Transcript aging - POGOe

Biology of Aging
Carmel Bitondo Dyer, MD
Kathleen Pace Murphy, PhD
The University of Texas Health Science Center at Houston
Department of Internal Medicine
Consortium on Aging
Learning Objectives
Successful students will be able to :
A. Define “aging” and four main characteristics of the aging process.
B. Describe changes that occur in the aging cell.
C. Describe theories of aging.
D. Differentiate between normal aging, usual aging, and successful
aging – Practical Aspects
What does AGING mean to the healthcare
provider?



Great heterogeneity in the older population
Increased attention to biological age versus
chronological age
No “one size fits all” approach to treating older adults
Biological vs Chronological Age
Define “aging” and four main characteristics of the aging process.
1. Destructive processes
2. Progressive, irreversible and ongoing
3. Intrinsically determined
4. Universal
Strehler, 1959
Destructive Processes

From age 25 – 85: a 130 fold risk of death

Your organs decrease in capacity – linearly

Reduced response to stimuli – example?

Increased susceptibility to disease
Homeostenosis
Chronological Age
How long have
You lived?
vs.
Biological Age
How old is
Your body?
Life Expectancy
The average number of years remaining for a living being
(or the average
for a class of
living beings)
of a given age
to live.
Life Expectancy


Improved public hygiene and the discovery of antibiotics in the
early to mid 1900s led to significantly prolonged lifespan
Further prolongation occurred in 1970’s and 1980’s with improved
treatments for cardiovascular disease
Characteristics of Aging (1 of 2)





Mortality increases exponentially
Biochemical composition of tissue changes
Physiologic capacity decreases
Ability to maintain homeostasis diminishes
Susceptibility and vulnerability to disease increases
Environmental and genetic factors
influence the rate of aging
Characteristics of Aging (2 of 2)




Loss of physiologic reserve and decreased homeostatic control may
result from:
Allostatic load (persistent activation of normal neuroendocrine,
immune, and autonomic responses to stress)
Development of homeostenosis (altered response to physiologic
stresses)
Changes are generally irreversible
Developmental-Genetic Progeria




Progeria is a disease of premature aging
Death typically by age 13 and usually due to atherosclerotic
disease, stroke, heart attack.
Hutchinson-Gilford Progeria linked to mutations in the nuclear
structural protein lamin A.
caused by a tiny, point mutation in a single gene, known as
lamin A (LMNA).
Werner’s Syndrome
Disease of premature aging. Patients appear normal for first
two decades of life but develop arteriosclerosis, malignant
neoplasms, DMII, osteoporosis, cataracts very young



Disorder isolated to a single gene on chromosome 8 which
encodes for a DNA helicase
This gene has been cloned and is an area of great research
DNA helicases are involved in the repair, replication and
expression of genetic material
Aging research has turned away from a single
gene answer to the cause of aging.
Increasing understanding that aging is a consequence of complex
interactions within differing systems of the body and the
surrounding environment.
Learning Objectives
Describe changes that occur in the aging cell
 Morphological alterations
 Enzyme function
 Gene expression
 Telomere shortening
Gene Regulation Theory
Aging is caused by changes in gene expressions, affecting both
aging and development
Gene Expression (1 of 2)



Compared with younger adults, the elderly can have decreased,
unchanged, or increased rates of gene expression
Mechanisms that influence gene expression with aging:
 Mutations in DNA sequences in/around certain genes
 Latent viral infections (eg, herpes viruses)
 Accumulation of environmentally induced cell damage
It is unknown whether age-related changes in gene expression are
functionally significant
Gene Expression (2 of 2)







