Transcript MCB 135K Discussion

MCB 135K Discussion
Monday, January 29, 2007
GSI: Ryan Klimczak
Information
• GSI: Ryan Klimczak
• E-Mail: [email protected]
• Review sessions will be held prior to
each exam
– Time and locations TBA
Discussion Material
1.
2.
3.
4.
Course Introduction
Demography
Comparative Aging
Delaying the Degenerative Diseases
of Aging
5. Theories of Aging
Course Introduction
• Age Related Terminology
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–
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Aging
Geriatrics
Gerontology
Senescence
Biomarkers
Life-Span
Average Life Span
Life Expectancy
Active Life Expectancy
Longevity
Maximum Life Span
1.
2.
3.
4.
5.
6.
Increased length of lifespan &
increased number of the elderly in
the human population
Increased proportion of persons
aged 65+ in the population as
compared to those aged 14-19
This change in the human
population is acknowledged by
the industries and professions
Need to better educate the
population in healthy habits
Need to support research in
biomedicine
Points 4 and 5 must take into
consideration the entire life cycle
as our health today depends on
our health yesterday and will
influence our health tomorrow
Divisions of the Lifespan
Prenatal Life
Ovum: Fertilization
end 1st
week
Embryo: 2nd-8th
week
Fetus: 3rd-10
lunar
month
Postnatal Life
Neonatal Period
Adulthood
Newborn: end of 2nd week
Prime & transition
(20-65 yrs)
Infancy: 3rd week-1st
year
Childhood: 2-15 years
Adolescence: 6 yrs after
puberty
Old age &
senescence (65 yrs+)
Life expectancy and infant mortality throughout human
history
Life expectancy Infant mortality rate
at birth (years) (per 1000 live births)
Prehistoric
Sweden, 1750s
India, 1880s
U. S., 1900
France, 1950
Japan, 1996
20-35
37
25
48
66
80
200-300
210
230
133
52
4
Questions
• Lecture 1 - The Journey of Life
 What is the primary reason that life span has doubled since
~1900?
 What was the average life span in prehistoric times, ~1900,
now?
 When does the process of aging begin?
 Why doesn’t the degree of pathophysiology correlate directly
with age?
 What is the reason for the increase in average life span from
~1880 - 1960? From 1960 - present?
Demography
• Statistical study of human populations:
– Size and density distribution
• Vital Statistics:
– epidemiology: Births, deaths, diseases
Life expectancy at birth by sex, France 1806-1997
Proportion of population aged 0-14 versus 65+(In Italy)
Centenarians
• Generally good health
– Escapers
– Late onset of disease
– Early disease that was
overcome
• SSC (Semi-Super)
– 105+
• SC (Super)
– 110+
• Possible role of IGF-1
Receptor
• Oldest Female
– 122 years
– Jeanne Calment
• Oldest Male
– 115 years
– Christian Mortensen
Questions
•
Lecture 2 - Demography of Aging
 What is epidemiology?
 How long was the longest recorded human life span, male and female?
 What are some probable causes that favor longevity in women?
 What does the concordance between centenarians and the increased
likelihood of prolonged lifespan in their offspring suggest?
 What physiological characteristics are generally observed in individuals who
live past the age of 100?
Comparative and Differential
Aging
• Aging amongst different animal species
• Aging differences between people of the
same species
• Chronological vs. Physiological Age
Figure 3.2: Comparison of the relationship of brain
weight to life span in vertebrates
Figure 3.1: Comparative Maximum Life Spans
**Detailed discussion of figure in the legend, pg. 26
Table 3 -1
Physiologic Corre lat es with Longevity
INDEX STUDI ED
CORRELATION
Body weig ht
Brain/ body weight
Basal me ta bolic rate
Direct
Direct
Inverse
St ress
Reproduct ive funct ion/Fe cundit y
Length of grow t h period
Evolut ion
Inverse
Inverse
Direct
Uncert ain
Examples of ways in which environment influences the genome (cont.)
C. Elegans
2 week lifespan
hermaphrodite
19,000 genes
959 cells
Among invertebrates, the most used models have been the fly
(Drosophila melanogaster) and the nematode (C. elegans)
Suppression of the receptor for insulin/IGF hormone will
produce a mutant nematode that will live 6x longer than
corresponding controls and be more resistant to all stress.
Kenyon et al. Science,
2003
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Figure 3.3: The
heterogeneity of the
elderly population
as illustrated by
scores in a
hypothetical test.
Transcriptional Profile of
Aging Related Genes in the
Human Brain
Rodwell et al. 2004
Recent approaches challenge the
inevitability of
function pathology by grouping the
aging processes into three categories:
1. Aging with disease and disability
2. Usual aging, with absence of overt
pathology but presence of some
declines in function
3. Successful or healthy aging, with no
pathology and little or no functional
loss
Assessment of Physiological Age in
Humans
Physiological age depends on
Physiologic competence: good to
optimal function of all body systems
&
Health status: absence of disease
Physiological age may or may not
coincide with chronological age
Laboratory Values in Old Age:
1. Most values unchanged (e.g. hepatic,
coagulation, electrolytes, renal, thyroid,
blood count, etc.)
