Biology of Aging Key concepts. A. Commonalities of aging B

1
Biology of Aging

• Key concepts.
• A. Commonalities of aging
• B. Theories of aging
• C. Cell defenses and aging
• D. Genetics and aging

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Aging vs Senescence

• Aging is the chronological passing of time
• Senescence is the increase in mortality rate seen
  with increasing age -or- the negative attributes
  associated with aging

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Senescence

• Sarcopenia
• Increased chance of dementia
• Decreased immune response
• Increased opacity in the lens of the eye
• Loss of hearing in the high frequency range
• Skilled motor movements are slowed
• Reduction in stage 3 4 sleep
• Decline in ability to learn new information
• Large decrement in olfactory function

4
Predicted Life Expectancy
Miller, R. A. (2002). "Extending Life Scientific
Prospects and Political Obstacles." The Milbank
Quarterly 80(1) 155-174.
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Aging Key concepts

• Commonalities
• Inflammation
• Sensory impairments
• Endocrine
• Immune
• Atrophy
• Hypertrophy
• Hyperplasia

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Aging Key concepts

• Gompertz curve.
• Rate of mortality (and disease) increases
  exponentially with age
• Log transform gives line slope is rate of
  aging, intercept is age-independent mortality
  rate

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Aging Key concepts

• Genetic dependencies.
• Each species has its own lifespan and Gompertz
  slope
• About 1 of the C. elegans genome influences
  maximum lifespan

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Stability of G within species
Finch, C.E., 1990. Longevity, senescence, and the
genome. The University of Chicago Press, Chicago.
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Aging Key concepts

• Hayflick phenomenon
• Cells in culture can only divide a limited
  number of times unless cancerous
• Relationship to in vivo aging unclear, but may
  be related to cancer via telomerase.

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Dietary RestrictionIncreased lifespan across
all animals tested
Michael Cooper-50 CR Taubes, Gary. The Famine
of Youth. Scientific America 11(2), 44-49.
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Dietary restriction slows aging
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Blocking creb-binding protein blocks effects of
dietary restriction to increase lifespan
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Aging Key concepts

• Hayflick phenomenon
• Cells in culture can only divide a limited
  number of times unless cancerous
• Relationship to in vivo aging unclear, but may
  be related to cancer via telomerase.

14
Aging Key concepts

• Successful vs. usual aging
• Aging is usually accompanied by slow
  deterioration, but some individuals seem to
  maintain health until near the end
• Goal Rectangularization of the morbidity
  curve

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Aging Key concepts

• Pathology vs. normal aging
• Pathologies are not universal
• Also display bimodal distribution

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Inflammation is the enemy!!Main diseases of
aging Too much inflammation
Commonalities

• Arthritis
• Atherosclerosis
• Brain
• GFAP
• Alzheimers disease

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Endocrine
Commonalities

• Menopause
• Universal
• Growth hormone decrease
• Universal
• DHEA decrease
• Universal but of unclear signficance

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Nervous system

• Cognition and neuroendocrine
• Largely central
• Sensory and motor
• Largely peripheral

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Immune
Commonalities

• Mainly loss of T-cell function
• Universal, some B-cell loss
• In part due to commitment
• Autoimmune disease not main problem
• E.g., diabetes

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Atrophy
Commonalities

• Muscle
• Universal, even in athletes

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Hypertrophy
Commonalities

• Adipose
• Change in body weight set point?
• Does metabolism slow down with age?
• Prostrate

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Theories of Aging

• A. Loose cannon vs. weak link
• B. Loose cannons
• Free radicals
• Glycation
• C. Weak links
• Immune
• Neuroendocrine

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Metabolism and Aging

• A. Conservation of heartbeats
• B. Dietary restriction extends, obesity reduces,
  lifespan
• C. Single-gene mutations that extend lifespan
• 1. Worms and the DAF/insulin pathways
• 2. Yeast and NADH
• 3. Mice and insulin-like growth factors

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Theories of aging
Free radical/oxidative

• Protein oxidation increases with age
• Anti-oxidants dont help
• Pro-oxidants dont decrease lifespan

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Theories of aging
Glycation

• Caloric restriction increases lifespan
• Decreases glycation
• Glycation does not increase w/age

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Theories of aging
Immune

• Striking and universal impairments
• T-cells especially
• HOWEVER, age-related deaths/disease not clearly
  related

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Theories of aging
Neuroendocrine Too much of a good thing!

• Some hormones decrease w/age
• GH, estrogen
• HOWEVER, hormones seem to cause aging!
• GH/insulin-like growth factor

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Cellular defensesIn many ways overactivate with
age

• Inflammation
• Anti-oxidant
• Heat shock

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Conclusions

• Key concepts.
• A. Commonalities of aging
• Degeneration not usual (Good!)
• B. Theories of aging
• Something about metabolism
• C. Cell defenses and aging
• Actually work pretty well
• D. Genetics and aging
• For lifespan at least, lifestyle (especially
  diet) way more important!

