Do You Want to Grow Older? Insulin Sensitivity May
Be a Key to Longevity
In which a smart cookie explains some of the
facts of long life to her one-track-mind friend
By Hyla Cass, M.D.
he scene: A medical research laboratory at Southern Illinois University School of Medicine, in Springfield. The time: One day in 2005; it’s late evening, after the researchers have gone home, or wherever it is they go after they’ve finished whatever it is they do all day. It’s quiet, except for occasional rustling and squeaking sounds (the lab is filled with mice). A conversation begins between a male mouse and a female mouse.
MM: Hey, Baby, you’re quite a knockout, if you don’t mind my saying so.
FM: Why, thank you—you have a pretty nice genetic defect yourself.
FM: What I mean is, you’re a knockout too.
MM: Oh. You got that right, Cheese—I mean, Sugar. So . . . do you come here often?
FM: I’m in a cage, you doofus, just like you. We both live here, in adjacent cages.
MM: Uh, right . . . I knew that.
FM [to herself]: Why me, Lord?
MM: Speaking of living, I guess it’s OK here for the most part, except for the chow—there’s so little of it. Are those white-coated clowns mean or just stupid? I’m so hungry all the time, I could eat a cat.
FM: Don’t say that word!
MM: Sorry. It’s just that I can’t understand why they don’t give us all the chow we want, like those mice over on the other side of the room. How do they rate?
FM: Well, I happen to understand it. You see, those white-coated clowns, as you call them, are interested in studying the effects of caloric restriction versus ad libitum feeding on longevity in growth hormone-receptor knockout mice—that’s us—because it appears that mutations affecting the somatotropic or insulin signaling pathways play a role, albeit possibly a sexually dimorphic one, in the biology of mammalian aging.
MM: Umm . . . yeah. I knew that too. Hey, about that sexually dimorphic thing—sounds kind of kinky. I love it when you talk like that. By the way, did I mention that you’ve got great paws? I’m a paw man, myself. How about if you stick one of those babies through the wire mesh so I can . . .
FM: Drop dead!
MM: Sheesh! I was just trying to be nice. Anyway, I probably should have croaked a long time ago, but for some reason, I just keep on living. It’s kind of weird …
Growth Hormone Sends the Signal for Growth . . .
That FM was a pretty smart cookie! Just in case you’re not as familiar with the biology of aging as she was, let’s analyze her explanation and then see what those clowns—I mean, researchers—found. First of all, a knockout mouse is one in which a certain gene or set of genes has been made
way, so it can’t exert its normal physiological role via the protein(s) it codes for. What the researchers knocked out in this case was the gene for the growth hormone receptor and the growth hormone-binding protein, the effect of which was to render the growth hormone itself physiologically inactive.
Growth hormone (GH) is a protein produced in the anterior lobe of the pituitary gland. In mice, as in humans, GH regulates growth (surprise!). A deficiency during childhood can cause dwarfism, and an excess can cause gigantism. The production of GH itself is regulated
by other hormones, and its levels are increased by dietary factors and by various stressors, such as low blood sugar, fasting, physical exercise, infection, trauma, and emotional stress. High-protein meals stimulate the production of GH, especially if they’re rich in the amino acid arginine. (As to the apparent paradox of why we need growth hormone even after we reach adulthood, see the sidebar.)
Why Do We Need Growth Hormone?
If you’re reading this, you’re either a precocious child or, more likely, a grownup. So why, if you’re all grown up, does your body need growth hormone? Is it going to make you grow taller? No, but it’s still an important molecule for your overall health and well-being. Let’s see why.
As the name implies, growth hormone (GH) is active—indeed, vital—from birth to adulthood, because it stimulates the growth of our bones and cartilage and increases the size and number of cells in our soft tissues. One might think that GH secretion would cease when we stopped growing—or, to be more logical, that we would stop growing when GH secretion ceased. But GH secretion does not cease—it merely declines, and the focus is shifted somewhat. As old cells die, new ones are created and must grow. Thus, although our bodies stop growing, our cells do not, and they need GH to stay on track.