Primary changes in gene expression with age:
Decreased transcription rates for key genes
Decreased messenger RNA (mRNA) turnover
Decreased inducibility of genes, such as immediate early genes,
acute phase reactants, and stress genes
Expression of genes related to stress response is up-regulated
during senescence
Consequences unknown
May be adaptations to accumulated environmental or oxidative
stress
Codon Restriction Theory
Accuracy of mRNA translation is impaired due to inability to
decode codons in mRNA
Error Catastrophe Theory
Decline in fidelity of gene expression over time resulting in
increased portion of abnormal proteins
Dysdifferentiation
A gradual accumulation of random molecular damage over time
impairs regulation of gene expression
Cellular Theory of Aging






Morphological Cell Changes – CELL SUICIDE.
Replicative senescence - irreversible arrest of cell proliferation
and altered function.
A greater heterogeneity of cell sizes
A shift to larger cell sizes
An increase in the size of the nucleus, nucleolus, number of
multinucleated cells.
Prominent Golgi apparatus, evacuated endoplasmic reticulum,
increased number of cytoplasmic microfilaments, vacuolated
cytoplasm, and large lysosomal bodies observed in senescent
human fibroblasts.
Cellular Theory of Aging



Each cell has a maximum number of divisions before it enters
senescence
The length of the telomere end of the DNA chain shortens with
each division and less telomerase activity is observed
A telomere is a region of highly repetitive DNA at the end of a
chromosome that functions as a disposable buffer
Telomere




Telomeres are protein-DNA structures that comprise the terminal
ends of eukaryotic chromosomes. In humans, telomeres are
composed of repeats of the sequence TTAGGG reiterated in
tandem for up to 15 kilobases at birth.
Telomeres stabilize chromosomal ends by binding to proteins that
prevent them from being recognized as double-stranded breaks by
repair enzymes.
This function protects chromosome ends against degradation and
end-to-end fusion and prevents inappropriate activation of
checkpoint pathways that respond to chromosome breaks.
Telomeres may also play a role in the determination of
chromosomal localization within the nucleus and regulation of
cellular replicative capacity.
Telomere



Aged cells with proliferative potential exhibit telomere shortening
and loss of telomerase activity
Conversely, telomerase hyperactivity is linked to cellular
transformation and cancer
Telomere length and telomerase activity might be clinical markers
of human aging and oncogenesis
Oxidative Stress Theory
Oxidative metabolism produces reactive oxygen species
which damage protein, lipids and DNA
Oxidative Stress Theory


In support:
 Mutations in oxidative stress pathway can extend life span
 Mutations in other pathways that increase longevity resist
oxidative damage
In opposition: Antioxidants do not delay human senescence or
disease
Apoptosis Theory
Genetically determined, programmed
cell death.
“Genome Crisis”
Neuroendocrine Theory
Changes in the neuroendocrine control of homeostasis result in
aging-related physiologic alterations


Synopsis: Hypothalamic and pituitary responses are altered (TRH,
GNRH, GHRH, TSH, LH, FSH, GH, ACTH)
In support: No direct support as causative of healthy aging, and
supplementation does not alter aging in humans
Immune Senescence Theory
Changes in the immune system with aging lead to increases in
infectious disease and increase in autoimmune disease in older
adults.
Theories of Aging: Immune Senescence



Synopsis: Time-acquired deficits, primarily in T-cell function,
increase susceptibility to infections and cancer
 Slower onset of lymphocyte proliferation
 Diminished cloning efficiency of individual T cells
 Fewer population doublings of fibroblasts
In support: Some diseases are associated with aging
In opposition: Immunologic function is apparently not directly
related to healthy aging
Life Span Extension: Metabolic And Insulin Signaling


There appears to be endocrine regulation of aging
 In a range of species, mutations in certain genes, especially
those that appear to play roles in metabolic and insulin
signaling (eg, GH, IGF-1), extend life span
 In contrast, life span is shorter in humans with untreated
isolated GH deficiency (but normal age-related GH decline
may have little to do with healthy aging)
 Low-expressing IGF-1 receptor alleles are more highly
represented among long-lived humans
These pathways are potential targets for drugs to delay or
prevent age-related changes
Can all of this knowledge be used to extend lifespan?
Vitamins?







