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BIOLOGY
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OBJECTIVES
Know and understand:
• The major theories about how aging occurs
• The effects of aging on the major organ systems
• How the changes that occur with aging contribute
to a systems-wide dysregulation
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TOPICS COVERED
• Introduction and Definition of Aging
• Theories of Aging
• Physiologic Changes of Aging
• Systems Biology and Aging
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INTRODUCTION (1 of 2)
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The biology of aging involves studying:
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The “why” of aging (evolutionary theories)
The “who” of aging (psychosocial theories)
The “how” of aging (physiologic theories)
The “what and where” of aging (molecular, cellular,
and organ system changes)
Inherent in these multiple approaches is the
debate: Is aging a normal physiological
outcome? Or pathology?
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INTRODUCTION (2 of 2)
Biologic age, based on an individual’s functional
capacity, is the metric for the biology of aging
• Functional capacity is a direct measure of the ability of
cells, tissues, and organ systems to function optimally
and is influenced by both genes and environment
• Aging is the progressive decline and deterioration of
functional properties at the cellular, tissue, and organ
level that lead to a loss of homeostasis, decreased ability
to adapt to internal or external stimuli, and increased
vulnerability to disease and mortality
E V O L U T I O N A RY T H E O R I E S
OF AGING
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19th-century theory of programmed death: aging
is a mechanism designed by natural selection to
free up resources for the reproductively fit young
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Currently, evolutionary biologists debate:
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Why do living things age?
How has aging evolved as a process?
Was there selective pressure for aging to occur?
Can aging be considered a positive or negative
selection factor affecting the organism’s fitness?
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E V O L U T I O N A RY T H E O R I E S O F A G I N G :
M U TAT I O N A C C U M U L AT I O N
Holds that aging is a nonadaptive trait, a byproduct
and inevitable result of the declining force of natural
selection with age
• No selective pressure is brought to bear on organisms
expressing a mutation at older post-reproductive ages,
so these late-acting genes accumulate over time
• The detrimental effects from these late-acting genes
are “aging”
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E V O L U T I O N A RY T H E O R I E S O F A G I N G :
A N TA G O N I S T I C P L E I O T R O P Y
Holds that aging is an adaptive trait, and pleiotropic
genes (those that can influence several traits) are
selected for and affect individual fitness in opposite
ways
• Pleiotropic genes have beneficial effects on early
fitness components in the young, but harmful effects
on late fitness components, and yet are favored by
natural selection
• There is thus an evolutionary trade-off between
reproductive capacity and longevity
E V O L U T I O N A RY T H E O R I E S O F A G I N G :
DISPOSABLE SOMA
Subset of antagonistic pleiotropy theory—this theory,
too, posits a trade-off between longevity/reproduction
• An allocation of metabolic resources between growth,
reproduction, and somatic maintenance is necessary
to keep the body (soma) in good condition
• The compromise in allocating energy to the repair
function causes the body to deteriorate gradually
• Aging is the cumulative damage done to the relatively
more vulnerable soma cells
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PSYCHOSOCIAL THEORIES
OF AGING (1 of 3)
Psychosocial theories address the “who” of aging by
focusing on individual changes in:
• Behavior
• Cognitive function
• Coping ability
• Relationships
• Roles
• Social interactions
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PSYCHOSOCIAL THEORIES
OF AGING (2 of 3)
5 main theories view aging from different perspectives:
Disengagement theory
• An individual’s quantity and quality of relationships with other
members of society diminish with age
Activity theory
• Regular activities, roles, and social pursuits should be
maintained or altered with age
Life-course theory
• Aging requires progressive adjustments to declining health and
physical strength, retirement and reduced income, the death of a
spouse or family members, new living arrangements, etc.
