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130 Part III: Epochal Hematology Chapter 9: Hematology in Older Persons 131

findings also point out the theory’s deficiency as a unifying mechanism, are implicated in age-associated impairments, including a reduction in
as there is no question that individuals with well-maintained glucose lean body mass and bone density. Furthermore, pharmacologic recon-
levels throughout their life span will still be subject to the acquired stitution using these or related hormones has met with some success at
changes typical of aging. reversing age-associated functional decline. 75,76

Free Radical Hypothesis Immunologic Theory
Another mechanism held responsible for crosslinking is the damage pro- Similarly, it has been argued that involution of the thymus gland and
duced by free radicals, which forms the basis of the free radical hypothesis subsequent decline in immune function discussed below is a key reg-
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initially promoted by Harman. 61,62 This theory offers that aging is the ulator of aging. The argument is based upon the observation that the
result of DNA and protein damage (e.g., mutagenesis or crosslinking) decline in immune function occurs in all mammalian species, but occurs
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by atoms or molecules that contain unpaired electrons (free radicals). later in those with longer survival. Furthermore, dietary restriction is
These highly reactive species are produced as byproducts of a variety associated with maintained thymic mass and measurable immune func-
of metabolic processes and are normally inhibited by intrinsic cellular tion as well as prolonged survival, suggesting an association of a decline
antioxidant defense mechanisms. Nitrate-based free radicals are also in immunity with primary aging processes.
generated by in vivo processes and another set of nitrogen free-radical The possibility is highlighted by the observation that differences
scavenging mechanisms are in place. If free radical generation increases in maximum survival of different mouse strains has been associated
with age, or the defense mechanisms that scavenge free radicals (e.g., with specific alleles in the major histocompatibility complex, which, in
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glutathione) or repair free radical damage decline, the accumulated free turn, code for immunologic determinants. This hypothesis, although
radical damage may account for altered DNA and protein function. Evi- not without its appeal, is not widely accepted as a major explanation
dence to support this widely held notion is incomplete. It is known that for aging. Perhaps this relates to the fact that biologic aging is a uni-
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free radical generation in mammals correlates inversely with longevity versal phenomenon and certain features are held in common, even in
and, similarly, the level of free radical inhibiting enzymes, such as super- organisms with primitive or no immune function. (The same could also
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oxide dismutase were higher in those species with longer life spans. be said for the neuroendocrine theory.) It is obvious that the immune
However, efforts at enhancing antioxidant mechanisms with dietary system is of great importance in minimizing the chance of early death,
vitamin E have resulted in only a modest enhancement of median sur- particularly from infectious diseases. However, immunologic reconsti-
vival in mice and no effect on maximum life span. 64–66 tution of middle aged or old animals has not been shown to prolong
Much attention has been focused on mitochondrial function in the survival. 80
context of free radical damage because the bulk of oxidative metabolism
and the production of reactive oxygen species occur in these organelles.
Although mitochondrial DNA codes for antioxidant enzymes in addi- LIFE SPAN: MEDIAN AND MAXIMUM SURVIVAL
tion to enzymes involved in energy production, it is currently believed From the perspective of those who study aging, an important distinc-
that energy production declines with age as a result of mitochondrial tion is made between median (life expectancy) and maximum life span.
DNA damage by those reactive products. Indeed, mitochondrial dam- Over the past century, a dramatic increase in median survival has been
age increases with age in experimental models, 67–69 and the shortened mostly attributable to modern sanitation and refrigeration, as well as
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survival of knockout mice deficient in mitochondrial antioxidant public health measures, including vaccination and antibiotics. Early
enzymes has supported the potential importance of this mechanism. 70 deaths have been diminished and more individuals are reaching old age.
The most compelling data to date in support of the free radical In the United States today, expected survival from birth is approximately
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hypothesis come from experiments in which transgenic Drosophila 80 years. Median survival is what concerns public health officials and
producing enhanced levels of superoxide dismutase and catalase had healthcare providers. In contrast, maximum survival is the focus of
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a maximum survival 33 percent greater than controls. Furthermore, those gerontologists interested in the biology of aging and longevity.
it is known that flies produce high levels of free radicals associated with The oldest human being alive today is approximately 120 years old.
their impressive metabolic requirements, and that survival is enhanced It is intriguing that the oldest age limit has remained stable, unchanged
dramatically when the ability to fly is experimentally hindered. by the public health initiatives mentioned above. In the laboratory, lim-
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However, the generalizability of these findings has been questioned. It its on age have been established for a variety of species. Drosophila, free
has been noted that transgenic mice overexpressing free radical scav- of predators, disease or fly swatters, can live 30 days, whereas C57BL/6
enging enzymes have produced very modest effects on life span. Thus, mice in a laboratory environment and allowed to eat a healthy diet ad
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the conclusion that augmentation of free radical scavenging mecha- libitum, may survive 40 months. Unlike health-related interventions in
nisms increases longevity in mammalian species is not established. humans, certain experimental interventions in lower species are asso-
ciated with a prolongation of maximum survival. In Drosophila, for
Neuroendocrine Theory example, transgenic offspring producing extra copies of the free radical
From a different perspective, very good evidence implicates a nonran- scavenging enzymes superoxide dismutase and catalase survive approx-
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dom, perhaps genetically regulated endogenous mechanism involved imately 33 percent longer than controls. In nutritional intervention
in aging. For example, the neuroendocrine theory suggests that the studies involving lower species, controlled restriction of dietary intake
decrements in neuronal and associated hormonal function are central (dietary restriction) has become a common experimental paradigm
to aging. It has been suggested that age-associated decline of hypotha- exploited in the investigation of primary processes of aging and max-
lamic–pituitary–adrenal axis function results in a physiologic cascade imum survival. 84,85
leading, ultimately, to the “frail” phenotype. This hypothesis is appeal-
ing because it is well established that this neuroendocrine axis regulates Dietary Restriction
much of development and also the involution of ovarian and testicular Dietary restriction typically involves a reduction of 30 to 40 percent
function. Furthermore, age-associated declines in growth hormone and in caloric intake with careful attention to the provision of adequate
related factors, dehydroepiandrosterone, and secondary sex steroids amounts of essential nutrients. It is associated with both a delay in the
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