Medical Physiology, 3rd Edition

Concepts in Aging

During the 20th century, the age structure of populations in developed nations shifted toward older individuals

The fraction of the U.S. population ≥65 years of age was only 4% in 1900 but 12.4% in 2000. This trend in age structure is projected to continue (Fig. 62-1). Moreover, because women have a greater life expectancy, they comprised 70.5% of the population >80 years of age in 1990 in developed nations.

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FIGURE 62-1 Age structure of the 1955 U.S. population and the projected age structure of the 2010 U.S. population. (From Tauber C: Sixty-five Plus in America. Washington, DC, US Bureau of the Census, 1992; revised 1993.)

The shift in the age structure of the U.S. population during the 20th century depended only modestly on an increase in life expectancy from birth. More important was the progressive decrease in birth rates. As a result, the elderly have become an ever-increasing fraction of the population, particularly in developed nations. Indeed, the effect of the post–World War II “baby boom” generation on population age structure is clearly apparent in Figure 62-1. If birth rates do not fall much further, future changes in the age structure of the U.S. population will depend mainly on further increases in life expectancy. imageN62-3

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Socioeconomic Impact of a Graying Population

Contributed by Edward Masoro

There is concern that the increasing fraction of the population ≥65 years will have a negative socioeconomic impact. Part of the potential problem is cultural in that individuals expect to exit the work force at or around 65 years of age. Also, with advancing age, there is progressive deterioration of physiological capacity and an increasing prevalence of age-associated diseases. Thus, with advancing age, individuals need greater assistance in living and more medical care. In the United States, hospital admissions in 1993 for those >65 years of age were more than twice the admissions for those 45 to 64 years of age.

The definition, occurrence, and measurement of aging are fundamental but controversial issues

The age of an organism usually refers to the length of time the individual has existed. Biogerontologists and members of the general public alike usually use aging to mean the process of senescence. For example, we may say that a person is young for her age, an expression meaning that the processes of senescence appear to be occurring slowly in that person. Aging—the synonym for senescence that we use throughout this chapter—is the progressive deteriorative changes during the adult period of life that underlie an increasing vulnerability to challenges and thereby decrease the ability of the organism to survive.

Biogerontologists distinguish biological age from chronological age. Although we easily recognize the biological aging of family members, friends, and pets, it would be helpful to have a quantitative measure of the rate of aging of an individual. Biomarkers of aging—morphological and functional changes that occur with time in the adult organism—could in principle serve as a measure of senescent deterioration. Alas, a generally agreed-on panel of biomarkers of aging has yet to emerge, so it is currently impossible to quantitate the aging of individuals.

Although measuring the aging of individuals is difficult, it has long been possible to measure the rate of aging of populations. In 1825, Benjamin Gompertz, a British actuary, published a report on the human age-specific death rate—the fraction of the population entering an age interval (e.g., 60 to 61 years of age) that dies during the age interval. For the British population, Gompertz found that, after early adulthood, the age-specific death rate increases exponentially with increasing adult age. The same is true for other human populations (Fig. 62-2) and for many animal populations. Based on the assumption that the death rate reflects the vulnerability caused by senescence, it has generally been accepted that the slope of the curve in Figure 62-2 reflects the rate of population aging. Although gompertzian and related analyses had long been viewed as the “gold standard” for measuring population aging, some biogerontologists have challenged this approach.

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FIGURE 62-2 Age-specific mortality for the U.S. population (men and women) for the year 2002. Data are projections from the 2000 U.S. census.

Aging is an evolved trait

Most evolutionary biologists no longer accept the once popular belief that aging is an evolutionary adaptation with a genetic program similar to that for development. The current view is that aging evolved by default as the result of the absence of forces of natural selection that might otherwise eliminate mutations that promote senescence. For example, consider a cohort of a species that reaches reproductive maturity at age X. At that age, all members of the cohort will be involved in generating progeny. Furthermore, assume that this species is evolving in a hostile environment—the case for most species. As the age of this cohort increases past X, fewer and fewer members survive so that all members of the cohort die before exhibiting senescence. In this cohort, genes with detrimental actions expressed only at advanced ages would not be subjected to natural selection. If we now move the progeny of our cohort to a highly protective environment, many may well live to ages at which the deleterious genes can express their effects, thereby giving rise to the aging phenotype. This general concept led biologists to put forward three genetic mechanisms that we discuss in the following three paragraphs. These are not mutually exclusive, and each has experimental support.