50% of seniors use them
Research is confounded
Elders excluded
Daily multivitamin?
Folate?
Glucosamine?
Vitamin D?
Other Agents

Omega-3Fatty Acids

Co-enzyme Q10

Green Tea

Growth Hormone
Landon Center on Aging Photo Contest
Exercise







Decreased falls
Improved glucose homeostasis
Improved cardiovascular function
Improved flexibility
Better sleep
Less depression and dementia
Less hip and knee pain due to arthritis
Landon Center on Aging Photo Contest
Life Span Extension: Caloric Restriction (1 of 2)



Caloric restriction increases average and maximum life spans in a
variety of species
Impact of caloric restriction varies considerably in mice and flies
Two robust markers of caloric restriction in rodents (reduced
body temperature, reduced plasma insulin) have been observed
in older men and in caloric-restricted rhesus monkeys
Life Span Extension: Caloric Restriction (2 of 2)



Sir2, an enzyme in the sirtuin family of proteins, mediates the
benefits of caloric restriction in yeast
Sirtuin-activating compounds (STACs) could conceivably
enhance life span in humans
 Resveratrol, a plant polyphenol in red wine, is a STAC that
prolongs life span in fruit flies and worms
 Resveratrol has anti-inflammatory, antioxidant, anticancer,
and vasoactive effects on human cells
It might be possible to develop calorie restriction mimetics to
increase human life span
Religious Participation
Learning Objectives
Differentiate between normal aging, usual aging, and successful aging.
Normal vs. Usual vs. Successful Aging



Normal aging is associated with progressive and universal
physiologic changes.
Usual aging includes age-related diseases.
Successful (or healthy) aging occurs with minimal deleterious
events and is associated with preserved function until advanced
age.
Why is hyperglycemia in the setting of
infection so common in old people?
Decreased Insulin Sensitivity
Why is hyperglycemia so common in old people?





Increased random blood
sugar in the elderly
No change in fasting glucose
Unaltered glucose
responsiveness to
catecholamines and
corticosteroids
Old have enhanced release
of steroids and
catecholamines in illness
Higher frequency of
hyperglycemia in illness
Why is apathetic hyperthyroidism essentially
unique to old people?
Decreased Beta Adrenergic Sensitivity
Why is apathetic hyperthyroidism unique to old people?
51-70
71-90

Heart
100%
Rate>100
58%
28%

New
0%
Atrial Fib.
0%
20%
Lid Lag
71%
35%
12%
Fine Skin
97%
81%
40%
Tremor
97%
89%
36%
30-50


Muted adrenergic component
to hyperthyroidism.
Decreased cardiac inotropic,
chronotropic and lusitropic
response to isoproterenol
Decreased vasodilatation in
response to beta agonist
Many manifestation of
hyperthyroidism are
adrenergically mediated.
Why do lipid soluble drugs have
such long half-lives in old people?
Increased Fat Mass in Old Persons
Why do lipid soluble drugs have long half-lives in old people?
100
Bone Mineral - 20%
Cell Solids - 35%
90
80

70
60
Water -10%
50

40
30

20
Fat + 100%
10

0
AGE 25
AGE 75
50% or more increase in
percent body fat in men
Older women can be
50% fat in body
composition.
Increased half-life for
lipid soluble drugs
Lipid soluble meds
stored in depots
Why do old people seem to get pressure
sores more often than young ones?
Decreased Skin Thickness
Why do old people seem to get pressure sores so often?




Loss of thickness in all three layers
Loss of elastin (tenting no longer reliable measure)
Flattening of dermal-epidermal junction
Decreased sensation of pressure related discomfort
Why do old guys get toxic on normal
doses of digoxin or Vancomycin?
Decreased Total Body Water
Why do old guys get toxic on normal doses of digoxin?

