MCB 135K Discussion

Monday, January 30, 2006

GSI: Laura Epstein

Information

• GSI: Laura Epstein

• E-Mail: Laura_Epstein@berkeley.edu

• 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”.