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PREFACE

"To me, fair friend, you never can be old,

For as you were when first your eye I eyed,
Such seems your beauty still."
-William Shakespeare, Sonnets 104: 1-3

The population of the world is aging. At the beginning of this century in the United
States, people over the age of65 accounted for only 4% of the population, whereas at the
end of this millennium, they will comprise 14% of the population. This represents a
growth of the older population in the United States from 30 million at present to approxi-
mately 55 million by the year 2030. Life expectancy in the United States has increased
from a mere 49.2 years in 1900 to 75.7 years in 1991. However, it is not only the indus-
trialized countries who are demonstrating this boom in their aging popUlations. Both
China and India will have gained an additional 270 million persons over the age of 60
years by the year 2000, and in the year 2020, Mexico will have the ninth largest elderly
population in the world. This graying of the world's populations makes it essential that
physicians recognize the unique aspects of physiology and disease that are associated
with the aging process.
Multiple physiological changes in hormones and the tissue responsiveness to
hormones occur with aging. This has led to increasing attempts to explore the use of
hormonal replacement as a modality to retard the aging process-the so-called
"hormonal fountain of youth, " although at present, only the use of estrogen in postmeno-
pausal women has been proven to increase longevity. The era of hormonal replacement
in older persons has opened up a veritable Pandora's box of exciting findings for the
inquisitive endocrinologist.
Changes in the autoimmune system lead to an increased propensity for the aging
person to develop endocrine failure syndromes. Further synergism toward the failure of
hormonal production that accompanies aging comes from lifelong environmental insults
and physiological changes.
The altered tissue responsiveness to hormones with aging results in altered mani-
festations of endocrine disease with aging. The classical presentation of any unusual mani-
festation of disease in older age is apathetic hypothyroidism. In addition, the physiological
changes of aging often mimic the signs and symptoms of endocrine failure, making the
diagnosis of endocrine disorders in older persons a biochemical rather than a clinical one.
Polypharmacy is rampant in older persons and leads to alterations in hormonal levels
and hormonal responsiveness, stretching the diagnostic imagination of even the most
aware endocrinologist.
For all of these reasons, it is timely to include in the Contemporary Endocrinology
series a volume concerning the Endocrinology of Aging. The first two chapters of this
volume explore the basic mechanistic changes that result in the aging process and their
physiological consequences. In addition, the putative role of hormonal replacement
therapy to retard the aging process is examined. The next series of chapters examine
the physiological changes in the hypothalamic pituitary axis that occur with aging and
their clinical consequences. Two chapters deal with bone disease in older persons.
v
VI Preface

Paget's disease is almost an exclusive disease of the older person, making it a highly
appropriate topic for inclusion in this volume.
The next three chapters examine the endocrinology of the sex hormone changes that
occur with aging. Androgen Deficiency in Aging Males (ADAM) has now established
itself as a real syndrome that occurs as men age. The potential use of testosterone replace-
ment therapy in these men, though still in its infancy, has opened up an exciting panoply
of possibilities. Gynecomastia occurs commonly in older males and has a variety of
causes that need to be recognized by the physician. Menopause represents one of the most
obvious aging changes and is an area where appropriate hormonal replacement therapy
has gained widespread acceptance.
Nearly half of all Type II diabetes occurs in persons over the age of 65 years. The
interaction of diabetes and cognitive function represents an extremely important area as
persons age. There is increasing evidence of positive benefits from maintaining good
control of glycemia into old age. The addition of the newer therapeutic agents to our
armamentarium has now made this feasible.
The interaction of nutrition and metabolism in older persons is addressed in two
chapters. The increasing awareness of the role of hypercholesterolemia in coronary artery
disease and the effects of obesity on functional status and disease pathogenesis are high-
lighted. The physiological changes in food intake and nutrient metabolism with aging are
then discussed. The role of these changes in producing the anorexia of aging and the
increased prevalence of protein energy malnutrition in older persons is delineated. Alter-
ations in vitamin and trace minerals with aging are discussed. In particular, the modern
trend of utilizing vitamins as therapeutic agents in phamacological doses is highlighted.
Finally, the last two chapters discuss the alterations in the sympathetic nervous system
with aging. Hypertension is rampant in older persons and the Systolic Hypertension in
Elderly Persons (SHEP) trial and the European Working Party for Hypertension in the
Elderly (EWPHE) have each demonstrated the importance of adequate blood pressure
control in the young old. Alterations in the endocrine system play an integral role in the
understanding and the development of appropriate management strategies of hyperten-
sion in older persons. Endothelin-producing tumors resulting in hypertension are a dis-
ease of old age.
Endocrinology of Aging has brought together a distinguished cast of international
authors to highlight the importance of understanding the unique aspects of endocrinology
in the aging process. It is our hope that endocrinologists, geriatricians, and practicing
physicians will all find information in this book that will enhance the function of older
persons throughout the world.
John E. Morley, MB, BCh
Lucretia van den Berg, MB, BCh
CONTENTS
Preface ........................................................................................................ v
Contributors .............................................................................................. ix