GH also serves physiological functions other than growth. In fact, it plays a vital role in the metabolism of fat and glucose (blood sugar) throughout the body. (Calling it the growth and fat-and-glucose-metabolism hormone, however, would be a mouthful, so scientists settled for growth hormone.) GH stimulates the breakdown of stored fat molecules (triglycerides) into their constituent fatty acids, which can be used as metabolic fuel by our muscles (including the heart). At the same time, it decreases our muscles’ uptake of glucose, the effect of which is to increase our blood sugar levels—but not to a harmful extent under normal conditions.
The combined effect of these two actions is to mobilize our fat stores as a major fuel source for our muscles, while conserving glucose for tissues that can’t use fatty acids and that therefore depend critically on glucose as a fuel source (the most important such tissue is the brain). This metabolic pattern works well to maintain our physical viability during prolonged fasting or other situations in which our body’s energy needs exceed the normally available supplies of glucose. Fasting causes GH levels to rise.
The age-related decline in GH levels generally leads to a loss of muscle mass and an increase in body fat, i.e., a shift in the muscle/fat ratio. This does not necessarily lead to weight gain, although it can, especially if we compound the problem by overeating and underexercising (as we are wont to do).
For elderly people who are clinically deficient in growth hormone, taking GH (which is available by prescription only) can be beneficial. The hormone is claimed to reverse some effects of aging, reduce body fat, increase muscle mass, and improve physical performance. There is some evidence to support these claims, when GH is administered by injection in pharmacological doses. It can’t be taken orally, because it’s destroyed in the digestive tract, and it can’t be absorbed through the skin or mucous membranes, despite some claims to the contrary.
Some athletes have used GH injections to improve performance, although studies have shown it to be of little value for that purpose—and it’s dangerous to boot. The long-term use of pharmacological amounts of GH entails the risk of numerous side effects, including edema, joint pain, carpal tunnel syndrome, headaches, lethargy, enlarged breasts (in older men), diabetes, and heart failure. It should be undertaken only under the direction of a reputable, competent physician.
Some over-the-counter products claim to have GH-like activity or even to contain small amounts of the hormone itself. These products, however, are highly unlikely to have any effect at all, except on your wallet. Caveat emptor.
The term growth hormone is actually a bit of a misnomer, because GH does not promote growth directly. What it does, mainly, is activate growth hormone receptors embedded in the cell walls of liver cells. This initiates a series of chemical reactions (called a signaling pathway) inside those cells, the result of which is the release into the bloodstream of an anabolic hormone called insulinlike growth factor-I (IGF-I).*
IGF-I is called that because it’s structurally and functionally similar to insulin (the functions of these two protein hormones are overlapping but not duplicative) and because it regulates growth, mainly by stimulating the synthesis of proteins in our cells. Excessive levels of IGF-I are harmful and are associated with several types of cancer. Thus, as with insulin, lower levels are generally better, as long as glucose metabolism and cellular growth are being adequately regulated.
. . . And Insulinlike Growth Factor-I Does the Job
The IGF-I molecule is the one that actually stimulates the division and growth of target cells throughout the body. It fulfills this role during our entire lives, reaching peak levels, not surprisingly, during our teen years. In addition to being produced by the liver in response to growth hormone, IGF-I is also produced by many other tissues throughout the body; there, however, it is not released into the bloodstream but is used locally. This process is affected by nutritional status, age, and tissue-specific factors, among others. It can occur either in response to GH or independently of GH, which makes the relationship between GH levels and IGF-I production difficult to understand, let alone predict.
For example, although subnormal nutrient intake or outright fasting increases the release of GH, which would normally be expected to increase IGF-I production, IGF-I levels are decreased instead. Apparently, nutritional deprivation reduces the sensitivity of GH receptors in tissues that produce IGF-I, so the IGF-I levels fall. This has important implications for longevity, as we will see.
Caloric Restriction—Effective but So Unpopular
There is one type of nutritional deprivation that is extremely beneficial to creatures across the vast reaches of the fungal and animal kingdoms, from yeasts to roundworms to fruit flies to mice to (very probably) primates, including humans. Called caloric restriction (CR), it’s a diet that is nutritionally well balanced but that contains about 30% fewer calories, typically, than a normal diet. It’s not a starvation diet, but it’s not pleasant.
