Biomarkers of Aging

The process (processes) of aging is a complex phenomenon. Aging in the biological sense is the loss of the ability to maintain homeostasis, that is, the loss of the ability to meet challenges from the environment, such as heat or cold or infection, by overcoming the challenge and restoring normal function. Loss of homeostatic ability can occur at the level of the whole organism or in one or more of its parts. Organisms of different species age at different rates. Fruit flies live about two months, mice three to four years, chimpanzees perhaps seventy-five years, and humans as long as 120 years. Despite these very big differences in maximum life span, all of these organisms age in the sense described above. A very few, such as bristlecone pines, turtles, and some fish species age very little. Within a species, individuals age at similar but not identical rates.

Given all the variability in rate of aging observed between and within species, how can we compare the aging status of one organism with that of another. Is a two-month-old fruit fly comparable to an eighty-year-old human? Clearly their chronological ages (age in days or years) are vastly different. Their biological ages are perhaps the same! How can we tell? To understand the concept of biological age as something different from chronological age, let us examine the following example. Suppose that after years of slaving away in the laboratory a gerontologist believes he has discovered the magic elixir that will double life span. How could he test this substance to determine that it actually works? If he gives it to a forty-year-old human subject with a life expectancy of eighty-five years, he will have to wait at least 130 years to be sure his elixir doubles life span. Obviously this is not possible, much less practical. What this scientist needs is a measure, or set of measures, that can determine the rate at which an organism is aging in less than the full life span of the organism. He could then measure the rate of aging of his test subject before and after giving the elixir to see if the rate of aging changes in response to this treatment. Such a measure would be called a biomarker of aging.

Biomarkers of aging, then, are measures of the rate at which organisms, or organ systems within an organism, are aging. The assumptions that underlie the concept of biomarkers of aging are that organisms age at different rates and thus chronological age is not a good predictor of remaining life expectancy, that different tissues, organs, and organ systems within an organism may age at different rates, that these differences can be measured and predicted, and finally that it may be possible to alter the rate of aging of any or all of the components of organisms.

From both a theoretical and a practical point of view, it is also assumed that no single biological measure is likely to ever be found that can accurately assess the rate of aging of a complex organism like a human being. It is therefore assumed that panels of biomarkers made up of a variety of measures will have to be constructed in order to assess the rate of aging of such an organism. These panels of biomarkers will likely be made up of measures that assess all or many of the organ systems within the individual, such as the cardiovascular system, the brain, the liver, bones, memory, and so on. Individual biomarkers might decline with age, like fine motor skills, rise, like the number of rings in a tree trunk, or even rise at one point in the life span and fall at another, like hormone levels.

The interrelationships between individual biomarkers within a panel of biomarkers may be important clues to the interactions of various organs and organ systems in determining the life span of individuals. These interactions will very likely be extraordinarily complex and certainly different from one individual to another. Each individual inherits a different set of genes, and these genes encounter different environments due to experiences and lifestyle differences among individuals. Biomarkers that have the greatest generality across individuals will signal important processes for that species. Biomarkers with great generality across species will signal very important processes for all living things. A primary motivation for biomarker research is to find such general characteristics.

While some potential biomarkers might be theoretically very accurate, it may be impossible or unethical to obtain them. Accurately counting the number of remaining functional brain cells, for example, would result in the death of the individual being assessed. Measuring the ability of the individual to recover from some extreme stress like pain or cold would be unethical.

In order for a biomarker of aging to be useful, certain criteria need to be met. These criteria include the following:

1. The rate at which the biomarker itself changes should reflect some measurable parameter that can be predicted at a later chronological age. For example, if the biomarker were rate of change in memory ability, it should be tied to a particular memory phenomenon that can be predicted at a known interval (e.g., one year) and can be measured (e.g., numbers recalled from a list after a few minutes of intervening activity).
2. The biomarker should reflect some basic biological process (e.g., heart rate).
3. The biomarker should not reflect disease (e.g., Alzheimer's disease).
4. The biomarker should be widely reproducible across similar species (e.g., all mammals).
5. The biomarker should not cause harm to the individual being assessed.
6. The biomarker should be reproducible and should be measurable in a relatively short time interval compared to the life span of the organism being assessed (e.g., days for fruit flies and months for humans).

A major problem in biomarker research is determining the validity of the biomarker. Validity of a biomarker means that it measures what it purports to measure, that is, rate of aging. Finding that a particular measure goes down in some predictable fashion as the organism ages does not mean that the measure reflects biological age. For example, skin wrinkles with advancing age, but skin wrinkling is almost entirely the result of exposure to sunlight and is exacerbated by smoking. Thus, skin wrinkling is a measure of exposure to environmental damage. Some individuals show little or no wrinkling because of lifestyle choices. Similarly, hair turns gray with advancing age. Some individuals are fully gray by their thirties while others show little gray at very advanced ages. While we all see graying hair as a symbol of age, graying hair is not a good predictor of remaining life. It is therefore not a good biomarker. Still other measures, like rings in the trunk of a tree, may be good chronometers (measures of the passage of time) but still not be good biomarkers (a ten-year-old tree of a short-lived species will have as many rings as a ten-year-old tree of a long-lived species).