1 Biological Theories of Aging ........................................................... I

Hosam K. Kamel, Arshag D. Mooradian, and Tanveer Mir
2 Tithonusism: Is it Reversible? ........................................................ II
John E. Morley
3 Hypothalamic Growth Hormone--IGF-I Axis ................................ 23
Ian M. Chapman
4 Hypothalamic-Pituitary-Thyroid Axis in Aging ........................... 41
Mary H. Samuels, A. Eugene Pekary,
and Jerome M. Hershman
5 Stress, Hormones, and Aging ......................................................... 63
Scott P. Van Sant, Emile D. Risby, and Charles B. Nemeroff
6 Water Balance in Older Persons ..................................................... 73
Myron Miller
7 Bone Disease and Aging ................................................................. 93
B.E. Christopher Nordin, Allan G. Need.
Howard A. Morris. and Michael Horowitz
8 Paget's Disease of Bone ............................................................... 109
Dongjie Liu and Kenneth W Lyles
9 Testosterone .................................................................................. 127
John E. Morley
10 Gynecomastia ................................................................................ 151
Harold E. Carlson
11 Menopause .................................................................................... 161
Morris Notelovitz
12 Diabetes in the Elderly .................................................................. 181
Graydon S. Meneilly and Daniel Tessier
13 Evaluation and Management of Obesity in the Elderly ............... 205
Amy Lee and Gayathri Dundoo
14 Nutrition, Exercise, and Aging ..................................................... 221
David R. Thomas
15 The Sympathetic Nervous System ................................................ 235
Mark A. Supiano
16 Metabolic and Cardiovascular Factors Contributing
to Hypertension in the Elderly ................................................. 249
James R. Sowers
Index ....................................................................................................... 263
Vll
CONTRIBUTORS