70
65

60
55
Body
Water

50
45

40
20
40
60
80
Total body water
decreases 15-20% in
men
Increased concentration
for water soluble drugs
Dosages calculated on
body mass, not true
lean body mass.
Magnified by decrease
in Renal function
Why is a heart rate of 120 in an 80 year old
in the setting of an infection
equivalent to 170 in a 25 year old?
Decreased Maximum Heart Rate
Why is a heart rate of 120 in an 80 year old equivalent to
170 in a 25 year old?

200
190
180
170
160
150
140
130
120
110
100


Max.
H.R.


20 40 60
Age 80

Reinterpretation of Sinus
Tachycardic, SOI
Underestimate response to
illness
HR of 120 in 75 year old
man is roughly 75% of max
heart rate, the same as 170
in a 20 year old
220-age=max HR for men
Men*0.85 in women
Resting HR does not change
with age
Why do the elderly develop CHF so frequently
when they go into Atrial Fibrillation?
Increased Dependence on Atrial Systole for LV Filling
Why do the elderly develop CHF when they go into A Fib?



In young people, left
atrial systole just “tops
off” the ventricle.
In old people, atrial
systole provides 40-50%
of left ventricular filling.
Atrial Fibrillation, loss of
a coordinated atrial
contraction, is a disaster,
manifest as heart failure
and low cardiac output.
Why is CHF with normal left ventricular
systolic function so common in old people?
Aging is Associated with Impaired Diastolic Function
Why is CHF with normal LVEF so common in old people?






Impaired relaxation of isolated muscle from old animal hearts
Impaired resequestration of calcium due to decreased levels of
Sarcoplasmic Reticulum calcium pump
Restoring pump protein normalizes function
Impaired tolerance of Volume loads (IV fluids) because of impaired
diastolic function
Diastolic measures are best predictor of maximum exercise
performance in elderly
Increased diastolic heart failure because disease related changes
are superimposed on age-related ones
Why is systolic hypertension so
common in older men and women?
Large Arteries Stiffen with Age
Why is systolic hypertension so common in older persons?
Stiffness (PWV in cm/sec)

1100
1000

900
800

700
600

500

400
10
30
50
Age (Years)
70
90

Likely due to collagen and elastin
changes
Stiffer arteries provide less
cushioning function (higher peaks
result)
Reflection of large artery changes
not small vessels changes
Not atherosclerosis
Diameter and length of aorta
increase (uncoiling of the old
aorta)
Disease changes add to age
changes
Why are old guys
so prone to orthostatic hypotension?
The Elderly are Predisposed to Orthostatic Hypotension
Why are old folks so prone to orthostatic hypotension?
Predisposing Factors:
 Decreased baroreceptor sensitivity
 Decreased arterial compliance
 Decreased cardiac compliance
 Impaired brain perfusion autoregulation
 Decreased renal sodium conservation
 Decreased plasma volume
 Increased venous tortuosity
 Blunted vasopressin response to standing
 Decreased renin, angiotensin, aldosterone levels
Protective Factors:
 Impaired beta-adrenergic vasodilation
 Normal alpha-adrenergic vasoconstriction
 Elevated circulating norepinephrine levels
Orthostatic Hypotension produces falls
Why do physical activities
become harder as we age?
Decrease in VO2 Max
Why do physical activities become harder as we age?

50
45
40
35
30
25
20
15
10
5
0



25 35 45 55 65 75 85
Age
All activities become a larger
relative percent of VO2max
and are perceived as harder
VO2 max decrease due to
cardiac plus muscle factors
Detraining effect of bed rest
may produce disability by
lowering VO2 max further
Exercise will improve VO2.
Why do old people develop hypoxia
in response to so many challenges?
Increased VQ Mismatching in Normal Aging Lung
Why do old people develop hypoxia so frequently?

100
95
90
85
80
75
70
65
60
55
50



PaO2
20 40 60 80
Decreased PaO2 of roughly 4
mm Hg per decade.
Worsened by lying flat in bed.
No change in alveolar PO2.
Preserved sensation of
hypoxia, but impaired
sensation of hypercapnia in
old.
If we all aspirate mouth contents, why do
old patients get pneumonia so often?
Decreased Lung Elasticity and Larger Residual Volume
Why do old patients get pneumonia so often?