A biomarker of aging may be valid even if it does not have face validity. The concept of face validity refers to the apparent relationship between a measure and what it is supposed to be a measure of. For example, gray hair, if it were actually a good biomarker, would have face validity, as we all believe that there is a relationship between gray hair and aging. But how about a measure of rate of fingernail growth? Is there any reason to suppose that fingernails grow faster or slower as a result of advancing age? Most of us would assume not, yet some investigators have proposed this measure as a biomarker. Such a measure may lack face validity and yet be a valid biomarker.

Still another important aspect of a good biomarker is its reliability. A reliable measure produces the same result (score) each time it is used (assuming that the thing being measured has not changed). This reliability should be demonstrable across different observers and across different subjects.

Another problem in finding good biomarkers of aging is that so many measures are indicators of disease rather than measures of "normal" function. Indeed, some gerontologists believe that aging is not a process or set of processes, but rather is the cumulative effect of damage caused by wear and tear and disease. Still others believe that aging is itself a disease. Searching for biomarkers of aging only makes sense if there really are underlying biological processes to be measured.

Since finding good biomarkers is apparently so difficult, why bother? One of the major reasons for searching for biomarkers is that their discovery might provide useful information about the underlying processes. If, for example, some measure of immune function were found that accurately predicted the survival of the individual or that individual's immune system, then it would follow that the measure is in some way tied closely to an important aspect of immune aging. Then a search could begin to understand how the immune measure is related to aging and why it changes with age. This in turn could lead to biological insight about aging and to new therapies to "repair" aged immune function.

By far the most common motivation for searching for biomarkers of aging outside of the laboratories of basic scientists is the search for a "cure" for aging and its debilitating diseases. The term antiaging medicine has been coined to describe this search. The search for a cure for aging is ancient and appears eternally attractive. A great deal of what is being presented to an avid populace at the beginning of the twenty-first century as valid antiaging medicine rests upon the assumption that valid, reliable biomarkers of aging have been identified and can be administered in the clinic or even in health food stores. Despite common assertions to the contrary, most reputable scientists do not believe that science has yet reached the point where the rate of aging of individuals can be measured in any meaningful fashion. This is a controversial area, and a great deal of money can be made selling "cures" in the form of dietary supplements, hormone replacement regimens, and even books about how to slow down aging.

The antiaging movement has investigators who run the gamut from solid, careful, and thoughtful to outright quacks. Certainly great caution should be exercised before following any so-called recommended antiaging regimen. Many are costly and useless, and some are very probably dangerous. No dietary supplement strategy or course of hormone therapy should be undertaken without first obtaining a physical examination by a physician.

In addition to the unethical abuse of the concept of biomarkers of aging by unscrupulous purveyors of "cures" for aging, the successful development of biomarkers would raise new ethical issues. If we were actually able to assess the rate of aging of an individual, and therefore predict remaining life span or even "healthspan," would our society put such information only to beneficent uses? Could we prevent discrimination in the workplace or in health care systems based on longevity potential? Would persons with shorter life expectancies be able to buy life insurance? Could we prevent the exploitation of such individuals by a new breed of charlatan pandering to the fears of "short-lifers"?

Finally, the development of biomarkers of aging as part of a strategy to find ways to lengthen life assumes that success in this endeavor would be a good thing. Not all theorists would necessarily agree. Other theorists are not worried as they do not believe that it is possible to develop biomarkers of individual rates of aging. Their view is that while it may be possible to develop measures that predict the average rate of aging for a large number of individuals in a population, it is not possible to assess the aging rate of each individual and predict his or her remaining life span.

The only known intervention at the beginning of the twenty-first century that reliably increases life span is caloric restriction. Calorically restricted animals (mostly rats and mice) are widely used for biomarker research and a great deal is known about the ways in which they age. Yet even after decades of intensive research, it is not possible to predict just which animal will live longest and which will die early. Human beings are more complex than rats and mice in many ways. Assertions by antiaging clinics and spas that they have valid biomarkers of aging and can use them to provide remedies and cures for aging should be viewed with the greatest of skepticism. The search for biomarkers of aging can provide humankind with potentially great rewards of greater health and a life of independence if pursued with compassion and integrity. Reputable scientists are working hard to produce such an outcome. Consumers need to be vigilant as well.