HAROLD E. Endocrinology Division, SUNY-Stony Brook, Stony Brook. NY

CARLSON, MD,
IAN M. CHAPMAN, MBBS, PHD, Royal Adelaide Hospital, Adelaide, South Australia, Australia
GA YA THRI DUNDOO, MD. Department of Geriatric Medicine. Saint Louis
University Medical Center, St. Louis, MO
JEROME M. HERSHMAN, MD, Division of Endocrinology and Metabolism, UCLA School
of Medicine, West Los Angeles VA Medical Center, Los Angeles, CA
MICHAEL HOROWITZ, PHD, Department of Medicine, University of Adelaide, Adelaide,
South Australia
HOSAM K. KAMEL, MD, Division of Geriatric Medicine, Nassau County Medical
Center, East Meadow, NY and SUNY Stony Brook School of Medicine,
Stony Brook, NY
AMY LEE, MD, Division of Geriatric Medicine, Saint Louis University Health Sciences
Center, St. Louis, MO
DONGJIE LIU, MD, Geriatric Division, Center for the Study ofAging and Human
Development, Department of Medicine, Duke University Medical Center,
Durham, NC
KENNETH W. LYLES, MD, Sarah W. Stedman Nutrition Center, Duke University
Medical Center, Durham, NC
GRAYDON S. MENEILLY, MD, FRCPC, Division of Geriatric Medicine, Department
of Medicine, University of Brititsh Columbia, Vancouver, BC, Canada
MYRON MILLER, MD, Division of Geriatric Medicine, Department of Medicine, Sinai
Hospital of Baltimore, Baltimore, MD
TANVEER MIR, MD, Division of Geriatric Medicine, Department of Medicine, Nassau
County Medical Center, SUNY Stony Brook School of Medicine. Long Island, NY
ARSHAG D. MOORADIAN, MD, Division of Endocrinology. Department of Internal
Medicine, Saint Louis University Health Sciences Center, St. Louis, MO
JOHN E. MORLEY, MB, BCH, Division of Geriatric Medicine. Saint Louis University
Health Sciences Center, St. Louis, MO
How ARD A. MORRIS, PHD, Division of Clinical Biochemistry, Departments
of Medicine and Pathology, Institute ofMedical and Veterinary Science, Adelaide,
South Australia
ALLAN G. NEED, MD, Division of Clinical Biochemistry, Departments of Medicine and
Pathology, Institute of Medical and Veterinary Science, Adelaide, South Australia
CHARLES B. NEMEROFF, MD, PHD, Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta, GA
B. E. CHRISTOPHER NORDIN, MD, DSc, Division of Clinical Biochemistry, Departments of
Medicine and Pathology, Institute of Medical and Veterinary Science, University
of Adelaide, Adelaide, South Australia
MORRIS NOTELOVITZ, MD, PIlD, Women's Medical and Diagnostic Center, Gainesville, FL
A. EUGENE PEKARY, PHD, Division of Endocrinology and Metabolism, UCLA School of
Medicine, West Los Angeles VA Medical Center, Los Angeles, CA
EMILE D. RISBY, MD, Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, GA
ix
x Contributors

MARY H. SAMUELS, MD, Division of Endocrinology, Diabetes and Clinical Nutrition,

Oregon Health Sciences University, Portland, OR
JAMES R. SOWERS, MD, Division of Endocrinology, Metabolism, and Hypertension,
Wayne State University School of Medicine, Detroit, MI
MARK A. SUPIANO, MD, University of Michigan and Ann Arbor VA Health System-
GRECC, Ann Arbor, MI
DANIEL TESSIER, MD, FRCPC, Division of Geriatric Medicine, Department of Medicine,
University of Sherbroke, Sherbroke, Quebec
DAVID R. THOMAS, MD, FACP, Division of Geriatric Medicine, Saint Louis University
Health Sciences Center, St. Louis, MO
LUCRETIA VAN DEN BERG, MB, BCH, Division of Geriatric Medicine, Saint Louis
University Health Sciences Center, St. Louis, MO
SCOTT P. V AN SANT, MD, Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, GA
1 Biological Theories of Aging

Hosam K Kamel MD,

Arshag D. Mooradian, MD,
and Tanveer Mir, MD
CONTENTS
INTRODUCTION
THEORIES BASED ON PROGRAMMED AGING
THEORIES BASED ON WEAR AND TEAR
CONCLUSION
REFERENCES

INTRODUCTION
Aging can be seen as an irreversible, time-dependent, functional decline that converts
healthy adults into frail ones, with reduced capacity to adjust to everyday stresses, and
increasing vulnerability to most diseases, and to death (1). As far as anyone knows, the
longest anyone has ever lived is 121 yr. The record-holder is Jeanne Calment, a French
lady who celebrated her landmark birthday in 1996 (2). Long lives always make us
wonder: What is the secret behind it? Is there a maximum life-span beyond which we
cannot live? What happens as we age? Would insight into longevity help us fight the
diseases and disabilities associated with the aging process?
Concomitant with recent developments in molecular biology techniques, research
activity into the mechanisms of aging at the cellular and molecular level has increased
substantially. As a result, a myriad of theories explaining the aging phenomenon have
been proposed, which can be grouped into two major categories (Table 1). The first
includes the programmed theories, which emphasize internal biological clocks or pro-
grams. The second includes the wear-and-tear theories, which emphasize the role of wear
and tear caused by random events over time. This chapter reviews the different theories
of aging. The effect of caloric restriction on the aging process will also be reviewed in
the context of theories of aging.