In 1952, Peter Medawar imageN62-4 proposed a variant of the foregoing model, now referred to as the mutation-accumulation mechanism. He proposed that most deleterious mutations in gametes will result in progeny that are defective during most of life, and natural selection removes such genes from the population. However, a very few of mutated genes will not have deleterious effects until advanced ages, and natural selection would fail to eliminate such genes.

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Peter Medawar

For more information about Peter Medawar and his work on acquired immunological tolerance, for which he shared a Nobel Prize, visit http://nobelprize.org/nobel_prizes/medicine/laureates/1960/index.html (accessed February 2015).

George Williams proposed another variant in 1957. He postulated that the genes that have deleterious actions in late life actually increase evolutionary fitness in early adulthood. Natural selection will strongly favor such alleles because they promote the ability of the young adult to generate progeny and because they have a negative impact only after reproduction—antagonistic pleiotropy. In this scenario, aging is a byproduct of natural selection.

In 1977, Tom Kirkwood proposed the disposable soma theory, according to which the fundamental life role of organisms is to generate progeny. Natural selection would apportion the use of available energy between reproduction and body (i.e., somatic) maintenance to maximize the individual's lifetime yield of progeny. As a consequence, less energy is available for somatic maintenance than needed for indefinite survival. This theory further proposes that a hostile environment increases the fraction of energy expended in reproduction, so that a smaller fraction is left for somatic maintenance.

Human aging studies can be cross-sectional or longitudinal

Measuring the effects of aging on the human physiology presents investigators with a difficulty—the subjects' life span is longer than the investigator's scientific life span.

Cross-Sectional Design

The usual approach to the foregoing difficulty is a cross-sectional design in which investigators study cohorts with several different age ranges (e.g., 20- to 29-year-olds, 30- to 39-year-olds) over a brief period (e.g., a calendar year). However, this design suffers from two serious potential confounders. One is the cohort effect; that is, different cohorts have had different environmental experiences. For example, in studies of the effects of aging on cognition, a confounding factor could be that younger cohorts have had the benefit of a relatively higher level of education. If aware of a potential confounder, the investigator may be able to modify the study's design to avoid the confounder.

The second potential confounder is selective mortality—individuals with risk factors for diseases that cause death at a relatively young age are underrepresented in older age groups. For example, in a study on the effect of age on plasma lipoproteins, mortality at a young age from cardiovascular disease would preferentially eliminate individuals with the highest low-density lipoprotein levels.

Longitudinal Design

To circumvent the confounders encountered in cross-sectional designs, investigators can repeatedly study a subject over a significant portion of his or her lifetime. However, this longitudinal design has other problems. Long-term longitudinal studies require a special organizational structure that can outlive an individual investigator and ensure completion of the study. Even shorter longitudinal studies are very costly. Some problems are inherent in the time course of longitudinal studies, including the effect of repeated measurements on the function being assessed, changes in subjects' lifestyle (e.g., diet), dropout of subjects from the study, and changes in professional personnel and technology.

Whether age-associated diseases are an integral part of aging remains controversial

Age-associated diseases are those that do not cause morbidity or mortality until advanced ages. Examples are coronary artery disease, stroke, many cancers, type 2 diabetes, osteoarthritis, osteoporosis, cataracts, Alzheimer disease, and Parkinson disease. These are either chronic diseases or acute diseases that result from long-term processes (e.g., atherogenesis).

Most gerontologists have held the view that age-associated diseases are not an integral part of aging. These gerontologists developed the concept of primary and secondary aging to explain why age-associated diseases occur in almost all elderly people. Primary aging refers to intrinsic changes occurring with age, unrelated to disease or environmental influences. Secondary aging refers to changes caused by the interaction of primary aging with environmental influences or disease processes.

In contrast, some gerontologists adhere to a view expressed by Robin Holliday: “The distinction between age-related changes that are not pathological and those that are pathological is not at all fundamental.” Moreover, the genetic mechanisms proposed for the evolution of aging (see p. 1235) may apply equally to the processes underlying both primary and secondary aging.