Transcript Physico-chemical-cellular

Three Definitions of Aging
• Mortality rate
– Patterns of age-stratified populations (timing and
acceleration).
– Two main demographic parameters were calculated from
Gompertz model of survival curves:
• Gompertz rate of mortality acceleration (G) after maturation
• Initial mortality rate at maturation (IMR)
• Reproductive fitness
– Aging as loss of reproductive capacity.
• Physico-chemical-cellular
– Changes of individual organisms (molecules to organ
pathology)
What Does
Physico-Chemical-Cellular
Aging Look Like?
Skin’s Structure
Younger vs. Older Skin
Cartilage
Juvenile state
Aged, eroding (arrow)
Normal Bone Structure
Bone Balances Synthesis, Destruction
<Osteoclast
^O’blasts in new bone
Osteoporosis Erodes Bone Mass
Normal Skeletal Muscle
Aging Skeletal Muscle
Sarcopenia
Coronary Arteries
Elastic and Muscular Arteries
Normal, Aged Cardiomyocytes
Extensive lipofuscin deposits
Normal, Aged Cardiomyocytes
Extensive lipofuscin deposits
Normal Pulmonary Structure
<Bronchiole
Alveolar sac>
Pathological
Alveolar
Changes
^ Normal-appearing
^ Fibrosis, rupture of emphysema
The Filtration Membrane
<Normal
^Infiltrated, thickened
Electron-Dense (AGEs?) Depositional
Changes in Filtration Membrane
Villus Atrophy
Diverticular Disease
CNS Changes
CNS Changes: VERY Hard to Isolate!
CNS Changes DO Occur
fMRI Scans Show CNS Changes
Surprise!
Is Cognitive
Decline
“Intrinsic”?
Ernst Mayr: “Portrait” Photo
Ernst Mayr at 98
At 100 of Age, Mayr Produced…
• Last of his 25 books
(81 yrs after his first)
• Last 7 of his 856
research papers
• Had manuscripts in
progress on his desk
when he died
Is Cognitive Decline “Intrinsic”?
Other Changes
• Immunity:
– Reduced sensitivity, acquired functions
– Elevated inflammatory functions
• Metabolism:
– BMR stable, but O2 use declines
– Is this bad, or good?
• Endocrine/Reproduction:
–
–
–
–
Loss of insulin sensitivity
HPA, other hormone feedbacks blunted
Men lose circadian testosterone cycle
Women lose monthly estradiol cycle
Ernst Mayr, 1961
To explain aging we
must explain:
• Where senescence
originates (why)
• Mechanisms of
senescence (how)
Theory
Natural
history
Experimental
outcomes
An “Ultimate” Aging Model Must
Explain Natural History…
•
•
•
•
WHY natural selection “favors” aging
WHY organisms lose reproductive fitness
WHY life history curves change
WHY most species age variably, & some
organisms appear not to age
• HOW organisms undergo observable tissue,
organ (& cell!) changes
• HOW members of 1 species can undergo
CUPID changes at different rates
An “Ultimate” Aging Model Must
Explain Experimental Data…
• WHY caloric restriction works
• WHY methuselah, stunted mutants exist
• WHY older organisms produce
dysfunctional proteins
Two “Ultimate” Models of Aging
• Geriatric hypothesis
• Disposable soma hypothesis
– Functional reserve capacity
– General Adaptation Syndrome
Geriatric Hypothesis Provides
Both Origin, Mechanism
Weissman, 1889 (Origin/Why)
• Aging removes organisms & makes
room for the next generation.
• Provides turnover necessary for
evolution.
Geriatric Hypothesis, cont.
Weissman, 1891 (Mechanism/How)
• Body has germ cells, somatic cells.
– Germ cells are immortal, totipotent
– Somatic cells are pluri- to unipotent, fixed
lifespan.
• Aging is restricted to somatic cells
– Unicellular organisms do not age
– Unicellular reproductive stage “resets”
multicellular metazoans
Geriatric Hypothesis, cont.
What evidence supports this model?
What predictions can we make?
What are weaknesses in this model?
Geriatric Hypothesis, cont.
Evidence?
• Programmed death in rotifers
• Protein failure in worms, rodents
• Correlation of metabolism to size, age
Predictions?
• Death is an evolved program inherent to
multicellular design
Weaknesses?
• Where is selection force acting?
Disposable Soma Hypothesis
Provides the Origin/Why
• MacArthur and Wilson, 1967
– Adds population, evolutionary theory to
geriatric hypothesis
• Premise: fecundity and longevity are linked
– Organisms have development, reproductive,
post-reproductive phases
– An organism has finite resources to maintain
body systems vs. reproduce
Disposable Soma Hypothesis
• Selection favors maximizing reproductive
fitness
– Eventually, repair gets too “expensive”
– Selection favors bodies that are
“good enough to produce maximal offspring”
• General corollaries
– Body size will correlate directly w/longevity.
– Metabolic rate will correlate directly w/
longevity.
Resource Allocation Strategies
Vary Along a Continuum
Longevity Resources
invested in
parental
soma
Resources
invested in
offspring
Offspring
number
r-selected Short
Low
Minimal
Many
k-loner
selected
Long
High
Usually
low
Many
k-social
selected
Long
High
High
Low
Disposable Soma Hypothesis, cont.
What is evidence to support this model?
What predictions can we make?
What are weaknesses in this model?
What is missing?
Functional Reserve Capacity:
The Mechanism/How
• Based on Selye’s general adaptation
syndrome
General Adaptation Syndrome
Hans Selye
• Stress
response
has 3
phases
• There is
eustress
vs
distress
(dys-stress)
Five Proximal Causes of Aging
Are Sources of Distress
Probabilistic
• Wear and Tear Model
• Mutation Model
• Mitochondrial Injury Model
Mixed
• Immune Dysfunction Model
Deterministic
• Genetic/Developmental Program Model