Download Mr. Charles Montgomery Burns (Cellular Aging)

Pathobiology of Aging (Kupsky)
DEFINITIONS:
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Aging: structural and functional changes that occur in a cell or organism over time, resulting in impairment of
performance, increased susceptibility to disease and ultimately death
General View: sum of all changes occurring with time
Specific View: particular post-maturational period of decline in health and physiological vigor (ie. senescence),
culminating in death
Stages of Life:
o ConceptionDevelopmentReproductionSageingSenescenceDyingDeath
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Gerontology: the study of aging
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Geriatrics: medical specialty dealing with diseases affecting the elderly
GERONTOLOGY: LIFE EXPECTANCY, LIFE SPAN AND DEATH
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Survival Curve:
General: plot of percent surviving individuals of a population cohort over time, until the last remaining individual
dies
Important Data Points:
o Maximum Life Span Potential (MLSP): time at which the last individual in the population dies (0%
survival)
o Life Expectancy (50% or Median Survival): time at which 50% of population has died (represents the
average survival of the individuals in the group)
o Life Span: the observed length of life for an individual
Shape of Survival Curves (2):
o Exponential Decline: implies that fraction dying remains constant over time
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Characteristic of populations in the wild

Reflects the constant intensity of exogenous hazards (accidents, predators, inadequate
nutrition)
o Sigmoid (Rectangularized) Decline: implies that fraction dying changes over time
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Characteristic of non-wild conditions (civilization, domestication)

Reflects diminution of exogenous hazards in early life

Exhibits the phenomenon of aging
Change in Survival Curves Over Time:
o Have shifted from exponential decline to rectangularized sigmoid curves due to societal improvements

Reduced birth and infant mortality
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Improved hygiene and nutrition
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Reduced mortality from infections (ie. antibiotics) and other medical conditions
o Although LE has increased significantly, MLSP has not
Implications of Shape of Survival Curves:
o Implies that there is an increasing probability of death with increasing age
o Mortality rate increases semi-logarithmically with age
o Gompertz formula calculates that human mortality rate doubles ~ every 8 years
Survival Curves in Other Organisms:
o Survival curves are usually more exponential
o Few individuals ever reach the senescent end of the curve or MLSP
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Conclusions:
LE is related to the intensity of the environmental hazards and can be prolonged by reducing them
MLSP is independent of LE
MLSP is species specific and appears to be limited in most cases
In the wild, few individuals ever reach MLSP or even attain the senescence part of the survival curve
Experiencing senescence is largely an effect of civilization
HYPOTHESES OF AGNG MECHANISMS:
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Theories must account for the following observations:
Individuals within a species have similar MLSP
Individuals from different species have different MLSP
Aging changes are similar among individuals of one species and share similarities among species and even among
widely different groups
There is a trend for increased survival to later ages
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Both Genetic and Environmental Influences on Life Span:
Family: longevity runs in families
o Differences in longevity between DZ twins larger than between MZ twins
Genetic Syndromes Mimicking Aging:
o General: have features that MIMICK aging (hair loss, loss of subQ fat, accelerated atherosclerosis,
osteoporosis, cataracts) but these diseases are not identical to normal aging
o Infantile Progeria Syndrome (Hutchinson-Guilford): sporadic or autosomal recessive disease
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LE: 12 years
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Defect: single gene defect in lamin A gene (nuclear membrane proteins)
o Adult Progeria Syndrome (Werner): autosomal recessive
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LE: 40 years
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Defect: single gene defect in DNA helicase gene (DNA repair and recombination)
Genetic Control of Aging: programmed sequences of events in populations of normal cells imply genetic control
of these processes of cell production, maturation, senescence and death
Hayflick Limit: number of doublings of non-transformed fibroblast-like cells is FINITIE (~50 for human cells), after
which the cell deteriorates (senescence)
o Number of doublings related to MLSP of the species
Molecular Mechanisms:
o Apoptosis: occurs during normal development and throughout life