8
7

6
5
Vital
Capacity
Residual
Volume
4
3



2

1
0
20
40
60
80
Ineffective cough
Increased closing volume
which is not cleared by
cough
Decreased elastic recoil in
old lung
Oropharyngeal Fibronectin
stickier for bacteria
Decreased mucociliary
transport and slower
recovery after insult
Competence of Epiglottis
decreased
Immune system
compromise adds to local
factors
Why do old people so often get confused or
develop delirium in the face of infections?
Cholinergic Compromise
Why do old people so often develop delirium with infections?






Choline Acetyl Transferase (ChAT) is a marker for cholinergic
pathways in brain
Decrease in ChAT in old hippocampus and neocortex
No changes in ChAT with age in other parts of brain
Increased frequency of delirium in normal old
Marked increase in demented old
Still debated as to whether delirium ever clears up
Why does a brief bout of bed rest
debilitate the old patient so much?
Old People have Marginal Muscle Strength
Why does a bed rest debilitate the old patient so much?






From age 20 to 70 strength decreases 50% in legs
 Non-linear decline that accelerates with increasing age
 30% decrease in strength from 50 to 70
 80 year olds are 30% weaker at knee extensor than at 70
Upper body strength decreases less rapidly
Muscle Mass Decreases with Aging, but
 Young are stronger than mass predicts
 Old are weaker than mass predicts
Significant problems at neuro-muscular interface with motor
neuron dropout, increased size muscle unit, stimulation
failure. These improve with training (100% increase in
strength with <10% increase in mass)
Old muscle injured more easily
Loss of 5% of strength per day of immobilization
Why do old patients get hyponatremia so often?
Increased frequency of Hyponatremia in Old
Why do old patients get hyponatremia so often?





Impaired ability to excrete water load (Minimum urine osmolality
200 instead of 75)
Impaired ability to retain salt
Impaired non-osmotic stimulation of ADH release by baroreceptor
Increased osmotic receptor sensitivity with enhanced ADH release
Old are more susceptible to SIADH
Why do old infections (TB, shingles, etc.)
resurface in old people?
Impaired Cellular Immunity Reduces Immuno-surveillance
Why do old infections resurface in old people?
IL-2 m-RNA is Decreased
after Stimulation in Aged Humans


Y



O
Y

O

Thymus Involutes (essentially
gone by age 70)
Thymic Hormones Decrease
Decreased T-cell Proliferation
Decreased Interleukin-2
production
Decreased Responsiveness of
Old Memory (CD45+) cells
Decreased Skin-Test Responses:
Remember Booster for TB
testing
No Change in CD4/CD8 counts
Why do falls occur more frequently in old people?
Typical Nursing Home Patients fall 1.6 times per year
Why do falls occur more frequently in old people?









Increasing sway especially without visual input
Slowed reaction time
Slower light dark accomodation
Decreased proprioceptive input
Loss of Cerebellar neurons
Weakness of ankle and knee musculature
Higher frequency of premonitory falls
Orthostatic hypotension common
50% of falls are “accidental”
Why are urinary tract infections
so common in old people?
Impaired Local Defenses
Why are urinary tract infections so common in old people?








Incomplete bladder emptying with age
Production of Tamm-Horsfall mucoprotein decreased
Loss of bactericidal prostate secretions
Decreased urine acidity and urea concentration
Atrophy of Urethra in women with menopause
More alkaline vaginal secretions
High frequency of obstruction, stones, prostatitis, etc.
Higher frequency of asymptomatic bacteriuria
Why is urinary incontinence
so frequent in older women?
Incontinence is Common in Hospitalized Older Women
Why is urinary incontinence so frequent in older women?

