March 13, 2003
Stephen L. DeFelice, M.D.
The Rationale and Clinical Approach
It is now possible to make dramatic progress in altering the aging process. Convincing clinical and laboratory studies indicate that: the aging process in humans and animals can be either slowed down or reversed; partial starvation has prolonged the lives of experimental animals; a combination of l-acetylcarnitine and alpha lipoic acid reverted very old rats to middle-age status; the use of growth hormones has reversed the fat/muscle ratio in elderly humans with ratios returning to levels found in younger people.
Other substances have also been clinically shown to reverse some aspects of aging. Yet the historic lack of interest in pursuing research on the aging process persists by all major parties in the medical-scientific community. It is no longer a question of whether or not aging can be reversed. The question we need to ask ourselves is, “Why aren’t we doing as much as we can in this area?”
The solution? Two steps must be taken before the anti-aging journey begins. First, there must be a national awareness of the nature of the anti-aging effort and what must be done. Second, we must be willing to modify the cultural values and regulatory policies that now prevent us from accomplishing this objective.
This is a complex matter. Let’s take a look at some of the issues involved in our present situation.
Ageing as a Disease Process
It is time that modern medicine accepted the concept that aging is an ongoing disease process with a one hundred percent mortality. Aging leads to multiple body organ and systemic failure, ranging from heart disease and Alzheimer’s to an impaired immune system that can lead to various types of cancer and infections.
Whether anyone actually dies of the disease “Old Age” has not yet been determined. Why? For the simple reason that “old age” has not been scientifically defined. Despite the lack of a precise definition, old age can be clinically determined simply by observing an aging person’s inexorable loss of energy and shrinking body mass.
It has always been assumed that aging is a natural, inevitable process that could not and should not be tampered with. “It’s natural and not a disease,” goes the saying, “and it cannot be treated.” Some even believe that it is morally wrong to do soÃ³and their numbers are not few. This worldwide cultural mindset has long been, and continues to be, the major culprit blocking any national anti-aging initiative.
Fortunately, within the past decade or so, U. S. physicians and scientists are beginning to open up their minds based on the aforementioned and other studies. Conceptually, the aging process now can be considered as a multi-factorial process with many abnormal events going on. Aging, by the way, is conceptually similar to the growth of an infant. As with aging, infant development is a multi-factorial process in which many biologic systems are involved.
Ageing and Genes
Though it may be wishful thinking, there could exist either a single anti-aging or aging-gene. Medical science could discover ways to influence them medically to retard or turn back the hands of time. On the assumption that one or both such genes exist, it would still take a very long time to find and prove that either gene can be manipulated in a manner that will prolong human life. In our present system, it would take decades to do the clinical studies required to finally obtain FDA approval.
Because it seems logical to conclude that aging is multi-factorial, it is then equally logical to believe that the attack against aging should also be multi-factorial. A multi-factorial combination of medical weaponÃ³such as pharmaceuticals, nutraceuticals (e.g., dietary supplements or fortified foods), medical devices, transplantation and other weapons could prevent or correct the physical processes that are taking us prematurely to the “Beyond”.
Unfortunately, in modern academic and powerful government circles, the concept of using mixtures continues to have an image of “guru- ism” and illegitimacy. The complex origins of this prejudice lie in the cultural-regulatory dynamics of the mid-twentieth century. For these reasons, the use of combination therapies to attack disease, let alone aging, has been effectively blocked.
However, we seemed to have forgotten or ignore the fact that children grow and maintain their health by eating a meal, the most miraculous nutraceutical combination in the world. Good meals keep us alive and fuel the multi-factorial process of healthy physical and mental growth. Of course, in addition to nutraceutical combinations, children also need vaccines, antibiotics, surgery and other treatments to maintain their healthy growth all of which, in a real sense, are part of the combined and broad medical therapy. And what doctors do not employ multiple modes of therapy in their patients?
The Inhibiting Impact of FDA Policies
The FDA has a policy that each single medical weapon, and all possible combinations of total combination treatments, must be individually tested and compared. This is simply absurd. If one were to study all of the ingredients of all possible combinations of a 20-product anti-aging formula, according to current FDA guidelines, it would require 1.23 to the 20th power! If a study had 1,000 patients in each group (a small number for such a study), and the cost was $10,000 per patient, then we can add another seven zeros to this figure. What would the cost then be? A sum greater than the gross national product of the entire world. This is clearly untenable. This fact is also a major reason why we need “Doctornauts.” (See DeFelice Commentary: Doctornauts.)
This one FDA policy alone is a huge barrier to encouraging anti-aging clinical research and must be changed. Such approval should simply be based on the risk/benefit ratio of the total combination approach. If the total beneficial effect of the combination exceeds the bad effects, then this should be the definition of the FDA standard of approval. But FDA does not see it this way and neither does the academic medical community.
The Role of Patents
There is also another powerful, related negative factorÃ³patents! The pharmaceutical industry understandably attempts to discover strongly patented substances in order to obtain sufficient product exclusivity in order to justify the enormous costs to obtain FDA approval for a drug. It would be economic suicide not to do this. Virtually all of the drugs that are approved are single substances and not combination products. This is a huge impediment to the development of the multi-factorial products needed to combat aging as well as disease.