THEORIES BASED ON PROGRAMMED AGING

These theories are based on the notion that the aging process is governed by certain
pacemakers at the organ system level or at the cellular level. Two organ systems, namely,

From: Contemporary Endocrinology: Endocrinology of Aging

Edited by: J. E. Morley and L. van den Berg © Humana Press Inc., Totowa, NJ

1
2 Kamel, Mooradian, and Mir

Table 1
Theories of Aging
Programmed theories
Neuroendocrine
Immune
Finite cell division
Wear and tear theories
Free radicals
Rate of living
Error catastrophe
DNA damage
Glycosy lation

the neuroendocrine system and the immune system, have been the focus of these theories.
This is mostly because these two systems influence an array of body functions.

Neuroendocrine Theory of Aging

This theory proposes that biological clocks act through hormones to control the
aging process (3). In 1889, C. E. Brown-Sequard noted that a day would come when the
degenerations of age could be mitigated by the use of testosterone, bringing fourth a
rejuvenation that would approximate that of a younger individual (4). Over the past
century, understanding of hormonal changes with age and the effect of hormonal reple-
tion in elderly individuals has increased dramatically. It is now established that a variety
of hormonal changes occur with aging (5; Table 2). Among these, aging of the hypo-
thalamic-pitutary-gonadal axis in women probably represents one of the best-studied
models of programmed senescence. Although the precise mechanism of the menopause
remains controversial, it is agreed that the neuroendocrine system orchestrates the loss
of reproductive ability (6). Estrogen replacement therapy alleviates the discomfort of
menopause (2). It also prevents the accelerated bone loss associated with the menopause
(7), and helps prevent cardiovascular disease in postmenopausal women (8).
With aging, there is a decrease in the levels of plasma testosterone and bioavailable
testosterone (9). This is attributed not only to primary testicular changes, but also to
changes, in the hypothalamic-pituitary axis (10). Reproductive hormonal alterations in
the aging male may have significant implications for the aging process (9). Testosterone
replacement therapy has been shown to reverse some of the phenotypic changes in older
hypo gonadal men (11,12). It remains to be determined, however, whether the benefits of
testosterone replacement therapy outweigh its long-term risks.
Dehydroepiandrosterone sulfate (DHEAS) is another reproductive hormone that decreases
dramatically with aging (13). Results from initial human studies suggest salutary effects
ofDHEAS on the aging process (14-17). These effects, however, need to be confirmed
by large-scale controlled studies.
Growth hormone (GH) is another hormone often implicated in the aging process.
There are many similarities between the syndrome associated with the lack of GH
in adults and the characteristics of normal older adults (18,19). There is a progressive
decline in GH and serum insulin-like growth factor (IGF)-I levels with aging (20). Rudman
et al. (21) demonstrated that administering recombinant human GH to a small group of
elderly men with low GH levels reversed some signs of aging, resulting in increased lean
Chapter 1 I Biological Theories of Aging 3

Table 2
Age-Related Changes in Serum Hormone Levels
Hormone Change with aginga
Growth hormone N in males; .J, in females
Somatomedin C (insulin-like growth factor I) .J,
Adrenocorticotrophic hormone N
Cortisol N
Dehydroepinandrosterone .J,
Renin N
Aldosterone .J,
Thyroid-stimulating hormone N or i
Thyroxin N
Triiodothyronine .J,
Parathyroid hormone i
Calcitonin .J,
1,25(OHhD .J,
Leuteinizing hormone i or N male; i in females
Follicle-stimulating hormone i or N male; i in females
Testosterone .J, or N male; i in females
Bioavailable testosterone .J,
Atrial natriuretic factor i
Insulin i
Glucagon .J,
aN, no change; t, increase; .1, decreased.

body mass, decreased excess fat, and increased skin thickness. When the GH treatment
was stopped, 3-mo later, these changes reversed, and the signs of aging returned. Researchers
are continuing to explore whether or not GH therapy can also increase muscle strength
(2). Prolonged administration of GH is complicated by the development of carpal tunnel
syndrome, gynecomastia, and hyperglycemia (22).