2. Some values decreased (e.g. HDL in
women)
3. Some values increased (e.g. LDL in men,
glucose)
**See Table 3.2**
Question
•Comparative and Differential Aging
How well does chronological age correlate with physiological
age? In young versus old individuals?
What parameters do you use to define "healthy" aging?
What sorts of behavior favor a long life span?
What are the mechanisms or traits associated with
"successful" aging?
What is aging vs. usual aging vs. successful aging?
Discuss the idea that women have more disability than men.
Delaying the Degenerative Diseases of
Aging
•Oxidative DNA damage as a function of aging
•Mitochondrial decay and aging
•ALCAR and Lipoic Acid, potential supplements to extend
lifespan/enhance quality of life
•Nutrient deficiency and aging
Estimated oxidative DNA adducts
per rat liver cell
70,000
Old (26-mo)
60,000
67,000
50,000
40,000
30,000
20,000
10,000
0
Young (4-mo)
24,000
Mitochondria in hippocampal neurons
Young
Old
Electron Microscopy Images
Cardiolipin (µg per 106 Cells)
Cardiolipin Levels in 3 and 24 Month Old Rat Hepatocy
30
20
**
10
Cardiolipin
(diphosphatidyl
glycerol) is an
important component
of the mitochondrial
membrane, typically
present in
metabolically active
cells of the heart and
skeletal muscle. It has
also been observed in
certain bacterial
membranes. It serves
as an insulator and
stabilizes the activity
of protein complexes
important to the
electron transport
chain.
0
Young
Old
10
R123 Fluorescence in old and young rat hepatocytes
0.03
Rhodamine 123 -
Normal cell number
Old
A popular green
fluorescent
mitochondrial dye
that stains
mitochondria in living
cells in a membrane
potential-dependent
fashion. Widely used
in flow cytometry
studies involving
mitochondrial
membrane potential.
0.02
Young
0.01
0.00
10
100
1000
Fluorescence/cell
11
Mitochondria from old rats
compared to those from young
rats:
1) Lower Cardiolipin
2) Lower Membrane Potential
3) Lower Oxygen Utilization
4) Increased Oxidant Leakage
L-Carnitine/Acetyl-L-Carnitine (ALCAR)
•
•
Transports long-chain fatty acids into mitochondria
Removes short- and medium-chain fatty acids that accumulate
•
•
•
Mediates the ratio of acetyl-CoA/CoA
Decreases with age in plasma and in brain
Improves cognitive function in rats
WIKIPEDIA DEFINITION:
Carnitine transports long-chain acyl groups from fatty acids into the
mitochondrial matrix so they can be oxidized for energy. Fatty acids
must be activated before binding to the carnitine molecule to form acylcarnitine. The free fatty acid in the cytosol is attached with a thioester
bond to coenzyme A (CoA). This reaction is catalyzed by the enzyme
fatty acyl-CoA synthetase and driven to completion by inorganic
pyrophosphatase.
The acyl group on CoA can now be transferred to carnitine and the
resulting acyl-carnitine transported into the mitochondrial matrix. This
occurs via a series of similar steps:
-Acyl-CoA is conjugated to carnitine by carnitine acyltransferase
(palmitoyltransferase) I located on the outer mitochondrial membrane
-Acyl-carnitine is shuttled inside by a translocase
-Acyl-carnitine is converted to acyl-CoA by carnitine acyltransferase
(palmitoyltransferase) II located on the inner mitochondrial membrane.
The liberated carnitine returns to the cytosol.
R--Lipoic Acid (LA) in mitochondria
• LA reduced to dihydrolipoic acid, a potent antioxidant, & chelator of
Fe & Cu
• Coenzyme of pyruvate and -ketoglutarate dehydrogenases,
involved in the citric acid cycle
• Involved with carbohydrate utilization for ATP production, shown to
increase the cellular uptake of glucose in vitro by recruiting a
glucose transporter to the cellular membrane
15
Effects of ALCAR and LA supplements
•ALCAR increases Cardiolipin levels, increases mitochondrial membrane potential
•ALCAR/LA reduce the amount of mitochondrial DNA adduct levels in old rats
-increases ambulatory activity of old rats
-enhances immune function
-improves spatial memory/ mental acuity
•Clinical trials in humans suggest LA can improve neuropathic symptoms and
deficits in diabetic patients
Micronutrient deficiency and heme synthesis in human cell
culture
Micronutrient Heme
Deficiency
Deficit
Pyridoxine
Complex
IV
Deficit
DNA
Early
Oxidative Damag
Senescen
Stress
e
ce
[+]
Zinc
++
+
#
#
[+]
++
Riboflavin
Iron
+
+
[+]
Copper
[+]
+
[+]
[+]
+
+
[+]
[+]
[+]
Biotin
Lipoic Acid
Pantothenate
+
+ = Atamna/Ames, ++Askree /Ames, #Ho/Ames [+] Literature
+
Calcium Deficiency
Fenech: chromosome breaks
Vitamin B12
Fenech: Chromosome breaks
Lipkin: colon cancer mice
Folate Deficiency
MacGregor/Ames/Fenech: chromosome
breaks mice/humans
Willett: epi colon cancer humans
Vitamin D Deficiency
Garland: epi colorectal cancer humans
Magnesium Deficiency
Bell: chromosome breaks humans
Larsson: epi colorectal cancer humans
Zinc Deficiency
Fong: esophageal cancer humans/rodents
Potassium Deficiency
Chang: Cardiovascular Disease
Selenium
Rao: DNA damage
Combs/Trumbo: Cancer humans
Omega-3 FA
Denkins: Cancer
Niacin
Kirkland/Depeint: DNA damage
Choline
da Costa: DNA damage in humans
Questions
•Discuss the correlation between DNA Oxidative Damage and aging.
