Responses

Question of the Week:

December 15, 2002

Response to the Scientific American article “No Truth to the Fountain of Youth.”[1]

In the June 2002 issue of Scientific American magazine, 51 prominent scientists who study aging issued the following statement:

. . . no currently marketed intervention—none—has yet been proved to slow, stop or reverse human aging, and some can be downright dangerous . . .

This article received a great deal of press coverage and generated much controversy about the legitimacy of anti-aging medicine. Therefore, as physicians practicing in one of the “longevity clinics” at which this group of scientists has taken aim, we believe it is incumbent upon us to explain why we think this assertion and a number of others in the article are mistaken or at the very least miss the point.

The best way to approach this is to distill their argument down to its basic elements and then examine each carefully. In essence, the argument goes as follows:

Aging is the process through which random damage to essential molecules in the cells of living organisms accumulates making them more vulnerable to dysfunction, disease, and ultimately death.
This process contributes to but is not synonymous with the diseases of aging.
Therefore, even if an intervention retards the appearance of these diseases (such as heart disease, cancer, or dementia), it cannot automatically be said to have slowed the aging process; therefore, it cannot claim to be ‘anti-aging.’
While we have learned a great deal about this fundamental aging process recently, we have not yet devised a test which accurately measures the rate at which this process occurs—what is called a ‘biomarker’ of aging.
Without the existence of a validated biomarker of aging, no one can prove that any intervention slows, stops, or reverses the aging process.
Thus, anyone “purporting to offer an anti-aging product today is either mistaken or lying.”
Not only is there no evidence supporting the efficacy of these interventions, some can also be dangerous.

By addressing each of these points individually, we shall show that his argument relies upon a sleight of hand in which the term ‘aging’ is very narrowly defined so as to refute the existence of any legitimate ‘anti-aging’ therapies. The term ‘anti-aging’ as we define it, and as most of the public thinks of it, assumes a very different definition of ‘aging’ which we will describe below. Under this definition, there is considerable evidence for the existence of anti-aging therapies as distinct from therapies aimed solely at disease prevention. We will present a few examples of such therapies. Finally, it is unfortunate that the authors are not as exacting about the evidence when it comes to their assertion that some of the anti-aging therapies can be dangerous. The last section of this article will debunk this assertion.

What one means by ‘aging’ makes all the difference: points 1-3.

Olshansky, Hayflick, and Carnes in the synopsis of the statement propose that in order to discuss aging and putative anti-aging therapies, one must first clarify the definitions of one’s terms. We wholeheartedly agree. They propose the following definition of aging.

. . . the accumulation of random damage to the building blocks of life—especially to DNA, certain proteins, carbohydrates and lipids (fats)—that begins early in life and eventually exceeds the body’s self-repair capabilities. This damage gradually impairs the functioning of cells, tissues, organs and organ systems, thereby increasing vulnerability to disease and giving rise to the characteristic manifestations of aging, such as a loss of muscle and bone mass, a decline in reaction time, compromised hearing and vision, and reduced elasticity of the skin. (p. 93)

We think it is important to note that this is actually two definitions, not one.

The first sentence represents what we call the strict molecular definition of aging. With the passage of time, molecules—proteins, fats, and DNA—in the cells of any living organism will accumulate damage from free radicals generated by the metabolic processes that support life. When Olshansky et al use the phrase ‘the fundamental process of aging’ they are referring to this strict definition. The reader should notice that under this definition, aging is essentially synonymous with living. As long as a cell burns fuel to live, free radicals will be generated, damage to its molecules will result, and aging will occur.

If one strictly adheres to this definition, there are only two ways to slow the aging process: decrease the production of damaging radicals, or lessen the damage these radicals do to the cells’ molecules. To decrease the production of damaging radicals, a cell’s metabolism must slow, or it must burn fuel more efficiently. To lessen damage, the cell must have improved antioxidant systems to neutralize the free radical before they can inflict damage, or have improved molecular repair systems. In other words, the cell can make less of a mess, or it can clean it up better.