70

60

50
40

30

20

10
0
<45 45-64 65-74 >75
Atrophy of pelvic muscles
Atrophy of Urethra
Decreased maximum bladder
capacity
Decreased bladder sensitivity
Involuntary bladder
contractions more common
Impaired mobility
Why does lean body mass decrease in normal aging
Muscle Mass Decreases in Normal Aging
Why does lean body mass decrease in normal aging?

110

Muscle Mass (%)
100

90

80

70

60
50
20
30
40
50
60
70
80
90

Decrease IGF-1 due to loss of
Nocturnal GH peaks
Inactivity
Loss of androgens
Major factor in decreased
muscle strength with aging
Creatinine production
decreases 30-50% from 25 to
90
Loss of total number of fibers
and decrease in CSA of each
fiber, especially type II
Increased intramuscular fat
with age
 At age 40, Non-contractile
tissue is 8% of CSA
 At age 70, Non-contractile
tissue is 18% of CSA
How does kidney function deteriorate with age?
Decreased Creatinine Clearance
How does kidney function deteriorate with age?

140
130

120

110
100

90

80

70
30 40 50 60 70 80
Decreased CrCl by 35% in
healthy older men. (No HTN,
No Dm, No Drugs)
Decreased concentrating and
diluting capacity
Increased number sclerotic
glomeruli to 30% of total
Dependence on prostaglandins
to maintain filtration
Decreased renal blood flow
and renal mass
Decreased clearance of renal
drugs
Why do old people get dehydrated so frequently?
Increased Loss of Water and Salt and Decreased Intake
Why do old people get dehydrated so frequently?

Na Excreted (% of control)
100


10


Young
Old
1
0
5
Days of salt
deprivation
Impaired recognition of thirst
and serious dysregulation of
thirst
Impaired retention of salt and
water
Takes much longer to reach
maximum retention
Maximum urine concentration
for old people still poor
Dropout of longest nephrons in
old kidney
Why do old people have increased probability of
developing hyperthermia during heat waves?
Old People Cannot Dissipate Heat Well.
Why do old people develop hyperthermia?







Decreased sweat production
Decreased numbers of sweat glands
Higher core temperatures to start sweating
Threshold to notice that it is hot is increased in the old
Acclimatization to hot temperatures is less likely to occur in the
elderly.
Decreased Heat Delivery to skin
Decreased maximum skin vasodilatation
Why is it impossible to take a history
from an old person with the TV on?
Central Processing Auditory Deficit
Why is it impossible to take an elder’s history with the TV on?







Impaired voice discrimination from background noise in noisy
room
Also difficulty in phoneme discrimination
Not equivalent to dementia
Ability to comprehend connected speech is more impaired
than the ability to understand single spoken words.
Hearing aids are ineffective as they amplify both target and
background
Central processing defect is only partly related to other
changes in cognitive function.
The older listener is more sensitive to accents and to varying
speakers than the young.
Which drugs are metabolized slower by the old liver?
Hepatic Changes
Which drugs are metabolized slower by the old liver?




Liver changes less magnitude and more variable then kidney
changes
Decreased Hepatic blood flow induces decreased first pass
metabolism of propranolol, verapamil, lidocaine, nitrates,
morphine
Drug metabolism of drugs requiring Oxidation is slower including
that by P450 enzymes like warfarin, diazepam, phenytoin,
naproxen
Reduced inducibility of hepatic enzymes by barbiturates, rifampin,
cigarette smoke
Credits
Content provided by:

George Taffet, MD

Mary McDonald, MD

Fadi Ramadan, MD

Bruce Troen, MD

Adam Golden, MD

Donald A. Jurivich, DO

© American Geriatrics Society
Photographs use for the cover are allowed by the morgueFile free photo agreement and the Royalty Free usage agreement at
Stock.xchng. They appear on the cover in this order:
Wallyir at morguefile.com/archive/display/221205
Mokra at www.sxc.hu/photo/572286
Clarita at morguefile.com/archive/display/33743
Images on slides 37, 44 and 99 are from the Microsoft Powerpoint clipart gallery.