Chemoprevention of Aging: Fact or Fantasy?
By Sarah L. Berga, MD
The inspiration for this topic comes from the many curbside consults I get from physicians repeating questions asked of them by their patients and from my own practice. The generic form of the question is whether some agent, preparation, vitamin, or practice will prevent a given condition and thereby prolong disease-free life. This question has seized the imagination of the public and popular press, in part, because of the flood of legitimate scientific and medical information being generated that addresses, however obliquely, this question. I don’t want to pretend that there are hard and fast answers; the purpose here is to develop a strategy that will allow us to provide a reasonable answer in the office.
It is helpful first to understand that aging is a molecular process of programmed senescence. Each cell type has its own script. Aging per se is not a disease, but aging may make us more vulnerable to diseases as elements of our cellular machinery are turned off and on. The clock for the tightly orchestrated process of aging is thought to be molecular and to reside within each cell. The question, then, is can we alter this endowed molecular process? It seems unlikely that we can do much to this highly scripted process, but the molecular biologists may be able to tell us more in a few years; there remains the possibility that eventually we will be able to influence the script. Until then, the more useful mindset is to understand that aging confers vulnerability; thus, we should look for ways to protect ourselves from these acquired vulnerabilities. I will examine some of what has been suggested and why.
First, as we age, our circadian rhythm changes. Our big clock, the one that synchronizes all the other tiny molecular clocks, is located in the suprachiasmatic nucleus of the hypothalamus. As we age, it becomes less well-entrained by the usual zeitgebers, the strongest of which is the daily light/dark cycle, and the signal it emits weakens or occurs at the wrong time. Thus, as we age, the inputs to the clock need to be bigger and clearer or the output of the clock needs to be buttressed. Since melatonin, the hormone secreted by the pineal gland in response to the ambient light/dark cycle, both helps to keep the suprachiasmatic nucleus on track and is the main signal to the rest of the cells of circadian time, it has been suggested that we should take melatonin. There is some logic behind this suggestion, particularly if it appears that one’s clock isn’t keeping time, but there are no studies done in older populations that concretely support this notion. Such studies should be done. If a pure source of melatonin were available, it might even be reasonable to condone this practice in the absence of good data. Here I must sound a cautionary note, however. Since melatonin is a naturally occurring chemical, it cannot be patented. Pharmaceutical companies are not going to spend the time to produce, test, and distribute a product that they cannot patent. It worries me that the source of melatonin might be bovine pineal glands recovered from slaughterhouses and that the extraction and purification process might not remove the etiologic agent of mad cow disease. I have no doubt that we have the technical capability to make a pure source of melatonin, but I am not aware that we can guarantee that one is currently available. If industry is unlikely to undertake these studies, then we must make sure that they are done in the public domain, such as through the National Institutes of Health.
Second, as we age, the adrenal gland makes less dehydroepiandrosterone (DHEA), the precursor for the main adrenal androgen, dehydroepiandrosterone sulfate. The exact physiological roles of DHEA and DHEA-S are not known, but their appearance in the circulation is developmentally regulated. Increased adrenal androgen secretion occurs around ages 6-8 years and is referred to as adrenarche; adrenarche is responsible for characteristic phenotypic changes, including the appearance of terminal hair and sebaceous secretion that confers body odor. The decline in DHEA and DHEA-S occurs gradually in the absence of a profound illness. The current line of reasoning is that DHEA and DHEA-S must be doing something important, even if we don’t know what it is. If we recommend hormone replacement therapy for meno pause, why not recommend DHEA supplements for the decline in adrenal androgen production? It is hard to argue with that line of reasoning, but it is worth noting that there are no large, long-term studies that demonstrate that taking DHEA will retard the aging process. DHEA is very likely important, but at the present, it is better to view it as a marker of aging than it is to promote it as an agent that can retard aging. It would be hard to get dogmatic about its use, pro or con, however, given the knowledge void. Here again, we should be doing clinical trials, but don’t expect them to be sponsored by industry; DHEA cannot be patented for the same reason that melatonin cannot. I worry, too, that the source of DHEA sold as food supplements might well be bovine adrenals and that the purity of the preparations is not subject to regulation.
Third, as we age, we are thought to be more vulnerable to genomic damage caused by oxygen radicals. Therefore, the logic goes, we should increase our consumption of antioxidants such as vitamin E. The initial data for this suggestion came from epidemiological studies showing that people with higher serum levels of vitamin E had less cancer and heart disease. However, trials were then undertaken in which vitamin E was given as a supplement and no benefit was seen. The interpretation offered is that vitamin E is a marker for high vegetable consumption and that vitamin E is not the important agent. More likely, there are numerous important substances in vegetables and it is unlikely we will be able to identify them all anytime soon. The best strategy is to eat vegetables and to not rely on vitamin supplements.
Fourth, as we age, our gonads secrete less hormone as well as fewer gametes. Obviously, gonadal senescence is more profound in women than in men; hence, we have elaborated a large body of information about the pros and cons of hormone replacement therapy. The point I want to make here is that there are safe replacement products available, the purity of which is known. The medical community has been accused of "medicalizing meno pause" when it promotes the use of these replacement products, but I don’t think this charge is fair. As I have tried to show above, it is a normal psychological urge to seek ways to ameliorate the aging process in the hope of prolonging our disease-free interval. This wish is only neurotic when it becomes an obsession or when one develops unrealistic expectations about the extent to which aging can be retarded. In other words, some vanity is a good thing. Hormone replacement therapy tampers with "mother nature" no more or no less than taking melatonin or DHEA, taking vitamins, altering our diet, taking growth hormone, or embarking on exercise regimens. Wanting to stay healthy is a reasonable attitude, and the use of science to help us achieve that objective is not evil. We need more science, not less, because the urge to take better care of ourselves is an intrinsic attribute of a healthy person and should not be discouraged. When patients ask, I support them in their endeavor to "stay young" and I point out what it is that we know and where we have gaps in our knowledge. I try never to forget to include practices such as smoking and alcohol consumption in my review of what comprises a healthy lifestyle.