To stop the aging process completely, organisms must halt all metabolism, i.e., freeze life, or continuously and completely repair all the damage. As it turns out, completely stopping the aging process is an option only available to single cells or very simple organisms. They can dry up or be frozen (often by scientists who want to preserve them for future experiments). While in this non-living state, cells do not age. Once watered or thawed, life and the aging process continues. Unicellular organisms can also stop the aging process by dividing into two cells. When cells divide, they purge themselves of damage, and are in a sense, reborn as two pristine cells. For this reason unicellular or very simple organisms are not thought to age significantly.

Complex organisms like ourselves, in contrast, are composed of aggregations of interdependent cells, some of which divide frequently, others of which rarely or never divide. Some cells, particularly those of the nervous and endocrine (hormone producing) systems, are responsible for orchestrating the interactions among the rest of the cells of the body. If these master conductor cells age more rapidly than others, then their signals can become confused and cause dysfunction in the other tissues that might not otherwise occur based on the rate of accumulation of damage to the molecules of the target cells. This is a form of the aging process that is superimposed on the fundamental, or strict molecular, aging process.

In order to stop aging completely, we would need systems that completely repair damage to these cells (or clone ourselves, the equivalent of unicellular division mentioned above). But such perfect systems would be unlikely to evolve because they are metabolically expensive and would confer very little evolutionary selective advantage. As Olshansky et al point out, complex organisms only need repair systems effective enough to ensure that the DNA of the their reproductive cells gets transferred to the next generation relatively unscathed. We are designed, therefore, to have a metabolic rate and repair systems adequate to keep us healthy up until peak reproductive age; after this age, Mother Nature, i.e. natural selection, loses interest in keeping us optimally functioning and disease-free.

If, as in the second sentence of Olshansky et al’s definition, aging is defined as the process that decreases organ function and increases vulnerability to death, then between conception and peak reproductive age, most species, including humans, do not age significantly. During this period they are developing, not aging, gaining greater resistance to environmental stresses in anticipation of competing for reproductive opportunities. To be sure, the strict molecular process of aging continues from conception onward, but not enough damage accumulates to compromise organ function. The second sentence, then, defines the process of aging that occurs after peak reproductive age in complex multicellular organisms.

These are the changes in organ systems that occur even in the absence of disease, and gradually increase the likelihood of disease and death. We call this the clinical-organismal definition of aging. It also happens to be much more in tune with what most people mean when they talk about aging. The changes that occur during clinical-organismal aging often occur in the absence of disease and are manifested by reduced function and altered structure that has not yet reached the threshold of disease.

The disagreement we have with the authors stems from their conflation of these two definitions to support their claim that no medicine or intervention has been shown to retard or reverse the aging process. While we agree that there is scant evidence for an intervention that meets the criterion of stopping the strict molecular definition of the aging process (although a few are on the horizon), we don’t think that this is the relevant criterion. This does not mean, however, that there are no interventions currently available that can retard or reverse aging under the clinical-organismal definition. When we talk about anti-aging medicine and the interventions it offers, we are employing this clinical definition. Before we present some of the evidence for medicines or interventions that we believe meet this criterion, let us turn to points 4 and 5, the ‘biomarker’ argument.

Biomarkers and anti-aging medicine: points 4-6.

Olshansky et al try to bolster their assertion that “anyone who claims that they can stop or reverse the aging process is lying” by noting that, despite a great deal of effort on the part of the National Institutes on Aging (NIA), no single test that can measure the aging process has been developed and therefore no intervention or medicine can be proven to work. Here again, Olshansky et al are using a definition of ‘biomarker’ that is quite strict, and one which they well know generates significant controversy among gerontologists.[2] This strict definition defines a biomarker as a test that can predict the life expectancy of an organism.