Immune Theory of Aging

This theory proposes that the immune system is the pacemaker of the aging process
(23). There are well-documented changes in the immune system with age (Table 3).
The most remarkable of these is probably the universal involution of the thymic gland.
Perhaps as a result, the T-cell-mediated responses are also impaired. Although the number
of T -cells remains about the same, the proportion of the functioning T-cell population
decreases (24). Most research on the aging immune system now centers on T-cells and
their lymphokine products, notably the interleukins. Some, like interleukin (lL)-6, were
found to rise with age; others, like IL-2, were found to fall with age (2). In addition,
evidence now links IL-6 to the development of postmenopausal osteoporosis (25). Study of
age-related immune changes may not only provide clues to the aging process, but may also
shed light on the possible role of cytokines in the pathogenesis of age-related diseases.

Finite Cell Division Theory of Aging

In 1961, Hayflik and Morhead reported (26) that human fibroblasts in culture can only
divide a limited number of times. These cells undergo approx 50 population doublings
4 Kamel, Mooradian, and Mir

Table 3
Age-Related Changes in Immune System
Thymic gland involution
Reduced T -helper and T-suppresser cells
Decreased cell-mediated cytotoxicity
Increased circulating autoantibodies
Increase in circulating immune complexes
Decreased levels of specific antibody response
Diminished delayed hypersensitivity
Diminished production of interleukin-2
Increased production of interleukin-6

before replicative ability ceases. In addition, fibroblasts "remember" how many divi-
sions they have had, even after having been frozen at -20°C for prolonged periods (27).
It was also observed that cell cultures derived from adult tissues consistently displayed
a lower growth potential than those derived from fetal tissue (28,29). Furthermore, cells
derived from individuals with certain genetic syndromes that display features of accel-
erated aging have diminished growth potential (30,31). The doubling potential of fibro-
blasts from diabetic subjects may also be reduced (32). In addition, it was observed that
there was a positive correlation between the growth potential of a culture and the maxi-
mum life-span of the species from which it was derived (33). These observations collec-
tively support the notion that cell doubling potential may be a biomarker of aging (32).
Researchers are discovering more clues to cellular senescence in the architecture of
DNA. It became evident that each chromosome has tails at the end, named telomeres,
which get shorter as cells divide (2). Tolemeres, composed of hundreds of repeated
copies of a hexanucleotide (TTAGGG) (63), were found to shed 50-200 base pairs each
replication cycle (64). As a result, these chromosome ends progressively shorten with
each cell division, until the telomere region is gone and cell division ceases. This led
researchers to believe that telomeres regulate cellular life-span in some way (2).

THEORIES BASED ON WEAR AND TEAR

Free Radicals Theory
A free radical is a molecule with an unpaired, highly reactive electron. A variety of free
radicals are generated during normal cellular metabolism. These include superoxide,
hydroxyl, lipid peroxy, purine, and pyrimidine radicals (32). Free radicals are implicated
as an important cause of errors in cellular function (34). Free radicals may cause damage
to cellular function through a scission reaction, such as DNA cleavage, mutations, addi-
tion reactions such as covalent bond formation, or aggregations of biomolecules through
crosslinking reactions (32). In addition, a major stable product of free-radical-induced
lipid peroxidation, malondiadehyde, can covalently bind to various proteins, resulting in
changes in protein function or antigenicity (35).
The free radical theory of aging, first proposed by Denham Harman (36), holds that
damage caused by oxygen radicals is responsible for many of the bodily changes that
accompany aging. Researchers could demonstrate that an increase in the free radical
level shortens the life-span of Drosophila, and leads to increase in the concentration of
lipofuscin (37). Free radicals have been implicated not only in aging, but also in several
Chapter 1 / Biological Theories of Aging 5