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PSYCHOSOCIAL THEORIES
OF AGING (3 of 3)
Continuity theory
• Preserving and maintaining internal and external structures is an
adaptive strategy to deal with changes that occur during aging
Gerotranscendence theory
• Older adults cope with changes that occur during aging through
a shift in perspective from a materialistic and rational view to
more cosmic and transcendent view
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PHYSIOLOGIC THEORIES
OF AGING
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Explain structural and functional changes with age
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Concentrate on:
 Genetic programs (specific genes)
 Molecules and their chemical reactions (free
radicals, glucose, and glycation)
 Activities of cell organelles (mitochondria)
 Whole-body homeostatic systems (immune,
endocrine)
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PHYSIOLOGIC THEORIES OF AGING:
TA R G E T T H E O RY O F G E N E T I C D A M A G E
• Holds that genes and chromosomes are
susceptible to inactivating hits from radiation
and other damaging agents, and cumulative
hits give rise to an aging phenotype
• But the DNA damage, mutations, and
chromosome abnormalities that increase
during aging may be a consequence of aging,
not the cause
PHYSIOLOGIC THEORIES OF AGING:
PROTEIN ERROR
Holds that damage is not to genes themselves but to
RNA and proteins (aka “error catastrophe theory”)
• Normally, errors in the subsets of proteins involved in
transfer of information from DNA to protein are below
a threshold, so a steady state exists, with random
perturbations
• Critical errors can destabilize protein synthesis,
causing an irreversible increase in the error level,
accelerating loss of molecular function, and causing
biologic changes seen as “aging”
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PHYSIOLOGIC THEORIES OF AGING:
MITOCHONDRIAL DNA DAMAGE
Nearly any adverse change in mtDNA will have
adverse effects on mitochondrial function:
• Less energy production
• More free-radical formation
• Reduced control of other cell processes
• Accumulation of damaged harmful molecules,
leading to aging and certain age-related
diseases
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PHYSIOLOGIC THEORIES OF AGING:
FREE RADICALS
• Emphasizes the role of free-radical formation and freeradical defense mechanisms in aging
• Positive correlations have been observed between:
 Metabolic rate and free-radical formation
 Age and rate of free-radical formation
 Age and amount of free-radical damage
• Negative correlations have been observed between:
 Longevity and free-radical production
 Age and free-radical defenses
PHYSIOLOGIC THEORIES OF AGING:
P R O T E I N M O D I F I C AT I O N
This group of theories posits that protein structures
are altered with increasing age:
• Abnormal post-translational modifications
• Deamidation of asparagines and glutamine
• Nonenzymatic protein glycation
• Cross-linking of lysine residues
• Racemization of L-amino acids
• Phosphorylation
• Sulfation and methylation
• ADP ribosylation
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PHYSIOLOGIC THEORIES OF AGING:
R AT E O F L I V I N G
Holds that organisms possess a finite amount of
some vital substance; when used up, death occurs
• A number of limiting substances have been proposed,
including number of breaths, number of heartbeats,
oxygen metabolism
• Aging is determined by the rate of metabolism because
aerobic metabolism causes damage, primarily through
the production of free radicals
• The higher the rate of metabolism, the faster the rate of
aging and the shorter the life span
PHYSIOLOGIC THEORIES OF AGING:
EPIGENETIC
Holds that altered gene expression, altered cellular function,
and the aging phenotype arise from epigenetic modifications
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A major mechanism maintaining the somatic cells’ appropriate,
differentiated phenotype is epigenetic, dependent on DNA–
protein interactions, DNA methylation, and histone acetylation
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In general, DNA methylation increases with age
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Hypermethylation in a gene’s promoter region is associated with
transcriptional silencing (eg, silencing of genes involved in tumor
suppression or defense against free radicals)
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Epigenetic silencing of repressive transcription factors may
contribute to cells’ switching to a senescent phenotype
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PHYSIOLOGIC THEORIES OF AGING:
ENDOCRINE
• Holds that changes in hormone levels and signaling
are major causes of loss of homeostasis
• With increasing age:
 The synthesis and secretion of a number of
hormones change
 Cell receptors on target organs can change in