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Neurobiology of Aging

• Sensory
• Cognitive
• Motor
• Neuroendocrine

Functional Neurobiology of AgingHof and Mobbs
(eds.)Academic Press, 2001
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Sensory Normal aging

• Vision
• Presbyopia
• Hearing
• Loss of acuity
• Some loss of hair cells universal and progressive

• Other senses largely OK

• Impairments in periphery, not in CNS

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Sensory Pathological

• Vision
• Macular degeneration
• Glaucoma
• Hearing
• Deafness may be largely exaggerated form of
  normal aging

• Essentially peripheral

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Cognition Pathologies

• Alzheimers disease
• Maybe 50 heritable (several genes known)
• Defined by plaques and tangles, but diagnosed by
  psychological testing
• Diagnosis of exclusion Does not include
  cardiovascular dementias

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Cognition Normal

• Main impairments
• Slower
• Tip-of-the-tongue retrieval failures
• Attention?
• Hippocampal and, for primates, prefrontal
  cortical
• Effects of heredity INCREASE with age!

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Performance of young and aged rats in water maze
(Rapp and Gallagher)((
Aged impaired
Aged unimpaired




Distance of rat from escape platform
Lower index score higher accuracy
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No obvious hippocampal neuronal loss with age
(Rapp and Gallagher)((
Neuronal packing density is similar in young and
aged rats
http//edoc.hu-berlin.de
37
No neuron loss with age or correlation of neuron
loss with cognitive impairments (Rapp and
Gallagher)
Lower index score higher accuracy
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Motor Normal

• Loss of muscle mass and strength

• Essentially peripheral

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Motor Pathological

• Parkinsons disease
• Largely environmental
• Central loss in dopamine neurons
• Huntingtons disease
• Completely genetic

• Entirely central

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Neuroendocrine Impairments with age influence
peripheral health, lifespan, and
neurodegenerative diseases

• Menopause
• Universal
• Growth hormone decrease
• Universal
• DHEA decrease
• Universal but of unclear signficance

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Obesity doubles in 20 person years, and 10
secular years
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Increased body weight is actively defended, not
passive accumulation Age-related increase in
set-point?
36.00
18 month
34.00
32.00
30.00
BODY WEIGHT (GRAMS)
28.00
26.00
6 month
24.00
22.00
Day 1 2 3 4 5 6 7 8 9

Fasting Refed
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Metabolic defense of body weight during aging
1200
28 grams
Metabolic Rate (cal/hr)
1000
29 grams
800
600
400
200
0
AD LIB
AD LIB
FASTING
FASTING
6 month
18 month
44
The metabolic syndrome Insulin resistance
increases with age

2
18-month
1.5
Plasma Insulin Levels (pg/ml)
1
6-month
0.5
0
0 min
15 min
30 min
45
Glucose resistance during aging
0.8
0.4
Food intake (gm/2 h)

0
NaCl Glucose NaCl Glucose
24 months
12 months
46
Impaired hypothalamic sensitivity to feeding with
age
1000

C-fos-positive hypothalamic neurons
500
0
12 24
Age (months)
47
POMC decreases with age and fasting
a
a
60
POMC mRNA
b
40
b
(Fed-6 mo)
b
b
20
0
Fed
Fast



Fed
Fast
Fed
Fast
6 mo 15 mo 24 mo
48
POMC transgene partially corrects obesity in
ob/ob mice
WT ob/ob ob/ob, POMCTg
Mizuno and Mobbs
49
POMC transgene partially normalizes adiposity in
ob/ob mice
4

b
3
Fat pad weight (g)
c
2
a
1
0
ob/ob, POMCTg
WT ob/ob
Mizuno/Mobbs
50
POMC transgene partially normalizes food intake
in ob/ob mice
10
b
8
c
a
Food
6
intake
4
(g/day)
2
0
ob/POMC-Tg
WT ob/ob
Mizuno/Mobbs
51
POMC transgene completely normalizes glucose
tolerance in ob/ob mice
600


400
ob/ob
Plasma Glucose (mg/ml)
200
ob/POMCTg
WT
0
0 1
2 3
Time post-glucose injection (hr)
Mizuno and Mobbs
52
POMC transgene completely normalizes PGC-1 in
liver of ob/ob mice (glucose production)
200
b
PGC-1 mRNA
a
a
(WT)
100
WT ob/ob ob/POMCTg
Mizuno and Mobbs
53
CBP expression predicts lifespan
54
CBP expression decreases with age and diabetes
55
CBP-1 and its interacting proteins are induced by
dietary restriction
Cbp-1
56
Preventing the induction of CBP-1 expression by
dietary restriction blocks increased lifespan
57
Preventing induction of CBP-1 by dietary
restriction blocks reduction in the rate of aging
Oxidative stress resistance
Mortality rate
Aggregation of Aß1-42
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Neurobiology of aging Key conclusions

• A. Normal is different from pathological
• Normal aging has little neuron loss or
  neurodegeneration
• Pathological aging is largely neurodegenerative
• Nature of cell vulnerability still largely
  unknown
• B. Early pathologies more genetic, later
  pathologies more sporadic
• C. Normal sensory and motor impairments mainly
  peripheral, pathological motor impairments mainly
  central
• Normal brain aging influences peripheral health,
  and converse as well