MCB 135K Discussion

February 2, 2005

Topics

• Functional Assessment of the Elderly

• Biomarkers of Aging

• Cellular Senescence– Lecture PowerPoint to be posted on website

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**

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

Figure 3. 6: % of persons 70 years & older having difficulty/inability to perform ADLs & IADLs

With advancing age, 1) disability intensity increases in men & women; 2) disability intensity is higher in women than in men at the same age (esp. at later ages); 3) females live a longer average life span but live longer with disability

Table 3-6 Physiologic Parameters in Aging, Physical Inactivity Weightlessness (In Space) Reduced Increased

Maximum oxygen consumption Systolic blood pressure and peripheral resistance

Resting and maximum cardiac output Vestibular sensitivity Stroke volume Serum total cholesterol Sense of balance Urinary nitrogen and creatinine Body water and sodium Bone calcium Blood cell mass Lean body mass Glucose tolerance test Variable Sympathetic activity and neurotransmission Endocrine changes Thermoregulation Altered EEG Immune responses Altered sleep

Changes in specific senses

A theory of “compression” of morbidity (rectangularization of survivorship) curve

Questions

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

5. Explain compression of morbidity

How genetic susceptibility may influence a disease:

• By itself

• By making the carrier more susceptible to disease

• By increasing the expression of a risk factor, or the risk factor may increase the genetic effects

Disease as a tool for the study of aging

• Sporadic cases of syndromes having multiple characteristics of premature (early onset, 20-30 years of age) or accelerated (rapid progression) aging occur in humans

These conditions are grouped under the name of progeria.

Examples of progeria syndromes are Werner’s syndrome (WS) and Hutchinson-Guildford

syndrome

Differences between WS & Aging

WS

• Rare

• NO hypertension

• NO dementia

• Tissue calcifications

Aging

•Universal

•Hypertension

•Dementia

•NO tissue calcifications

Questions

1. What are three ways that genetic susceptibility influences disease?

2. What is progeria?3. What is a biomarker and how can progeria

be used as one?4. What are some characteristics of WS?5. List the differences between diseases and

aging

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