In countless laboratory studies, it has been shown that calorically restricted animals are healthier and have dramatically longer lifespans than animals that get as much food as they want (the latter is called ad libitum feeding). The price the CR animals pay for their health and longevity is being hungry enough to eat a cat, or perhaps a horse. For some reason, the idea of CR has not exactly captured the fancy of human beings.
Why Did CR Fail in the Knockout Mice?
In their study, the Illinois researchers used growth hormone-receptor knockout mice. Because their GH is rendered physiologically inactive, these mice have profoundly reduced circulating levels of IGF-I, as well as insulin, which is also affected; they also have numerous signs of delayed aging, and markedly increased lifespan. The researchers subjected groups of these mice, along with groups of genetically normal mice, to a 30% calorically restricted diet; for controls they used knockout and genetically normal mice that were fed ad libitum (AL). The study began when the mice were 2 months old and lasted until they had all died (about 4 years).
As expected, the normal mice on the CR diet lost considerable weight and lived much longer than their AL counterparts—the median increase in longevity was about 25%. The knockout mice (which weighed only half as much as normal mice to begin with because their growth had been stunted) also lost a significant amount of weight, and even without CR (i.e., with AL feeding), their longevity was increased by about as much as that of the CR normal mice. In other words, the mere suppression of GH activity, which suppressed IGF-I and insulin activity, greatly increased their longevity.*
That much had already been known. What was new (and surprising) was that caloric restriction in the knockout mice did not extend their already extended lifespan any further, as had been expected. This was true, at least, when the combined data for the male and female knockout mice were analyzed. When the data were analyzed separately, it turned out that, although there was no effect on maximum longevity in the males, there was a small increase in the females. This is an example of sexual dimorphism, a physiological difference between the two sexes. (With the normal mice, there was no CR-related sexual dimorphism.)
Perhaps Because It Didn’t Improve
What do these results mean, considering that failure to observe life extension in CR mice of any kind is apparently unprecedented? Based on a variety of experimental evidence and theoretical arguments too complicated to discuss here, the authors suggested that the failure of CR to extend lifespan further in the knockout mice was probably due to its inability to improve their insulin sensitivity, a factor that is believed to play a major role in the control of mammalian aging. They concluded,
A broader implication of the present findings is that insulin signaling emerges as an important determinant of mammalian aging and longevity. This implication raises the issue of the potential (and, we believe, likely) impact of insulin-resistant states, including the current “epidemic” of metabolic syndrome, on life expectancy in this society and others.
And in an interview with Reuters Health, the principal author, Dr. Andrzej Bartke, said,
Although it would be irresponsible to recommend that healthy people start using antidiabetic drugs, it is reasonable to suggest that treatment(s) causing an improvement in insulin sensitivity combined with modest reduction in insulin release would reduce risk of age-related disease and likely also delay aging.
A major component of the metabolic syndrome, and a precursor condition to type 2 diabetes, is insulin resistance, the opposite of insulin sensitivity. Among the nutritional supplements believed to help inhibit insulin resistance, the most promising is cinnamon, which contains chemical compounds that have an insulin-mimetic effect, i.e., they mimic the action of insulin in the body. This reduces the body’s need to produce insulin. (For more on this subject, see the
article on page 17 of this issue.)
Something to Smile About
Perhaps, like many other people these days, you have been encouraged to get in touch with your inner child; it can be an enlightening experience. But how about also getting in touch with your “inner mouse”—a calorically restricted inner mouse who’s going to outlive ordinary mice and be healthier all the while? We don’t expect you to go on a CR diet, but dietary supplements might just help you to stay healthier longer—and the longer you stay healthy, the longer you’ll live, probably. Say cheese!
- Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A.
Targeted disruption of growth hormone receptor interferes with the
beneficial actions of calorie restriction. Proc Natl Acad Sci USA 2006;
- Rauscher M. Growth hormone, insulin may be key to longevity.
Reuters Health, May 8, 2006.
Dr. Hyla Cass is a nationally recognized expert in integrative medicine, an assistant clinical professor of psychiatry at the UCLA School of Medicine, and the author or coauthor of several popular books, including Natural Highs: Supplements, Nutrition, and Mind-Body Techniques to Help You Feel Good All the Time and 8 Weeks to Vibrant Health: A Woman’s Take-Charge Program to Correct Imbalances, Reclaim Energy, and Restore Well-Being.