It assumes that there is an as yet undefined single process the rate of which when measured at middle age will tell us how much longer an animal or human has to live. Many do not believe than any such test will ever be developed because they do not believe that there is a fundamental process of aging that has the same rate in all tissues and organs of complex multicellular organisms like humans.[3]

We think that a more useful definition of a biomarker can be derived from the clinical-organismal definition of aging. It is a test that measures the degree of decline in structure and function of an organ system from the level found at peak reproductive age, the time at which the organ is optimally functioning. There are many tests of organ structure and function that demonstrate a decline with age in the absence of disease. Under this definition, if an intervention brings the organ system closer to its functioning at peak reproductive age, then it can be said to reverse the aging process. In the following section, we will present just a small portion of the evidence for such tests and interventions.

Arterial Compliance and aging

William Osler, the father of modern medicine said, “man is as old as his arteries,” presaging the rise of studies documenting the changes in the cardiovascular system with age in the absence of disease. While it is certainly true that the number one risk factor for heart attacks and stroke is age, many studies have shown that even in the absence of clinical cardiovascular disease, there is a decrease in the elasticity of the main arteries of the body ( called arterial compliance) and an increase in the thickness of the lining of these arteries.[4-6]

In fact, arterial compliance is one of the best biomarkers of aging available today.[7, 8] These changes compromise the functioning of the cardiovascular system and are correlated with the well-documented decline in maximal exercise capacity and oxygen uptake that occur with aging in the absence of disease.

Is it true that no antioxidant has ever been shown to alter the aging process? Not if you accept that arterial compliance is a reasonable measure of aging. A recent randomized, placebo-controlled study by Mottram et al demonstrated that Vitamin E improves arterial compliance in middle-aged, disease-free, men and women by 40%.[9] Under a clinical-organismal definition of aging, this is an anti-aging intervention that is effective and safe. Moreover, if estrogen replacement therapy (ERT) is discontinued, a woman’s arterial compliance will likely be reduced, i.e., correlate more closely with that of a woman of older age not on ERT.[10, 11]

Body composition and aging

Many studies have demonstrated a decline in body composition with aging. For example, The Baltimore Longitudinal Study of Aging demonstrated that lean body mass and bone mineral density declines, and fat mass increases with age.[12]

Other studies have documented a decline in testosterone and growth hormone with aging.[13-17] These phenomena are related and replacement therapy with growth hormone and testosterone has reversed this decline body composition in men[18-20] and women.[21] Skin thickness decreases in men and women with age, even in areas unexposed to sun[22], and estradiol has been shown to increase skin elasticity in women.[23]

What effect does exercise have on the aging process? Can we do better?

Regular exercise is very important for maintaining health as we age. Our arteries are healthier, our body composition is better, and we have a lower incidence of diseases. However, exercise alone, even that on the level of master athletes cannot stave off the decline in our maximum oxygen uptake that time erodes away.[24] In fact, it seems that the process occurs at the same rate as in sedentary individuals. Perhaps this in part is due to the blunted growth hormone secretion response to exercise that occurs with age.[25, 26] Moreover, growth hormone replacement therapy with and without sex steroids has been shown to increase VO2 max in elderly men and women.[27]

Immune system functioning and aging

It is generally accepted that immune system function declines with even healthy aging.[28] The decline is in part responsible for the increased incidence of severe infections and clinically apparent tumors. T-cell function is most affected by age, and within this compartment of the immune system it is the ratio of naïve T-cells to memory T-cells that seems to decline most inexorably.[29, 30] Naïve T-cells are able to respond to novel infectious agents and tumor growth, whereas memory T-cells are already programmed to respond only to a particular agent they encountered in the past. Thus, an older person’s ability to respond to new infectious agents or tumor growth is compromised as is his or her response to vaccination.

Can any these age-related changes be reversed? Meydani et al have shown that vitamin E in higher doses than currently recommended in the RDA can significantly increase the response to vaccination in older subjects.[31] Similarly, pycnogenol, a potent antioxidant extracted from the bark of the maritime pine, can improve T and B-cell function in mice with bred to age rapidly.[32] Khorram et al have demonstrated that growth hormone releasing hormone can rejuvenate immune system function in the elderly.[33]

These are just a few examples of validated therapies to reverse the effects of aging and demonstrate that there are indeed effective anti-aging treatments.