conditions seen in aging, including atherosclerosis, Parkinson's disease, Alzheimer's

disease, and immune deficiency of aging (2).
Most of the support for the free radical theory comes from studies of antioxidants.
One of these antioxidants, superoxide dismutase enzyme, converts oxygen radicals into
hydrogen peroxide, which is then degraded by another enzyme, catalase, to oxygen and
water (38). Researchers have found that superoxide dismutase levels are directly related
to life-span in several species, suggesting that the ability to fight free radicals has some-
thing to do with longer life-spans (2). Higher levels of superoxide dismutase and catalase
have been found in long-lived Drosophila melanogaster (39). Furthermore, levels of
superoxide dismutase in rat erythrocytes have been shown to decline with age (40), but no
correlation has been found between maximum life-span and levels of superoxide dis-
mutase in primates (41). Levels of other antioxidants, such as vitamin E and ~-carotene,
have also been correlated with life-span (2).
The observation reported by Harman (34), that mice treated with antioxidants had an
extension of their life-span, raised hope that the aging process could be retarded by
simply taking antioxidants. Subsequent studies, however, could not confirm the life-
prolonging effect of antioxidants, even though age-related accumulation of cardiac lipo-
fuscin was reduced (42,43). More recently, it was found that treatment of rats with
L-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, increased their life-span by
34%. The inhibition of MAO-B reduces the autoxidation of catecholamines, and subse-
quently reduces free-radical-induced tissue injury at critical sites in the nervous system
(32). Epidemiological studies provide evidence that increased dietary intake of antioxi-
dants, such as vitamin A, vitamin E, and ~-carotene, is associated with decreased risk of
many cancers. Randomized clinical trials, however, have found that therapeutic levels
of antioxidants do not reduce lung or skin cancer risk. Based on the currently available
data, it is unlikely that dietary intake of antioxidants would fundamentally affect the
aging process (24,38,44).

Rate of Living Theory

The rate of living theory, proposed by Pearl in 1928 (28), suggests that the life-span
of an organism is inversely related to its metabolic rate. Support for this theory is mostly
based upon observations that larger animals with lower metabolic rates generally live
longer than smaller animals with higher metabolic rates, and that life-span is prolonged
experimentally in lower species, such as invertebrates and fruit flies, when they are raised
in cooler temperature (24,45,46). These observations, however, are not universal. For
example, bats have both high metabolic rates and long life-span, and marsupials have
low metabolic rates and short lives (1,47). Furthermore, recent studies have found poor
correlation between metabolic rates and longevity (24). It is now believed that the dif-
ferences in longevity between species may not be associated with the metabolic rate, but
rather with the balance of accumulation and detoxification of metabolic end products,
such as free radicals (24,48).

Error Catastrophe Theory

The error catastrophe theory, proposed by Orgel in 1963 (49), is based on three general
assumptions. The first assumption is that, as a function of age, nonfunctional proteins
accumulate presumably because of errors in the transcription of genes and the translation
of messenger RNA into proteins. The second assumption is that the error frequency
6 Kamel, Mooradian, and Mir

increases with time, because, as errors in cellular function are made, the chances of
making subsequent errors increase. The final assumption intrinsic to this theory is that,
over time, the error frequency reaches a catastrophic threshold level that results in cell
death. Orgel's theory has been studied in great detail experimentally (50-53). Results
from these experiments do not support a significant role for this theory in explaining the
aging process (32).