•How may ALCAR or LA mediate their potential effects?
•What are the effects of aging on mitochondria and mitochondrial
function?
•List some nutrient deficiencies and describe their potential contribution
to accelerated aging.
Theories of Aging
Classification and brief description
of main theories of aging
Molecular
Cellular
Codon restriction
Wear-and-tear
Somatic mutation
Free radical accumulation
Error catastrophe
Apoptosis
Gene regulation.
Dysdifferentiation
Evolutionary
Disposable Soma
Antagonistic Pleiotropy
Mutation Accumulation
System
Rate-of-living
Neuroendocrine
Immunologic
Evolutionary Theories of Aging
Disposable Soma - Somatic cells are maintained only to ensure
continued reproductive success, following reproduction
the soma is disposable. (life span theory)
Antagonistic Pleiotropy - Genes that are beneficial at younger
ages are deleterious at older ages.
(Pleiotropism = The control by a single gene of several distinct
and seemingly unrelated phenotypic effects)
Mutation Accumulation - Mutations that affect health at older
ages are not selected against (no strong evidence).
Evolution in the Laboratory
Offspring of “young” flies are selected
- Early adult fecundity increased
*antagonistic pleiotropy
% Surviving
Offspring of “old” flies are selected
- Reproductive period extended
- Stress resistant, -super flies
- Early adult fecundity reduced
*antagonistic pleiotropy
Normal
young flies
selected
Age in Days
Molecular Theories of Aging
Codon restriction
Fidelity and/or accuracy of mRNA message translation is impaired with aging due to cell inability
to decode the triple codons (bases) in mRNA molecules
Somatic mutation
Type of stochastic* theory of aging that assumes that an accumulation of environmental insults
eventually reaches a level incompatible with life, primarily because of genetic damage.
Error catastrophe
Errors in information transfer due to alterations in RNA polymerase and tRNA synthetase may
increase with age resulting in increased production of abnormal proteins
Gene regulation
Aging is caused by changes in the expression of genes regulating both development and aging
Dysdifferentiation
Gradual accumulation of random molecular damage impairs regulation of gene expression
* Involving Random Chance
Cellular Theories of Aging
Wear-and-tear
Intrinsic and extrinsic factors influence life span
Free radical accumulation
Oxidative metabolism produces free radicals which are highly
reactive and thus damages DNA and/or proteins and thus
degrades the system structure and function.
Apoptosis
Process of systematically dismantling key cellular components as
the outcome of a programmed intracellular cascade of
genetically determined steps.
System Theories of Aging
Rate-of-living
An old theory that assumes that there is a certain number of calories or heart beats
allotted to an individuals and the faster these are used the shorter the life.
Neuroendocrine
Alterations in either the number or the sensitivity of various neuroendocrine
receptors gives rise to homeostatic or homeodynamcis changes that results in
senescence.
Immunologic
Immune system reduces its defenses against antigens and thus results in an
increasing incidence of infections and autoimmune diseases.
Free Radical Theory of Aging
The free-radical theory of aging (FRTA) is that organisms age
because protein, lipid and nucleic acids (DNA, RNA) accumulate free
radical damage with the passage of time. Free radical attack on
protein, lipid and nucleic acids leads to a reduction in their respective
function, thereby decreasing cell function, then organ function, and
finally, organismal function.
Any element that has an unpaired electron in its outermost shell is
considered to possess a "free radical”. In biochemistry, the free
radicals of interest are often referred to as reactive oxygen species
(ROS) because the most biologically significant free radicals are
oxygen-centered. But not all free radicals are ROS and not all ROS are
free radicals.
Questions:
Describe the genetic changes that may underlie the short lived and
long-lived phenotypes in the evolutionary fly studies.
What is a real world example that demonstrates the disposable
soma theory?
How can the lifespan extending effects of caloric restriction be
explained by the various theories of aging?