Ryan Klimczak Discussion 7 April 16th, 2007 Lectures 27,28,29- 32.
MCB 135K Discussion Monday, January 29, 2007 GSI: Ryan Klimczak.
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Transcript of 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. Course Introduction
2. Demography
3. Comparative Aging
4. Delaying the Degenerative Diseases of Aging
5. Theories of Aging
Course Introduction
• Age Related Terminology– Aging– Geriatrics– Gerontology– Senescence– Biomarkers– Life-Span– Average Life Span– Life Expectancy– Active Life Expectancy– Longevity– Maximum Life Span
1. Increased length of lifespan & increased number of the elderly in the human population
2. Increased proportion of persons aged 65+ in the population as compared to those aged 14-19
3. This change in the human population is acknowledged by the industries and professions
4. Need to better educate the population in healthy habits
5. Need to support research in biomedicine
6. 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 LifeOvum: Fertilization
- end 1st week
Embryo: 2nd-8th week
Fetus: 3rd-10 lunar month
Neonatal Period
Newborn: end of 2nd week
Infancy: 3rd week-1st year
Childhood: 2-15 years
Adolescence: 6 yrs after puberty
Postnatal Life Adulthood
Prime & transition (20-65 yrs)
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 20-35 200-300
Sweden, 1750s 37 210
India, 1880s 25 230
U. S., 1900 48 133
France, 1950 66 52
Japan, 1996 80 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
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
Table 3-1 Physiologic Correlates with Longevity
INDEX STUDIED CORRELATION
Body weight Direct
Brain/ body weight Direct
Basal metabolic rate Inverse
Stress Inverse
Reproductive function/Fe cundity Inverse
Length of growth period DirectEvolution Uncertain
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.
C. Elegans 2 week lifespanhermaphrodite19,000 genes959 cells
Examples of ways in which environment influences the genome (cont.)
Kenyon et al. Science, 2003
QuickTime™ and aTIFF (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.
Recent approaches challenge the inevitability of
function pathology by grouping the aging processes into three categories:
1. Aging with disease and disability2. 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 onPhysiologic 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
0
Old (26-mo)
Young (4-mo)
70,000
60,000
50,000
40,000
30,000
20,000
10,00024,000
67,000
Cardiolipin Levels in 3 and 24 Month Old Rat Hepatocytes
Ca
rdio
lipin
(µ
g p
er 1
06 C
ells
) 30
20
10
0Young Old
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.
R123 Fluorescence in old and young rat hepatocytes
Fluorescence/cell
No
rma
l ce
ll n
umbe
r0.03
Young
1000100100.00
0.01
0.02
Old
11
Rhodamine 123 -
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.
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)
• Mediates the ratio of acetyl-CoA/CoA• Decreases with age in plasma and in brain• Improves cognitive function in rats
• Transports long-chain fatty acids into mitochondria• Removes short- and medium-chain fatty acids that accumulate
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 acyl-carnitine. 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
MicronutrientDeficiency
HemeDeficit
Complex IV
Deficit
Oxidative Stress
DNA Damag
e
Early Senescen
ce
Pyridoxine [+] ++ ++
Zinc + # #
Riboflavin
Iron + + [+] [+]
Copper [+] [+] [+]
Biotin + + + + +
Lipoic Acid [+]Pantothenate [+] [+]
Micronutrient deficiency and heme synthesis in human cell culture
+ = Atamna/Ames, ++Askree /Ames, #Ho/Ames [+] Literature
Calcium Deficiency Vitamin B12
Fenech: chromosome breaks Fenech: Chromosome breaks
Lipkin: colon cancer mice
Folate Deficiency Selenium
MacGregor/Ames/Fenech: chromosome Rao: DNA damage
breaks mice/humans Combs/Trumbo: Cancer humans
Willett: epi colon cancer humans
Vitamin D Deficiency Omega-3 FA
Garland: epi colorectal cancer humans Denkins: Cancer
Magnesium Deficiency Niacin
Bell: chromosome breaks humans Kirkland/Depeint: DNA damage
Larsson: epi colorectal cancer humans
Zinc Deficiency Choline
Fong: esophageal cancer humans/rodents da Costa: DNA damage in humans
Potassium Deficiency Chang: Cardiovascular Disease
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.
MolecularCodon restriction
Somatic mutation
Error catastrophe
Gene regulation.
Dysdifferentiation
Classification and brief description of main theories of aging
CellularWear-and-tear
Free radical accumulation
Apoptosis
SystemRate-of-living
Neuroendocrine
Immunologic
Evolutionary
Disposable Soma
Antagonistic Pleiotropy
Mutation Accumulation
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).
0
20
40
60
80
100
120
0 4 812 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
100
Evolution in the Laboratory
young flies selected
Normal
% Surviving
Age in Days
- Early adult fecundity increased *antagonistic pleiotropy
Offspring of “young” flies are selected
- Reproductive period extended- Stress resistant, -super flies- Early adult fecundity reduced *antagonistic pleiotropy
Offspring of “old” flies are selected
Molecular Theories of AgingCodon 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 catastropheErrors in information transfer due to alterations in RNA polymerase and
tRNA synthetase may increase with age resulting in increased production of abnormal proteins
Gene regulationAging is caused by changes in the expression of genes regulating both
development and aging
DysdifferentiationGradual accumulation of random molecular damage impairs regulation of
gene expression
* Involving Random Chance
Cellular Theories of Aging
Wear-and-tearIntrinsic and extrinsic factors influence life
span
Free radical accumulationOxidative metabolism produces free radicals which
are highly reactive and thus damages DNA and/or proteins and thus degrades the system structure and function.
ApoptosisProcess 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 AgingThe 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?