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MCB 135K Discussion
Monday, January 30, 2006
GSI: Laura Epstein
Information
• GSI: Laura Epstein
• E-Mail: [email protected]
• Review sessions will be held prior to each exam – Time and locations TBA
• Course is graded on a straight scale unless your performance dictates a curve
Discussion Material
1. Course Introduction
2. Demography
3. Comparative and Differential Aging/Assessment of Aging
4. Cellular Senescence
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 LifeAdulthood
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
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?
What is the epidemiologic transition?
What is the mortality transition?
How long was the longest recorded human life span, male and female?
What are some probable causes that favor longevity in women?
Comparative and Differential Aging
• Aging amongst different animal species
• Aging differences between people of the same species
• Chronological vs. Physiological Age
Figure 3.1: Comparative Maximum Life Spans
**Detailed discussion of figure in the legend, pg. 26
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
Geriatric AssessmentInvolves a multi-dimensional diagnostic process designed
to qualify an elderly individual in terms of:
• Functional capabilities• Disabilities
• Medical & Psychological characteristics
A list of typical assessments is summarized in Table 3.3
For our discussion, we will consider particularly: • Activities of Daily Living (ADL)
• Instrumental Activities of Daily Living (IADL) **See Table 3.4**
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
Functional Assessment
1. Tests examining general physical health
2. Tests measuring ability to perform basic self care (ADLs)
3. Tests measuring ability to perform more complex activities (IADLs), reflecting the ability to live independently in the community
The severity of the disability may be measured in terms
of whether a person:
• Does not perform the activity at all
• Can only perform the activity with the help of another
person
• Can perform the activity with the help of special equipment
Table 3-4 Categories of Physical Health Index MeasuringPhysical Competence
ACTIVTIES INSTRUMENTAL ACTIVITIESOF DAILY LIVING OF DAILY LIVING
Feeding CookingBathing CleaningTo ileting Using telephoneDressing WritingAmbulation ReadingTr ansfer from toilet LaundryVisual acuity Driving a carOthers Others
A theory of “compression” of morbidity (rectangularization of survivorship) curve
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?
Questions Continued
1. What are the components of Geriatric Assessment?
2. What are the categories of these assessment programs
3. What are the differences between ADL’s and IADL’s? Provide some examples
4. Discuss the idea that women have more disability than men.
Senescence
• Replicative Senescence
• Cellular Senescence
• Senescent Phenotype
• Cellular Senescence and Cancer
• Senescence and Aging
• Antagonistic Pleiotropy
Cellular Senescence
What is it?
Response of normal cells to potentially cancer-causing events
First description: the Hayflick limit
Pro
lifer
ativ
e ca
paci
ty
Number of cell divisions
FiniteReplicativeLife Span"Mortal"
InfiniteReplicativeLife Span"Immortal"
EXCEPTIONSGerm line
Early embryonic cells (stem cells)Many tumor cells
What happens when cells exhaust their replicative life span
What happens when cells exhaust their replicative life span
REPLICATIVE SENESCENCE
•Irreversible arrest of cell proliferation(universal)
•Resistance to apoptosis(stem cells)
•Altered function(universal but cell type specific)
SENESCENT PHENOTYPE
Cellular Senescence
What causes it?(what causes the senescent phenotype?)
Cell proliferation (replicative senescence)= TELOMERE SHORTENING
DNA damage
Oncogene expression
Supermitogenic signals
What do inducers of the senescentphenotype have in common?
Inducers of cellular senescence
Cell proliferation(short telomeres)
DNA damage
Oncogenes
Strong mitogens
PotentiallyCancerCausing
Normal cells(mortal)
Immortal cells(precancerous)Inducers
of senescence
Cell senescence Transformation Apoptosis
Tumor suppressor mechanisms
Cellular SenescenceAn important tumor suppressor mechanism
•Induced by potentially oncogenic events
•Most tumor cells are immortal
•Many oncogenes act by allowing cells to bypassthe senescence response
•Senescence is controlled by the two most importanttumor suppressor genes -- p53 and pRB
•Mice with cells that do not senesce die youngof cancer
Cellular SenescenceAn important tumor suppressor mechanism
What does cellular senescence have to do with aging?
•The senescent phenotype entails changes in cell function
•Aging is a consequence of the declining forceof natural selection with age
Aging before cell phones ……
100%
Su
rviv
ors
AGE
Natural environment: predators, infections, external hazards, etcMost of
humanevolution
Modern, protectedenvironment
(very VERY recent)
Antagonistic pleiotropy:Some traits selected to optimize fitness in young
organisms can have unselected deleteriouseffects in old organisms
(what's good for you when you're young may be bad for you when you're old)
Questions
1. What causes cellular senescence, what are the inducers and what do they have in common?
2. What is replicative senescence?
3. List 3 characteristics of the senescent phenotype.
4. What is the relationship between carcinogenesis, aging, and senescence?
5. Explain antagonistic pleiotropy.
Questions continued
• What are the 2 categories of risks for developing cancer?
• What are the 2 things necessary for developing cancer?
• What is the Hayflick limit? What are the exceptions to this idea?
• Explain the significance of telomeres.• How is senescence both “good” and “bad”.