DNA Damage Theory

In the normal wear and tear of cellular life, DNA undergoes continued damage. This
damage may be in the form of strand breaks, covalent modification, and/or chromosomal
rearrangements (2). Extrinsic factors, such as ionizing radiation and chemical mutagens,
or intrinsic factors, such as the free radicals generated by oxidative metabolism, may be
responsible for this damage (38).This theory proposes that this DNA damage gradually
accumulates and leads to malfunctioning genes, proteins, cells, and deteriorating tissues
and organs (54), and, thus, differences in longevity among species might be attributed to
variations in the rate at which DNA damage occurs, or is repaired (1).
In the cell, numerous enzyme systems operate to detect and repair damaged DNA. Hart
and Setlow (55) demonstrated that rate of repair of DNA damage induced by ultraviolet
light in cultured fibroblasts correlated with the life-span of the species from which the
cell cultures were obtained. This has been demonstrated in both mammals (55) and
primates (56). Furthermore, patients with Warner's syndrome, a disease with several
features of premature aging, have been found to have a defect in one of their enzyme
repair systems, namely, the helicases (2). Mitochondrial DNA, being in a highly oxida-
tive environment, is more susceptible to damage than nuclear DNA (2). This damage
increases exponentially with age, and mutations in mitochondrial DNA have been associ-
ated with age-related disease, including ischemic heart disease and Parkinson's disease (24).

Glycosylation Theory
The glycosylation theory proposes that, over time, proteins dehydrate and combine,
nonenzymatically, with glucose, to form advanced glycosylated end products (AGEs)
(57). These AGEs have been linked to stiffening of collagen, hardening of arteries,
cataracts, loss of nerve function, and less efficient kidney, all of which are age-related
features (2,32,58). These features also appear at younger ages in patients with diabetes
who have high glucose levels. In fact, diabetes is now considered by some researchers
as an accelerated model of aging. Not only do its complications mimic the physiological
changes that can accompany old age, but its victims have shorter life expectancies (2).
Glucose appears to react with cell constituents other than proteins. When DNA is incu-
bated with glucose, nonenzymatic bonding occurs, altering its structure (2). Studies in
bacteria suggest that DN A altered in this manner may interfere with genetic functioning.
Similar studies are currently underway to evaluate the effects of AGEs on human DNA
(32). Although glycosylation has been linked to the development of some age-related
diseases, the precise role of glycation in the aging process itself is currently unknown.

Caloric Restriction and Modulation of Longevity

At the present time, dietary restriction appears to be the only intervention known
to increase life-span in mammals (59). Animals who live on restricted diet, being fed
30-40% fewer calories than normal (but inclusive of all necessary nutrients), survive
Chapter 1 / Biological Theories of Aging 7

months longer than those not on such dietary restriction (2). Caloric restriction has
increased the life-span of nearly every animal species studied, including protozoa, fruit
flies, mice, rats, and other laboratory animals. Researchers are now investigating whether
caloric restriction will affect aging in primates, humans' closest relatives in the animal
kingdom (2). Reducing caloric intake in rodents resulted in retarding the development
of a broad range of age-associated physiologic changes, such as senescence of the repro-
ductive system and deterioration of the immune system (59). The timing of the institution
of caloric restrictions affects the extent of its prolonging effect on life expectancy. Food
restriction, started immediately in the postweaning period, prolongs life more effectively
than dietary restrictions instituted later in life (60).
The mechanisms by which calorie restriction prolongs the life-span are not exactly
clear. Because caloric restrictions appear to affect the rate of aging, it is not surprising
that the theories of aging discussed above are also implicated as possible mechanisms in
the life-prolonging effect of caloric restriction (32). Current evidence suggests that the
effects of calorie restriction on the aging process may be mediated through a reduction
in glycation (61), oxidative damage, or alterations in specific gene expression (62).

CONCLUSION
Although much is currently known about the aging process, much is yet to be explained.
No single theory accounts for all the changes that take place as people age. Aging should
be viewed as many processes, interactive and interdependent, that determine life-span
and health. Currently, there are more questions than answers. However, with the current
advances in molecular biological techniques, answers to most of these questions may be
found in the near future.

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2 Tithonusism
Is It Reversible?

