At the present time, the only scientifically verifiable (reproducible) way to extend life span is through sustained caloric restriction. This has been known since 1934, following McKay’s landmark research, and has been repeated many times in other laboratories throughout the world. However, these studies have only been successfully conducted using laboratory animals (not human), in highly controlled environmental conditions.
The phrase "undernutrition without malnutrition" has been used to describe these studies of caloric restriction using 40% less than the animal controls, who are allowed to feed without restriction. Undernutrition is prevented by compensating these experimental animals with nutrient supplements. These consist of high levels of antioxidants, far more than are obtainable in an ordinary diet. In fact, if these quantities of antioxidant nutrient supplements were given in comparable amounts to humans, they would be the equivalent to the nutrients you would receive in a 20,000 calorie per day diet!
The irony is that these same type of studies have never been conducted in humans over any significant period of time to discern any measurable results. It is estimated that a study period of 30 years would be necessary. And, it would be a very difficult study to complete. It is not realistic to expect ordinary humans to accept that level of chronic hunger. After all, the laboratory animals have to be kept in separate cages to keep them from eating each other!
Biomarkers of Caloric Restriction May Predict Longevity in Humans
As stated above, the most robust intervention for slowing aging and maintaining health and function in animals is dietary caloric restriction (CR). (Weindruch, Walford; 1988). Although most studies of this phenomenon have been conducted in rodents and lower animals, data accumulating from rhesus monkeys suggest that CR may also be relevant for primates, including humans. These findings include CR-induced attenuation of age change in plasma triglycerides (Lane, Black, Ingram, Roth, 1998,) and melantonin (Roth, et al, 2001) as well as oxidative damage (Zainal, et al., 2000) and glucose tolerance (Lane et al., 1995). Current mortality data from ongoing studies, although not yet statistically significant, reveal that mortality in CR monkeys is about half of that observed in controls (15% compared with 24%, respectively) (Roth, 2002).
Moreover, because it has already been demonstrated that two of the most robust biomarkers of CR in rodents, reduced body temperature and plasma insulin, also occur in rhesus monkeys on CR, it became important to assess their association with human survival. CR also slows the rate of decline in human serum dehydroepiandrosterone sulfate (DHEA-S) such that restricted (CR) monkeys maintain more youthful levels of this adrenal steroid. DHEA-S, which declines in both rhesus monkeys and humans during normal aging, may be important in health maintenance and may serve as another potential longevity marker (Kalimi, Regelson, 1999). All three biomarkers indicate that CR causes a fundamental shift in metabolic processes.
Roth, et al, examined the effects of the DHEAS study of men from the Baltimore Longitudinal Study on Aging (BLSA). Only individuals surviving at least 3 years were followed. Subjects’ age ranged from 19 to 95.
The effects of the corresponding markers were compared. Consistent with the beneficial effects of CR on aging and lifespan in other animals, men with lower temperature and insulin, and those maintaining higher DHEAS levels had greater survival than did the non-survivors. The BLSA men were not on CR. However, whatever environmental or genetic factors result in CR-like effects on physiological markers examined here would appear to be related to longevity and, therefore, worthy of further investigation. Moreover, the fact that monkeys on CR exhibit reduced insulin, body temperature, and decline in DHEAS further supports the likelihood that this nutritional treatment will enhance survival in primates. (Science. Vol 297; 2002:811).
Is There a Longevity Gene?
Aging and life-span are still poorly understood aspects of basic biology, although it is widely accepted that genetic factors play a role. To identify specific genes that influence life-span, many researchers have turned to model organisms such as yeast, worms and flies. Preliminary data from a team of investigators at the University of Connecticut Health Center, (Rogina, et al. Science Volume 290, pg. 2137. 15 Dec 2000), have found that altered expression of a single gene in the fruit fly Drosophila nearly doubles the life-span of the flies without adverse effects on fertility, or physical activity such as flying.
The protein encoded by this gene, called Indy for "I’m not dead yet," transports and recycles metabolic products. It resembles a sodium dicarboxylate cotransporter, a membrane protein found in many organisms from bacteria to mammals, including humans. In mammals, dicarboxylate cotransporters show up in cells in the digestive tract, placenta, liver, kidney, and brain, where they transport metabolic intermediates across the cell membrane. It is active in fat bodies…which function as the liver in insects…the midgut, and in cells called oenocytes, which appear to store glycogen and be involved in metabolism. It is hypothesized that this gene is "altering the nutrients , either their utilization or absorption, or making intermediate metabolism slightly less efficient…"either way, it may be the genetic equivalent of caloric restriction."
If this gene could be combined with one that alters oxydative stress, another reputed cause of aging, and if the flies then lived even longer, it would suggest that there are, in fact, many routes for intervention in the aging process.
Despite all the enthusiasm, researchers in aging know that much work remains. Sensible people know better than to believe in pills that promise perpetual youth; or weight loss without dieting. Researchers have not studied cotransporters extensively in humans, except those in the kidney. So exactly how they work in, say the gut of humans, or flies remains unclear. Researchers must also find out how the protein works in different mutant strains.
But, the future is hopeful. The Indy protein’s location and nature suggest that eventually, "it may be possible to design a drug that can extend life. The drug may very well work with weight control, too." And that sounds like a chance even sensible people might be willing to take.
Engineered Negligible Senescence, a Strategy for Reversing, Not Merely Retarding, the Degenerative Effects of Aging
An aspect of biogerontology research that has been dangerously neglected during the recent spate of interest in genome-related breakthroughs, is the active reversal of various aspects of age related degeneration. This is more-or-less by definition, an area that cannot be informed by comparative analyses between organisms with different rates of aging, which is the focus of micro-array and related studies. I do not belittle the value of comparative work, but I feel that far more attention needs to be drawn to ongoing research with the potential to influence human life histories more dramatically than anything based purely on emulating other organisms.
The term "negligible senescence," defined in 1990 by Finch, describes the life history of organisms whose risk of death does not measurably rise as they get older, but remains the same as when they reach adulthood. Thus, "engineered negligible senescence" means restoring and maintaining, by biotechnological intervention, the health (and consequent resistance to life-threatening diseases) that we possessed in early adulthood.
I regard Engineered Negligible Senescence as the true objective of biogerontology research. This is in contrast to the view of many gerontologists, who prefer to stress "successful aging" as their goal. "Successful aging" means extending healthy life (health-span) so that the period of ill health at the end of life (frailty-span) is very short, but without substantially increasing maximum total lifespan, which they consider to be totally unrealistic. My view is that not only is extending maximum lifestyle realistic, it is the only realistic way to shorten frailty-span much beyond present levels, because it entails health-span (and thus postponing frailty) indefinitely.