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	New research, such as that related to the metabolic stability hypothesis, often casts earlier research in a new light. Several years ago a team led by Bruce Ames, chairman of Juvenon’s Scientific Advisory Board, found that metabolic stability in rats was enhanced by the addition of micronutrients. To see the results of this study, published in the Proceedings of the National Academy of Sciences, click here. "Age-associated mitochondrial oxidative decay" PNAS, February 19, 2002; Vol 99 No 4 This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

By Benjamin V. Treadwell, Ph.D.

Can life span be extended? The optimist answers with a resounding yes, the pessimist an equally intense no, and the realist with "let’s see more data." Over the years, numerous theories have been put forth about the mechanisms involved in the aging process. As described in this month's issue, evidence suggests that a new hypothesis on the mechanisms of aging appears to explain more pieces of the puzzle, but a truly unifying principle remains elusive.

A fresh hypothesis on aging was recently stated by Lloyd Demetrius, a mathematician/ biologist at Harvard. In general, species with higher metabolic rates have the shortest life spans. Demetrius’s hypothesis holds that it is not the stresses of life, such as oxidative stress produced by free radicals, or the relative metabolic rates, that are important in determining life span. He believes the more important issue is metabolic stability, which is defined as the capacity of the networks of cellular metabolic pathways to continue to run smoothly, even during times of stress. This hypothesis has the appearance of a unification theory, since it encompasses other theories of aging rather than opposing them.

Longevity and Metabolic Stability: The Connection

Metabolic stability is dependent on several factors, including capacity to repair damaged cellular machinery, and the innate robustness of individual cellular components, such as enzymes. It also depends on integration of networks of metabolic pathways and their capacity to readjust under varying conditions of stress to maintain a stable steady-state metabolism - like shifting into lower gear on a hill to maintain steady speed. The cell contains numerous biochemical pathways that must be in sync with one another to maintain a constant concentration of metabolites for optimum cellular health. So metabolic stability is the ability of the cell to maintain its cool, even during times of stress.

All Animals Age, but at Different Rates

The metabolic stability hypothesis states that animals with low metabolic stability have short life spans. The mouse, with a 2-3 year life span, is often cited as an example. Compared to humans, with a maximum life span of 120 years, the mouse is 40 times more metabolically unstable. This theory goes on to predict that any method that promotes metabolic stability should have a much greater effect on the mouse, relative to the more metabolically stable human. One established method to increase life span in the mouse is caloric restriction (CR). Of interest, and in support of this theory, is experimental evidence showing that caloric restriction does in fact tend to stabilize metabolic pathways. For example, the insulin signaling pathway for glucose metabolism, and the pathway involved in the production of energy, readjust to a healthy steady-state and generate fewer toxic by-products in animals maintained on a food-restricted diet. The animals are healthier in virtually all respects, experiencing less cancer, vascular disease and other age-associated disorders. The hypothesis predicts that in the more metabolically stable human, CR will have very little effect on longevity, provided the subject is not obese or experiencing diseases associated with excess food intake (heart disease, diabetes, etc.).

Aging and the Accumulation of Cellular Garbage

Ample evidence demonstrates a correlation between the age of a cell and the amount of damaged cellular components it contains. The older the cell, the more stability-impairing garbage it contains. Most of the cellular garbage is the product of damage to cellular constituents (proteins, lipids, RNA/DNA), caused mostly by free radicals released during metabolism, especially during the production of energy in the mitochondria. The radicals react with and distort the active conformation of these cell constituents (supportive of the Free Radical Theory of Aging). In general, the higher metabolic rate of an organism (the metabolic rate of the mouse/gram is 7 times the rate of man), the greater the production of free radicals (supportive of the Metabolic Rate Theory of Aging).

Support for the metabolic stability hypothesis can be appreciated when examining a major flaw in the metabolic rate theory of aging. For example, the bat (a mammal) has a high metabolic rate that is similar to the short-lived shrew, yet it can have a life span as long as 35 years as compared to only 2-3 years for the shrew. Birds also appear to break the rules with respect to metabolic rate. The humming bird has an enormously high metabolic rate yet its life span can be 15 years.

The metabolic stability hypothesis would explain the long life span of the bird and the bat as a consequence of an extraordinary capacity of one or more of their metabolic pathways to maintain metabolic homeostasis, or a steady state. In other words, they rapidly readjust to keep metabolites at a steady constant level, or to use the auto analogy, smooth down-shifting to make it up that hill with constant speed.

An Example of a Metabolic Stabilizer

Although cellular garbage accumulates with age, cells also have anti-garbage defenses. The most important are two cellular machines, the proteosome and the lysosome. The former removes damaged cellular proteins, and the latter largely eliminates oxidized and damaged cellular structures, such as the mitochondria. Caloric restriction has been demonstrated to improve the efficiency of at least one machine, the proteosome. In effect, caloric restriction prevents the accumulation of garbage, thus helping to stabilize cellular metabolism.

Is Metabolic Stability the Answer?

The hypothesis does help explain many aspects of aging, but it too appears to have flaws. For example, experimental evidence supports a gradual decrease in metabolic stability with age. Our cells don’t respond to environmental stresses as well when we age, and as a consequence damage accumulates more rapidly than it did in our youth. So it appears that a steady decrease in metabolic stability occurs with time. Thus the metabolic stabilizer, caloric restriction, may prove to have enormous effects on human health and longevity.

Can Metabolic Stability Be Improved by Lifestyle or Diet?

The hypothesis does not preclude the use of possible methods to increase life span. Demetrius is an optimist at heart! For example, enzymes - proteins with catalytic activity that constitute the metabolic pathways - are notoriously less stable in the absence of metabolites they specifically act on. So by adding enough of the enzyme-specific metabolite (such as taking a supplement containing it), one could stabilize the enzyme, and in effect increase metabolic stability. Furthermore, obesity, the product of an unhealthy diet and/or lifestyle, clearly affects metabolic stability negatively. Restricting the amount of calories one consumes, at least after mid-life when metabolic stability may begin to sharply decline, may have a significant effect on attenuating or perhaps reversing this decline. Exercise, as with caloric restriction, also should improve metabolic stability. Current research in our laboratories is directed toward discovering agents that pep-up our cellular anti-oxidant defense systems, which dramatically decline with age. This too should help promote metabolic stability, and a long healthy life span.