A positive issue related to patents presents itself. If the combination product is active, either in the laboratory or the clinical study, a company can, if certain conditions are met, then obtain a composition patent that sometimes can be sufficiently strong to justify the financial investment needed for the FDA approval. There are other patent opportunities as well as problems, but the overall ability to obtain commercial exclusivity needs to be encouraged.
The Anti-Aging Act
There is an additional way that product exclusivity can be strengthened. Congress, as it did with the successful Orphan Drug Act, can pass the Anti-Aging Act which would grant a company a period of exclusivity to commercialize the combination. Patent or no patent, no commercial competition would be allowed during this period.
It is extremely important to appreciate that the anti-aging combination studies will, almost by definition, fall outside FDA standard clinical guidelines.
The following is an example of one approach under the Anti-Aging Act: A laboratory would look into human aging cells that are losing their energy and on their way to cell death (or apoptosis). Researchers would determine what natural substances are low in concentration. The loss of energy is the hallmark of aging. Perhaps by clinically administering a rational medical combination of low-level substances to replenish the aging cells, the energy of such cells could then be increased. Not only might this combination increase the energy performance of the already weakened cells in the heart, brain and other parts of the body, but also, it might also prolong cellular life span.
In addition, we now know that there are cells in the body that are dormant with the capacity to be awakened and rejuvenated. Further, there are adult stem cells that can be stimulated in the laboratory to produce new youthful cells with specific body functions.
Another conceptual clinical study could evaluate the potential for a combination of growth factorsÃ³such as growth hormone, anti-inflammatory pharmaceuticals and multiple nutraceuticalsÃ³to create normal energy-producing cells. Periodic intravenous administration of certain single natural substances contained in the mixture may be required in order to achieve sufficient blood levels which would permit them to enter the cells and do their job.
How to Measure Success
What will be our measure, clinically? Unfortunately, it is impractical to measure whether a particular combination will prolong human life. This is not yet a generally recognized fact. We must, instead, rely on surrogate markers or measurements that are considered to be medically beneficial. An example of a surrogate marker would be cholesterol. If a substance lowers cholesterol in clinical studies, it is then presumed to have a beneficial effect (surrogate marker). However, we cannot be sure that lowering cholesterol levels with this particular substance prevents heart attacks unless a clinical study is done. The latter is considered a clinical endpoint. With respect to aging, the clinical endpoint would be the prolongation of life.
Regarding mental and emotional clinical effects, a general scale of measurements should be designed to include memory function and feelings of well-being. Regarding physical measurements, cardiac performance and general muscle strength, along with the responsiveness of the immune system, should be evaluated.
Assuming that the combination successfully reverses the aging process, what would be sufficient evidence for the FDA to permit the formulation to be made available to physicians in medical practice?
If the results of preliminary clinical studies are encouraging Ã±which means that the clinical benefit observed exceeds the riskÃ³then long-term studies in large numbers of patients should be initiated to determine if the risk/benefit ratio of the combination is maintained. If it is maintained, then the product should be made available to physicians for use in the appropriate populations. However, there is also an obligation to continue with post-marketing studies for a specified period of time. If the combination is given to the very old population, then these post- marketing studies can last for a lifetime.
Specific clinical guidelines for anti-aging combinations are not feasible and should be structured on a case-by-case basis.
What About the Bad Effects?
We must, of course, constantly be on the alert for the adverse effects or toxicity of any therapy for any condition. They inevitably occur to one degree or another and, therefore, the volunteer patient must be closely monitored. But there is an important caveat. We must be careful not to be in a hurry to attribute such unwanted side effects to the therapy itself. Many such events can occur in the natural process of aging itself. Practically all of the aging volunteers will have accompanying diseases (e.g., depression, memory loss, sexual dysfunction, arthritis, heart disease, diabetes and cancer). These conditions will normally worsen with the passing of time.
In our present cultural mentality, if one volunteer should die during a clinical study, even of natural causes, we can expect to see a national, media-driven uproar resulting in the cancellation of the study and probably other similar ongoing ones. (See DeFelice Commentary: Doctornauts) There is no avoiding this and no amount of legal or ethical efforts, when it comes to clinical research, can change our risk-averse cultural mentality.
To sum it up: Our cultural risk- averse mentality, the corporate and personal physician costs and risks, the difficulty in obtaining strong patents, coupled with the federal policy that an investigator must test every substance and all possible combinations of substances in the combination therapy in a clinical study, effectively close the door to a robust and productive anti-aging effort. To make matters worse, I have not met a single soul that is aware of this sad, truly tragic reality.
When I behold an elderly man who is stooped, walks slowly and carries a cane, and whose condition will inexorably worsen from week to week, I am reminded of what the great poet Yeats wrote, ” An old man is a paltry thing.” I say to myself, “This need not be. We presently have the medical technology that can permit him to throw his cane away.”
What then is the solution? Paraphrasing President Reagan’s famous words, “Here I go again!” To begin with one answer comes to mind that will permit the others previously mentioned to be effective: Congress must enact the Doctornaut Act, which will permit physicians to volunteer for clinical studies under conditions of significantly reduced costs or risks to the institutions involved in the studies. I can see no effective alternative.
Without a Doctornaut Act, we must all resign ourselves to the inevitable trials and tribulations of old age and the cane market will continue to grow. ButÃ³we will not let this happen. There must, and will be, a Doctornaut Act for the benefit for all Americans and their posterity.