Controlled by specific genes and proteins (mitochondrial bcl-2 and extrinsic TNF pathways)
o Telomeres: repetitive short DNA sequences (TTAGGG) at the ends of the chromosomes that regulate
the number of cell divisions

Shorten with each division and are lost by ~the 50th division (no more divisions

Results in cell cycle arrest and cell senescence

Telomerase enzymes lengthen these sequences during development but is later progressively
lost and absent from somatic cells
 Plays a role in carcinogenesis
 Interaction with telomeres may play a role in aging and progerias
o Sirtuins: NAD-depending protein deacetylases implicated in a variety of cell functions (DNA
recombination, repair, gene expression)

Sirtuins may protect against acetylation of molecules (ie. histone proteins) that may cause
interference with normal function
Nutrition: evidence to suggest that dietary caloric restriction can reduce incidence of certain age-related
diseases and increase longevity in short-lived mammals (ie. rats)
o May be due to reduction in oxidative free radical injury
o Role in humans uncertain
Direct correlation between brain size and longevity: ability to acquire, process and transmit knowledge may be
useful to survival of the overall species
Hypothesis of Aging Mechanisms:
Possible Mechanisms of Aging:
o Changes in properties of replicating cells
o Loss or injury in replicating or postmitotic cells
o Primary changes in intracellular or extracellular materials
o Alteration of regulatory systems
Genomic Mechanisms:
o Basics: aging is effect through function of specific aging genes (gerontogenes)
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Cell doubling limitations (telomerase)

Programmed cell death (apoptosis)
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Gene regulation (sirtuins)
o Somatic Mutations Theory: errors in somatic or mtDNA replication (transcription) accumulate and
ultimately impair the capacity of cells/organisms to survive

May be important in the pathogenesis of increased cancer rate in elderly
Wear and Tear Mechanisms:
o Basics: aging occurs through accumulation of damage due to random (stochastic) events

Free radical damage, glycosylation reactions, trauma
o Free Radical Theory: endogenously generated free radicals causing damage to nucleic acids, proteins
and membrane lipids ultimately lead to cell dysfunction and death

May contribute to pathogenesis of diseases like cataracts, CAD and cancers
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Regulatory System Mechanisms:
o Basics: aging occurs through read-out of physiologic programs involving specific body systems
o Immunologic Theory: changes in the immune system lead to abnormal immune function, ultimately
causing aging and death

May be related to increased incidence of autoimmune disease and neoplasms in elderly
o Neuroendocrine Theory: impairment or loss of function in hypothalamic-pituitary-adrenal axis
ultimately impairs homeostasis of the whole organism

Includes concept of brain pacemaker or master timekeeper (site has not been localized)
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Evidence includes observations of normal control of reproductive function
o Metabolic Energy (Rate of Living) Theory: MLSP is proportional to the amount of energy consumed by
the organism during its lifetime