What rodents tell us about growth hormone and aging: points 6 and 7.

Can growth hormone replacement actually cause the opposite of the intended effect? The authors suggest that the use of growth hormone in humans to retard the aging process may be deleterious based on recent studies done in rodents.

They come to this conclusion based on two sets of experimental data: studies with transgenic mice that under produce growth hormone and have increased longevity;[34, 35]studies with transgenic mice that are genetically engineered to overproduce growth hormone and have decreased longevity.[36, 37]

The authors omit important details about these models of aging. These strains of mice either over or under produce growth hormone from a very early age and therefore grow to very different sizes. The mice that have almost no expression of growth hormone are called ‘Dwarf mice’ for a reason: they are about a third to half the size of their normal counterparts. The mice that have very high levels of growth hormone from birth become giants, reaching on average twice the size of normal mice. These models, therefore, are not very helpful in determining if taking growth hormone from middle age onward, i.e., replacement therapy, helps to retard some of the manifestations of aging in normal healthy mice or human adults. Nor is it reasonable to conclude from these models, as the authors do, that taking growth hormone may “be dangerous.”

In fact, one doesn’t even need these mice models to know what happens when humans produce too much or too little GH. There are human disease states that already tell us what happens in these conditions. Unlike their mouse counterparts, humans born with low levels of GH (or even those who acquire the deficiency later in life) have decreased life expectancy, primarily because of increased cardiovascular disease. Children who develop a benign tumor of the pituitary that causes them to have extremely high levels of growth hormone become giants (e.g., Andre the giant of wrestling fame, or Jaws of James Bond film fame) and also have reduced life expectancy. The deleterious nature of these extremes of growth hormone production during development are not in question, but to suggest that these models should give one pause about GH replacement in middle age flies in the face of the facts.

Is there an experimental evidence in rodents that is relevant to this question? The answer is a definite ‘yes;’ why it is not mentioned by the authors, when it is more germane to the issue of anti-aging medicine certainly raises suspicion about the motives of the authors in selectively citing the available evidence.

Research they have neglected to mention includes the following. Khansari et al administered GH in physiologic replacement doses to middle age mice for the duration of their lives; they found an improvement in immune system function and found that after 13 weeks of treatment 61% of the placebo treated mice were dead compared with only 7% of the GH treated group.[38] This is fairly direct evidence of a relevant anti-aging effect. Other beneficial effects of physiologic replacement doses of GH on the aging process have been demonstrated recently. Banu et al found that GH reversed more than exercise the age-related decrease in bone density in rats, and that caloric restriction had mostly negative effects on bone density.[39] Other studies have found that if long-term GH replacement does not always increase the lifespan of rodents, it certainly is not deleterious.[40] French et al demonstrated that growth hormone administered to aging rats reverses age-associated changes in thymus and bone marrow architecture and function.[41] In fact, the authors unequivocally state:

“This age-associated decline in bone marrow leukocytes, as well as the increase in bone marrow adipocytes, was significantly reversed by in vivo treatment with GH.” This would appear to be a significant anti-aging effect.

Other indirect evidence of GH’s beneficial effect in aging rodents is growing. The ability to quantify the changes in gene expression of many tissues has enabled researcher s to compare the gene expression of an aging tissue with that of a young, healthy tissue. Tollet-Egnell et al have shown that growth hormone reverses many of the changes in gene expression that occur in the livers of aging rats.[42]

Where does the truth lie?

If one accepts the strict molecular definition of aging, then almost by definition one will believe that there are no effective anti-aging therapies. But if one defines aging, as do most of us, with the clinical-organismal definition, then the truth is that there are many therapies scientifically proven to at least slow, and in some cases reverse, the changes in the function and structure of aging human bodies.

Anti-aging medicine is the young clinical discipline that applies these therapies to treat the particular manifestations of the aging process in each unique patient. The evidence for the success of these interventions grows every day.

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