terms of number and functional signal transduction
 The circadian cycles of certain hormones become
irregular
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PHYSIOLOGIC THEORIES OF AGING:
IMMUNE
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Holds that a decline in adaptive immune function
and an increase in innate immunity disrupt
homeostasis
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With increasing age:
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progressive quantitative & qualitative loss in ability to
produce antibodies
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decline in T lymphocyte function
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thymus atrophy with age
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increase in hypercoaguable state, thrombotic events
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increase in ‘pro-inflammatory’ state (altered cytokines)
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PHYSIOLOGIC THEORIES OF AGING:
TELOMERE/CELLULAR SENESCENCE
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Emphasizes a gradual loss in telomerase activity,
which normally maintains sufficient length of the
telomere-capping regions of chromosomes to
enable repeated replication
• Once telomeres are reduced beyond a threshold
length, cells enter a non-replicating state in which:
 Their genetic program changes
 Production of pro-inflammatory cytokines
increases
 Self-renewal at cellular/tissue level is limited
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PHYSIOLOGIC CHANGES
OF AGING (1 of 5)
Body system
Nervous
Change
↓ Number of neurons
↓ Action potential speed
↓ Axon/dendrite branches
Consequences
↓ Muscle innervation
↓ Fine motor control
Muscle
Fibers shrink
↓ Type II (fast twitch) fibers
↑ Lipofuscin and fat deposits
Tissue atrophies
↓ Tone and contractility
↓ Strength
Skin
↓ Thickness
↑ Collagen cross-links
Loss of elasticity
Skeletal
↓ Bone density
Joints become stiffer, less
flexible
Movement slows and
may become limited
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PHYSIOLOGIC CHANGES
OF AGING (2 of 5)
Body system
Heart
Change
↑ Left ventricular wall
thickness
↑ Lipofuscin and fat deposits
Vasculature
↑ Stiffness
↓ Responsiveness to agents
Pulmonary
↓ Elastin fibers
↑ Collagen cross-links
↓ Elastic recoil of the lung
↑ Residual volume
↓ Vital capacity, forced
expiratory volume, and
forced vital capacity
Consequences
Stressed heart is less
able to respond
↓ Effort-dependent and
independent
respiration (quiet and
forced breathing)
↓ Exercise tolerance
and pulmonary
reserve
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PHYSIOLOGIC CHANGES
OF AGING (3 of 5)
Body system
Eyes
Change
↑ Lipid infiltrates/deposits
↑ Thickening of the lens
↓ Pupil diameter
Consequences
↓ Transparency of the
cornea
Difficulty in focusing on
near objects
↓ Accommodation and
dark adaptation
Ears
↑ Thickening of tympanic
membrane
↓ Elasticity and efficiency of
ossicular articulation
↑ Organ atrophy
↓ Cochlear neurons
↑ Conductive deafness
(low-frequency
range)
↑ Sensorineural
hearing loss (highfrequency sounds)
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PHYSIOLOGIC CHANGES
OF AGING (4 of 5)
Body system
Change
Consequences
Digestive
↑ Dysphagia
↑ Achlorhydria
Altered intestinal absorption
↑ Lipofuscin and fat
deposition in pancreas
↑ Mucosal cell atrophy
↓ Iron absorption
↓ B12 and calcium
absorption
↑ Incidence of
diverticulum, transit
time, and
constipation
Urinary
↓ Kidney size, weight, and
number of functional
glomeruli
↓ Number and length of
functional renal tubules
↓ Glomerular filtration rate
↓ Renal blood flow
↓ Ability to resorb
glucose
↓ Concentrating ability
of kidney
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PHYSIOLOGIC CHANGES
OF AGING (5 of 5)
Body system
Change
Consequences
Immune
↓ Primary and secondary
response
↑ Autoimmune antibodies
increase
↓ T-cell function; fewer naive
and more memory T cells
Atrophy of thymus
↓ Immune functioning
↓ Response to new
pathogens
↓ T cells, NK cells,
cytokines needed for
growth and
maturation of B cells
Endocrine
↑ Atrophy of certain glands
↓ Growth hormone, DHEA,
testosterone, estrogen
↑ Parathyroid hormone, ANP,
norepinephrine, baseline
cortisol, erythropoietin
Changes in target organ
response, organ system
homeostasis, response
to stress, functional
capacity
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SYSTEMS BIOLOGY AND AGING
• The biologic changes that occur with aging act across
multiple systems and create expanding perturbations
to homeostasis and functional capacity
 Examples: decreased detection and response to
thermal variance; malnutrition
• The challenge for the geriatrician is to provide care in
the context of numerous primary aging-related
physiologic changes, along with increasing comorbid
medical conditions, frailty and other geriatric
conditions, and disability