Lifespan Energy Potential (LEP): average energy consumed over a lifetime per unit of body
weight (fixed)
Criticisms of these Hypotheses:
o Hypotheses dependent on random events (stochastic theories) are difficult to reconcile with relative
uniformity of the aging process
o Many mechanisms imply death of individual cells as the endpoint (how does damage to individual cells
translate to aging and death of the whole organism?)
o No single mechanism explains all phenomena (likely a combination of genetic and regulatory factors
interacting with environmental factors)
GERIATRICS: AGING IN HUMANS
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Causes of Death in Humans: vary according to age, ethnicity, geography etc.
Causes of Death in the Elderly (>85):
o Heart disease (46%)
o Malignant neoplasms (15%)
o Cerebrovascular disease (7%)
o Respiratory disease (4%)
o Other/indeterminate (28%)
Spectrum of Diseases in Elderly Parallels Causes of Death:
o Common Diseases in 80-100 year olds:
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Neoplasia (carcinomas, leukemias/lymphomas)
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Dementias
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Osteoporosis
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Accidents
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Infections
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CV and cerebrovascular disease
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Classification of Afflictions of Elderly Individuals:
Age Related Diseases: diseases increasing in frequency with aging but not caused directly by aging
o Examples: atherosclerosis, septicemia, pneumonia, emphysema, cancers, AD, PD
Age Dependent Diseases: diseases largely limited to aging populations and directly related to effects of age or
chronic exposures
o Examples: osteoporosis, osteoarthritis, cataracts, prostatic hyperplasia and carcinoma, temporal
arteritis, otosclerosis
Aging Changes: non-disease conditions present in virtually every elderly individual
o Examples: menopause, gonadal atrophy, wrinkles, graying and loss of hair, intracellular accumulation
of lipofuscin, arcus senilis
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Aging Changes:
Criteria to Recognize Normal Aging Changes:
o Universal: occurring in all members of a species
o Intrinsic: not related to environmental factors
o Progressive: continuous and gradual over time
o Deleterious: to an organism (reducing function)
o Irreversible: usually not treatable
Normal Aging Often Difficult to Assess:
o Manifestations of aging can vary in severity and time of onset among racial/ethnic groups, families and
individuals
o Aging changes can be obscured by concomitant occurrence of illness (primary vs. secondary aging)
o Some changes have strong environmental causes (ie. skin wrinkling due to sun exposure)
Many Physiologic Aging Changes: estimates suggest that each physiologic system declines by 5-10% per decade
after age 30
o Changes in body composition:
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Increased proportion of body fat
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Decreased bone and muscle mass (lean mass)

Decreased tissue water
o Alterations in CV/Respiratory/Renal function:
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Decreased compliance of large arteries
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Decreased beta-adrenergic responsiveness of myocardium
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Decreased baroreflex sensitivity
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Increased EDV
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Increased systolic BP
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Thickening of calcification of cardiac valve leaflets
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Decreased lung compliance with hyperinflation (senile emphysema)
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Decreased RBF, GFR and creatinine clearance
o Alterations in immune function:
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Postpubertal involution of thymus
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Decreased proliferative response of lymphocytes to mitogens
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Decreased T cell function
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Diminution in capacity of B cells to produce Abs
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Increase in generation of autoantibodies
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Increased incidence of autoimmune diseases and cancers
o Neuroendocrine and metabolic changes:
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Involution of the gonads (decreased estrogen/testosterone)
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Atrophy of adrenal cortex and thyroid
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Impaired glucose tolerance (insulin resistance)
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Reduced capacity to handle stress
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Cell loss in some brain areas (catecholaminergic brainstem nuclei, cholinergic neurons)
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Alteration of neuronal dendritic trees
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Change in sleep/wake cycles and EEG rhythms
Aging Changes to Biomolecules:
o Proteins: cross-linking, oxidation, glycosylations, loss of amide groups
o Nucleic Acids: oxidation, base pair substitutions, insertions or deletions, mitochondrial DNA damage,
shortening of telomeres
o Lipids: oxidation, lipofuscin
Other Important Points:
o These aging changes are often complexly interrelated
o Aging changes provide clues for possible interventions, although most have little effect on the
inevitable
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Examples: antioxidants, vitamin D, hormones, exercise
Relationship Between Aging Changes and Disease:
General: concurrence of aging changes and one or more underlying diseases may affect the presentation,
natural history and therapeutic response of diseases occurring in elderly as compared to younger individuals
Common Features of Disease in Elderly Patients:
o Symptoms may be vague, atypical, unreported
o Presentation and course may be more subacute/chronic rather than acute
o Multisystem involvement is common
o Response to treatment may be altered
o Risk of iatrogenic morbidity/mortality is increased
Examples:
o Impaired immune/vascular function, poor nutrition  poor wound healing
o Impaired handling of fluids/electrolytes by CV system and kidneys  dehydration/volume overload
o Diminished hepatic and renal function  poor metabolism of drugs
o Neuronal loss in certain brain regions  susceptibility to drug side effects
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