthier and live longer—which it does.

The only problem with this explanation is that it appears not to be correct. According to the Italian authors of a newly published study, prior research has shown that oxidative metabolism is increased, not decreased, in calorically restricted mammals.3 This is accompanied by an increase in mitochondrial biogenesis, i.e., the synthesis of more mitochondria in the organism’s cells—evidence of the important role that energy generation plays in regulating the aging process. The ability to regulate the number of mitochondria, in fact, is seen as crucial for many physiological processes, including embryonic development, physical movement, fat metabolism, and aging.4

Liquor and Longevity

Barroom ditty, author unknown

The horse and mule live thirty years,
And nothing know of wines and beers.
The goat and sheep at twenty die,
And never taste of Scotch or rye.
The cow drinks water by the ton,
And at eighteen is mostly done.
The dog at fifteen cashes in,
Without the aid of rum or gin.
The cat in milk and water soaks,
And then in twelve short years it croaks.
The modest, sober, bone-dry hen
Lays eggs for nogs, then dies at ten.
All animals are strictly dry;
They sinless live and swiftly die.
But sinful, ginful, rum-soaked men
Survive for threescore years and ten.
And some of them, a very few,
Stay pickled till they’re ninety-two.
So if you’d like to test your fate,
Let’s drink and try for ninety-eight!

Nitric Oxide (from Arginine) Enters the Picture

The Italian group’s own research with mice has shown that CR promotes mitochondrial biogenesis via the action of nitric oxide (NO). This biologically important molecule is produced in our bodies from arginine, a food amino acid that can also be taken as a nutritional supplement. NO is best known for its role in reducing blood pressure by acting as a vasodilator, thereby regulating the flow of blood to our tissues. It thus also regulates the supply of oxygen and other nutrients to our mitochondria; in fact, NO regulates the chemical binding and release of oxygen from the hemoglobin molecules in our red blood cells.4

Caloric restriction, by the way, increases our NO levels by inducing the expression (i.e., stimulating the action) of the gene that codes for an enzyme called endothelial nitric oxide synthase (eNOS).3 This enzyme catalyzes the body’s synthesis of NO from arginine.

NO Connection with Longevity Gene

It has also been known for several years that CR induces the expression of a gene that regulates longevity in a wide variety of organisms, from yeasts to rodents. If this gene (which is called by different variations on the name Sir2) is overexpressed, thereby increasing the levels of the protein, Sir2p, for which it codes, lifespan is increased. Conversely, if Sir2 is underexpressed, the levels of Sir2p are decreased, and so is lifespan. [A vital cofactor for Sir2p is NAD (nicotinamide adenine dinucleotide), which is derived from nicotinamide, a common form of niacin, or vitamin B3. For more on this subject, see “Nicotinamide Induces Rejuvenation in Human Cells” and “Can NAD Help Extend Human Lifespan?” in the June and July 2002 issues, respectively.]

The Italian researchers found that the expression of SIRT1 (the mammalian version of Sir2) was enhanced in many tissues of calorically restricted mice compared with those of mice that were allowed to eat at will. Increased SIRT1 activity induces fat loss, which is known to have a beneficial effect on longevity. The researchers attributed not just mitochondrial biogenesis but also the overexpression of SIRT1 in the mice to the action of NO. In their words, “. . . nitric oxide plays a fundamental role in the processes induced by calorie restriction and may be involved in the extension of life span in mammals.”

What About Us Humans?

All this would be of scientific interest only, but for one thing: we humans are mammals too. Not only do we have the SIRT1 gene, but there is good reason to believe that what it does for a vast range of lower organisms—increase longevity—it could do for us as well. The trick is to figure out how to accomplish this without having to endure the draconian deprivation of caloric restriction. At present, there is no viable way of doing it, but it’s tantalizing to know that such a simple compound as nitric oxide, derived from arginine, plays such an important role in the CR process.*

*Another compound of great interest to longevity researchers is resveratrol, the red-wine polyphenol best known for its healthful effects on cardiovascular function. It turns out that this compound dramatically increases the lifespans of various lower organisms, apparently through its effect on the Sir2 gene or the Sir2p protein. (See “Resveratrol May Be a Longevity Molecule” in the November 2003 issue.)

We’ll close with a quotation from a paper published three years ago by a Cambridge University biochemist:4

If NO indeed regulates mitochondrial number in human skeletal muscle, it might be possible to stimulate production of mitochondria in muscles with drugs or gene therapy, in order to increase sports performance, reduce obesity, or even reverse aging. . . . we now know that low levels of NO produced by eNOS can stimulate aerobic metabolism by increasing blood perfusion, unloading oxygen from hemoglobin, inducing growth of new blood vessels, and stimulating the biogenesis of mitochondria.


  1. Pauling L. How to Live Longer and Feel Better. W. H. Freeman and Co., San Francisco, 1986.
  2. Nikolich-Zugich J, Messaoudi I. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol 2005;40:884-93.
  3. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005;310:314-7.
  4. Brown GC. NO says yes to mitochondria. Science 2003;299:838-9.

Getting the Benefits of Arginine

For those who desire the myriad health benefits of arginine, Life Enhancement recommends taking this amino acid—the body’s precursor molecule to nitric oxide—in the form of a drink mix that also contains the antioxidant vitamins C and E, as well as choline (a precursor to the neurotransmitter acetylcholine) and its cofactor pantothenic acid (vitamin B5), which help to potentiate some of arginine’s biological effects.

The generally recommended serving sizes for maximum benefit are 18 g/day of arginine for men and 12 g/day for women, preferably taken all at once on an empty stomach, about an hour before exercise or athletics or sexual activity, or at bedtime. This optimizes the release of growth hormone by the pituitary gland, which is stimulated by arginine, and provides NO-mediated vasodilation when it is most needed.

For supporting proper cardiovascular function, it’s preferable to take half the maximum amount of arginine and to divide the daily serving into three portions of 3 g (for men) or 2 g (for women) each. The totals are then 9 g/day for men and 6 g/day for women. It’s best to drink the three portions at midmorning, midafternoon, and bedtime so as to avoid conflict with protein-containing meals.

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

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