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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
• Organ System Changes with Aging
• Normal Aging versus Age-Related Pathologies
• Complexity, Homeostenosis, and Integrated
Systems 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)
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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
EVOLUTIONARY THEORIES
OF AGING
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Evolution deals with the impact of natural
selection (selective pressure) on the reproductive
fitness of a species
There are currently two main evolutionary
theories of aging:
 Mutation Accumulation Theory
 Antagonistic Pleiotropy Theory
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EVOLUTIONARY THEORIES OF AGING:
MUTATION ACCUMULATION
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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EVOLUTIONARY THEORIES OF AGING:
ANTAGONISTIC PLEIOTROPY
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 at different stages of life
• Pleiotropic genes have beneficial effects on early
fitness components in the young, but harmful effects
on late fitness components, and are favored by natural
selection
• There are thus inverse relationships between fecundity
and lifespan or between longevity and brood size or
metabolic rate.
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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
• Relationships
• Roles
• Social interactions
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PSYCHOSOCIAL THEORIES
OF AGING (2 of 3)
4 more common theories:
Activity theory
• Highlights the maintenance of and alterations in regular
activities, roles, and social pursuits as a coping strategy
Life-course theory
• Views aging as the progressive adjustment of older individuals to
changes associated with increasing age (declining health and
physical strength, retirement and reduced income, death of a
spouse or family members, new living arrangements, etc).
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PSYCHOSOCIAL THEORIES
OF AGING (3 of 3)
Continuity theory
• States that older adults may seek to use familiar strategies in
familiar areas of life as an adaptive strategy to deal with changes
that occur during normal aging.
Gerotranscendence theory
• Holds aging as part of a natural progression toward a goal of
achieving maturation and wisdom, with a shift in perspective
from a materialistic and rational view to a more cosmic and
transcendent view
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PHYSIOLOGIC THEORIES
OF AGING
•
Address how we age
•
These theories involve:
 Protocols for maintaining DNA integrity and
stability
 Synthesis fidelity
 Defense against free radicals
 Clearance of damaged/defective components
 Energy metabolism
 Systemic physiologic signaling
 Response to pathogens and/or injury
 Physiologic reserves
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PHYSIOLOGIC THEORIES OF AGING:
TARGET THEORY OF GENETIC DAMAGE
• Holds that genes are susceptible to
inactivating hits from radiation or 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
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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:
TELOMERE THEORY
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Telomeres are specialized sequences found at
the ends of linear chromosomes which are
shortened every time DNA replicates
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Once telomeres are reduced beyond a threshold
length, cells enter a non-replicating state
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PHYSIOLOGIC THEORIES OF AGING:
TRANSPOSABLE ELEMENT ACTIVATION
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Transposable elements are pieces of DNA that
can move from one location in the genome to
another, resulting in insertional mutagenesis
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Recent work has demonstrated that transposition
increases in frequency with age
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Activation of transposable elements is proposed
to be an important contributor to the progressive
dysfunction of aging cells and to induced cell
senescence and cell loss
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PHYSIOLOGIC THEORIES OF AGING:
EPIGENETIC THEORY
Holds that altered gene expression, altered cellular
function, and the aging phenotype arise from epigenetic
modifications
• A major mechanism maintaining the somatic cells’
appropriate, differentiated phenotype is epigenetic,
dependent on DNA–protein interactions, DNA
methylation, and histone acetylation
• In general, DNA methylation increases with age
• Epigenetic silencing of repressive transcription factors
may contribute to cells switching to a senescent
phenotype.
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PHYSIOLOGIC THEORIES OF AGING:
ERROR CATASTROPHE THEORY
Holds that damage is not to genes themselves but to
RNA and proteins
• Cumulative errors in subsets of proteins involved in
transfer of information from DNA to protein are
normally below a threshold
• Critical errors can destabilize the information transfer
machinery, causing an irreversible increase in the
error level and accelerating loss of function.
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PHYSIOLOGIC THEORIES OF AGING:
FREE RADICAL THEORY
• Highly reactive oxygen-derived free radicals damage
protein, lipid, and DNA, leading to altered structure and
functional capacity.
• Evidence in favor of this theory:
•


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Positive correlations between:
Metabolic rate and free-radical formation
Age and rate of free-radical formation
Age and amount of free-radical damage
• Evidence against this theory:
 Antioxidant treatment does not increase lifespan reproducibly
 Genetic manipulation of mice to under- or over-express key
components of free radical metabolism does not have a
consistent effect on lifespan
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PHYSIOLOGIC THEORIES OF AGING:
ACCUMULATION THEORIES
Aging is associated with accumulation of cellular and
extracellular components with altered structure that
compromise cellular function
• Molecular: example is lipofuscin accumulating in
lysosomes, compromising the organelle’s capacity for
catabolism
• Macromolecular: example is protein modifications
theory (collagen cross-linking in skin and bone,
neurofibrillary tangles and plaque formation in the brain)
• Damaged organelles: such as mitochondria,
lysosomes, peroxisomes, cell membranes, and the
inability to remove them through autophagy
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PHYSIOLOGIC THEORIES OF AGING:
RATE OF LIVING THEORY
Holds that aging is determined by the rate of
metabolism, because aerobic metabolism causes
damage, primarily through the production of oxygenfree radicals
• The higher the rate of metabolism, the faster the rate of
aging and the shorter the life span
• Although this is indeed the case in most animals, two
major exceptions are mammals and birds, which have
life spans longer than their rates of metabolism would
predict.