John E. Morley, MB, BCH

CONTENTS

INTRODUCTION
REVERSIBLE AND PREVENTABLE DISEASE PROCESSES
EXERCISE
NUTRITION
TROPHIC FACTORS: THE HORMONAL FOUNTAIN OF YOUTH
PERSONAL NEUROCHEMISTRY ADJUSTMENT
GERIATRIC VISION 2020: MODULATION OF TITHONUSISM
REFERENCES

INTRODUCTION
Aurora, goddess of dawn, became particularly enthused about the qualities of her
morning lover, Tithonus. She felt that losing him would be unbearable, and so she went
to her father, Zeus, and asked him to bestow immortality on Tithonus. Unfortunately, she
forgot to ask for eternal youth for him as well. Over the years, Tithonus lost his strength,
had a decrease in his libido and potency, and eventually began to babble incessantly.
Although she still loved him for what he had been to her, Aurora now found Tithonus'
existence annoying and banished him to a far room in her castle, where she had him turned
into a grasshopper.
The concept that chronological aging is associated with an inexorable physiological
deterioration, which eventually leads to the development of frailty and a failure to thrive,
is well encapsulated by the term "Tithonusism." Peak performance is reached by the third
to fourth decade (1), with biochemical (e.g., calmodulin [2J, testosterone [3J, and physio-
logical changes, e.g., body fat [4J, V0 2max , and athletic performance [5]) being statis-
tically present in the fifth to sixth decade (Fig. 1). It is clear that all aging individuals do
not deteriorate at the same rate, and that the slippery downhill slope of aging, as originally
postulated by Nathan Shock (6), may, in fact, be punctuated by periods of no change or
even periods of improvement, as shown by the longitudinal studies of creatinine clear-
ance in the Baltimore Longitudinal Study on Aging (7). The rate at which Tithonusism
develops can be accelerated by the occurrence of disease and slowed by the success of
the rehabilitation process following the disease (Fig. 2).

From: Contemporary Endocrinology: Endocrinology of Aging

Edited by: J. E. Morley and L. van den Berg © Humana Press Inc., Totowa, NJ

11
12 Morley

~ V~ ~~t~Age-related memory
I { disturbance
tHearin~
/ ' _-~
~ ~ Sense of smell
Hypodipsia , .
/ ~ ~ Anorexia of aging
+ Muscle mass/ <./ ~ /
I ~ ~ V02 max

J~ HYPO:::::~s:SiS
and strength ~

Fig. 1. Examples of the physiological changes of aging (Tithonusism).

Fries (8) has argued that the life-span is relatively fixed, and that, with appropriate
health promotion and prevention, the quality of life can be improved, so that the illness
and disability curve is rectangularized, with each person spending only a small portion
of the end of their life in a state of frailty. Animal studies in both Drosophila (9) and
C. elegans (10) have suggested that population life extension is feasible with genetic
manipulation, and that, in these species, those animals with genetically increased life-
spans have greater vitality and decreased sexual activity, but the populations continue to
display a bell-shaped curve for survival, with no hint of rectangularization. This would
suggest that, even in a genetically homogeneous population, the rate at which Tithonusism
develops and progresses shows a wide variability.
The purpose of this review is to examine the evidence that the rate at which Tithonusism
develops can be retarded. Rowe and Kahn (11) have argued for a focus on successful
aging, i.e., examining the unique characteristics of highly functional aged individuals,
but the approach that is suggested in this article leans toward examining how persons may
age successfully, i.e., overcome their disabilities to allow continued enjoyment of the
aging process, in the belief that this approach is more likely to result in a rectangularization
of the curve of functional deterioration associated with aging. This concept of aging
successfull y was originally put forward by Eric Pfeifer (12) at a conference at Duke
University in 1973, and is epitomized by Grandma Moses, who took up painting in late
life, when she developed arthritis.

REVERSIBLE AND PREVENTABLE DISEASE PROCESSES

A number of studies (13-15) have suggested that health promotion and prevention
programs for free-living older persons can improve their functional status. In addition,
the controlled studies of geriatric evaluation and management units have demonstrated
relatively dramatic improvements when intensive rehabilitation is targeted to specific
groups of frail elderly (see ref. 16 for meta-analysis). Certain easily treatable endocrine
disorders, such as hypothyroidism and vitamin B12 deficiency, occur at rates as high as
5% in persons over 80 yr of age (17), and their diagnosis and treatment clearly improves
functional status, including cognitive function (18).