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SUMMARY (1 of 2)
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Aging is a loss of homeostasis, or a breakdown in
maintenance of specific molecular structures and
pathways; this breakdown is the inevitable
consequence of the evolved anatomic and physiologic
design of an organism
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Evolutionary theories of aging (mutation accumulation,
antagonistic pleiotropic, and disposable soma theories)
address the “why” of aging
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Physiologic theories of aging (eg, genetic damage,
protein error, mtDNA damage, free-radical, protein
modification, rate of living, epigenetic, endocrine,
cellular senescence) address the “how” of aging
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SUMMARY (2 of 2)
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The many theories of aging are not necessarily
competing or mutually exclusive; rather, they reflect our
current understanding of the individual multiple
maintenance and homeostasis mechanisms that allow
us to live as long as we do
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Some of the molecular and cellular changes that occur
with aging are unique to the specific cellular and tissue
context of the organ, while others occur across a
number of organ systems with a common effect on
functional capacity
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QUESTION 1 (1 of 2)
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With regard to protein and energy requirements of adults
>75 years old, which of the following statements is true?
A. Resting energy expenditure increases in older adults.
B. Energy expenditure of activity accounts for a
significantly greater proportion of total daily energy
expenditure for older men than for younger men.
C. Older adults need proportionally lower amounts of
protein in their diets than younger adults.
D. The most physically active older adults on average lose
similar muscle mass over time compared with more
sedentary adults.
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QUESTION 1 (2 of 2)
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With regard to protein and energy requirements of adults
>75 years old, which of the following statements is true?
A. Resting energy expenditure increases in older adults.
B. Energy expenditure of activity accounts for a
significantly greater proportion of total daily energy
expenditure for older men than for younger men.
C. Older adults need proportionally lower amounts of
protein in their diets than younger adults.
D. The most physically active older adults on average lose
similar muscle mass over time compared with more
sedentary adults.
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QUESTION 2 (1 of 3)
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• A study examines longevity within a cohort of adult
identical twins.
• Results indicate that, compared with younger
identical twin pairs, older identical twin pairs exhibit
significant differences in histone acetyltransferase.
• These differences are found to be further increased
in twins who have spent their lives apart.
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QUESTION 2 (3 of 3)
Which of the following theories of aging would
be most applicable to this study?
A.
B.
C.
D.
Rate of living
Epigenetic modifications
Free-radical theory
Target theory of genetic damage
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QUESTION 2 (3 of 3)
Which of the following theories of aging would
be most applicable to this study?
A.
B.
C.
D.
Rate of living
Epigenetic modifications
Free-radical theory
Target theory of genetic damage
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QUESTION 3 (1 of 2)
Dolly, a female domestic sheep, was the first mammal to
be cloned by nucleus transfer. The donor was a middleaged (6-year-old) sheep. Dolly lived for 6 years, half the
normal lifespan that is typical of her species.
Which of the following theories of aging is the most likely
explanation for her early death?
A. Mitochondrial DNA damage
B. Depletion of stem cell reserves
C. Loss of chromosomal telomere length
D. Mutations in gene expression profiles
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QUESTION 3 (2 of 2)
Which of the following theories of aging is the most likely
explanation for her early death?
A. Mitochondrial DNA damage
B. Depletion of stem cell reserves
C. Loss of chromosomal telomere length
D. Mutations in gene expression profiles
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GRS8 Slides Editor:
Annette Medina-Walpole, MD, AGSF
GRS8 Chapter Authors:
Matthew K. McNabney, MD
Neal S. Fedarko, PhD
GRS8 Question Writer:
George A. Kuchel, MD
Medical Writers:
Beverly A. Caley
Faith Reidenbach
Managing Editor:
Andrea N. Sherman, MS
Copyright © 2013 American Geriatrics Society