PHYSIOLOGIC THEORIES OF AGING:
ENDOCRINE THEORY
• Holds that changes in hormone levels and signaling
are major causes of loss of homeostasis and that
aging arises from dysregulated hormone signaling
• With increasing age:
 The synthesis and secretion of many 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 THEORY
Holds that immunosenescence contributes to aging
by limiting systemic defensive and repair responses
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Immunosenescence is the gradual decline in acquired
immune system maintenance, and has been
associated with increased morbidity and mortality in
late life
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An aging-associated increase in innate immune
system activation yielding an elevated proinflammatory state is perhaps a compensatory
mechanism for declining acquired immunity
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PHYSIOLOGIC THEORIES OF AGING:
STEM CELL/PROGENITOR CELL THEORY
Holds that stem cell/progenitor cell pools involved in
tissue remodeling and repair or in organ system
maintenance are depleted over time.
• Precursor cells become depleted either by phenotypic
drift or perhaps by injury, illness, or environmental
challenge
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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
↓ Number of neurons in the
utricle, saccule, and ampullae
↓ Size and number of otoliths
↑ Conductive
deafness (lowfrequency range)
↑ Sensorineural
hearing loss (highfrequency sounds)
↓ Detection of gravity,
changes in sped,
and rotation
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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
diverticula, 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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NORMAL AGING VS. AGE-RELATED
PATHOLOGIES
• Normal aging involves cumulative diminution in
molecular and cellular properties and processes that
exhibit physiologic effects only when internal or
external stressors, or both, perturb homeostasis.
• In pathology, or disease, compromised function is
evident in the resting (nonstressed) state
• There is a greater incidence of certain pathologies
with increasing age, such as diabetes,
atherosclerosis, hypertension, cancer, coronary heart
disease, stroke, osteoporosis, Alzheimer disease, and
many others
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COMPLEXITY AND HOMEOSTENOSIS
• The complexity in the dynamics of interacting
physiologic systems decreases with age, resulting in a
loss of integrated physiologic homeostasis
• Homeostenosis is used to describe the narrowing of
reserve capacity that contributes to a decreased ability
to maintain homeostasis under stress
 Examples: body temperature maintenance,
malnutrition
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INTEGRATED SYSTEMS AND AGING
• The biologic changes that occur with aging act across
multiple systems and create expanding perturbations
to homeostasis and functional capacity
• 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 anatomy and physiology
of an organism
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Evolutionary theories of aging (mutation accumulation,
antagonistic pleiotropic) address the “why” of aging
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Physiologic theories of aging (eg, DNA damage,
mtDNA damage, telomere, transposable element
activation, epigenetic, free-radical, error catastrophe,
accumulation, rate of living, endocrine,
immunosenescence, stem cell) 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 homeostatic 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 3)
Cellular Senescence
• Irreversible state of cell cycle arrest
• Triggered in response to various DNA-damaging stressors
(eg, telomeric erosion, oxidative damage, oncogene
activation)
• May halt proliferation of damaged or potentially transformed
cells in the adult
• Potent tumor suppressor
 beneficial early in life
 plays a role in tissue remodeling during embryo development
But:
• May contribute to age-related declines in tissue
regenerative capacity and health
• May fuel proliferation of premalignant cell populations
during biologic aging
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QUESTION 1 (2 of 3)
Which one of the following evolutionary theories of aging is
most compatible with cellular senescence?
A. Mutation accumulation theory
B. Antagonistic pleiotropy theory
C. Disposable soma theory
D. Homeostenosis theory
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QUESTION 1 (3 of 3)
Which one of the following evolutionary theories of aging is
most compatible with cellular senescence?
A. Mutation accumulation theory
B. Antagonistic pleiotropy theory
C. Disposable soma theory
D. Homeostenosis theory
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QUESTION 2 (1 of 3)
Ames and Snell dwarf mice are classic examples of mouse
aging models.
• Possess mutations in the Prop1 and Pit1 genes,
respectively
• Live much longer than their normal siblings
• Are deficient in growth hormone, prolactin, and thyroidstimulating hormone
• Exhibit delays in many age-related phenotypes, such as
immune function and connective tissue senescence
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QUESTION 2 (2 of 3)
With the various physiologic theories of aging in mind,
which one of the following might NOT be associated with
the increased longevity of these animals?
A. Decreased circulating insulin
B. Decreased metabolic rate
C. Suppression of superoxide dismutase (SOD) and
catalase activity
D. Reduced plasma glucose
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QUESTION 2 (3 of 3)
With the various physiologic theories of aging in mind,
which one of the following might NOT be associated with
the increased longevity of these animals?
A. Decreased circulating insulin
B. Decreased metabolic rate
C. Suppression of superoxide dismutase (SOD) and
catalase activity
D. Reduced plasma glucose
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GRS9 Slides Editor:
Tia Kostas, MD
GRS9 Chapter Authors:
Matthew K. McNabney, MD, AGSF
Neal S. Fedarko, PhD
GRS9 Question Writer:
Morgan Carlson, PhD
Managing Editor:
Andrea N. Sherman, MS
Copyright © 2016 American Geriatrics Society