Lec 9 - Aging

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What is aging?

Process of getting older

When we think of aging, we usually think of it in terms of chronology

i.e. Over linear timespan

Chronological aging however, is not an accurate predictor of physiological aging

​​​​​​​Cells of elderly look the same as young cells

But they do not withstand challenges as well as younger cells

Homeostenosis = decreased ability to maintain homeostasis under stress

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Programmed & error theories of aging

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Premature aging diseases

Certain genetic diseases display a 'rapid aging' phenotype

Sudden & dramatic onset

These diseases may provide clues as to genes involved in aging process

Longevity genes

Disease associated genes

i) Werner's syndrome

Individuals usually develop normally until puberty

In their 20's, patients experience sudden onset of 'aging-related' characteristics:

Greying of hair +hair loss

Thin, hardened skin

Cataracts

Skin ulcers

Type II diabetes

Diminished fertility

Atherosclerosis

Oesteoporosis

Caused by mutation in WRN gene

Defective DNA repair!

However, dissimilarities between Werner's syndrome & normal aging do exist

Werner's patients do not experience the below pathologies that normal aging people experience:

prostate problems

high blood pressure

strokes

Alzheimer's disease

ii) Hutchinson-Guilford syndrome

Dramatic rapid appearance of aging which begins in childhood

Clinical signs of Hutch-G syndrome:

Growth failure

Alopecia

Small characteristic face with prominent eyes, thin nose, thin lips & protruding ears

Aged-looking skin

Atherosclerosis & CVS problems

Arthritis

Mental development is NOT affected

Individuals typically survive until late teens

Unlike Werner's syndrome, Hutch-G syndrome is not caused by defective DNA repair

Caused by mutations in Lamin A protein gene

Lamin A = Essential scaffolding component of nuclear envelope, giving nucleus its shape

Mutated Lamin A makes nuclear envelope unstable - causes progressive damage to nucleus

Means cells more likely to die prematurely

Like Werner's syndrome, Hutch-G patients do not develop certain types of age related conditions:

No prostate problems

No increased risk of cancer or cataracts

High BP = rare

Don't get Alzheimer's disease or suffer mental degeneration

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Programmed senescence

i) Hayflick's Limit

Umbilical cord fibroblasts removed & cultured

Discovered that human cells derived from embryonic tissues could only divide a finite number of times in culture

​​​​​​​~50-70 divisions

They will NOT divide past this point

'Replicative senescence'

RS has been found in many cell types:

Keratinocytes

Endothelial cells

Lymphocytes

Adrenocortical cells

Vascular smooth muscle cells

Chondrocytes

What's causing the cells to stop dividing?

Telomere degeneration!​​​​​​​

**Hayflick's limit may explain the reason why Dolly the cloned sheep did not survive very long & aged quickly**

ii) Telomeric theory

Telomeres = Non-sense TAGG DNA sequences at end of chromosomes

'Cap' which protects DNA at end of chromosomes

Prevents DDSB repair enzymes from assuming end of chromosome = broken DNA strands!

Each time cell divides, telomeres of chromosomes shorten slightly

Why?

DNA polymerase cannot replicate the tips of chromosomes

This means they shorten every time a cell divides

Not detrimental until a critical length is reached

Signal is transmitted that causes cell to become senescent

Telomerase = Enzyme which is capable of filling the replication gap

Ensures telomeres are kept long enough to prevent any important information being lost

So does this mean cells can live forever?!

...not quite

Over time telomerase levels decrease

Leads to progressive irreversible shortening of telomeres until senescence

Cancer cells exploit telomerase to escape senescence

Allows tumour cells to continually divide without the restraint of telomere shortening

Tumour can become larger & accumulate more mutations - becomes more agressive

What could we use telomerase for?

Measure its levels to detect cancer?

Create telomerase inhibitors which would prevent cancer cell proliferation?

Use it to speed up wound healing?

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Immunosenescence

Decline in immune function with aging

Leads to:

Increased incidence of infections

Pneumonia

Flu

TB

Meningitis

UTIs

Increased incidence of autoimmunity

Rheumatoid arthritis

Lupus

Hepatitis

Thyroiditis

MS

Increased tolerance to organ transplants

Increased cancer incidence

Prostate

Breast

Lung

Stomach/colon

Skin

Leukemia

Pancreas

(**See mol med lec Cancer & genetic instability pg.6)

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Free radical theory

ROS responsible for causing lots of damage to cells, ultimately causing organs to stop functioning

Mitochondria!

Experiments have found data that both supports & negates claim ROS have in aging

Vitamin E 'scavenges' free radicals

Ends up becoming more carcinogenic than the original free radical

High doses vitamin E supplements appear to increase cancer risk in people

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Cross linking theory

Reducing sugars cause protein damage by glycosylation

Glucose molecules attach to proteins (without use of enzymes)

Accumulation of glycolysed cross-linked proteins = cell & tissue structural damage

Cells become rigid

​​​​​​​Loss flexibility of connective tissue

​​​​​​​Arthritis?

Microvascular changes in arteries​​​​​​​

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Nutritional model theory

Food has a role to play in aging process

i) Calorie restriction & aging

Experiments in rats involving calorie restriction

Calorie restricted rats lived 75% longer than controls

Phenotype of calorie-restricted rats:

Maintain youthful activity levels longer

Maintain immune function longer

Better performance memory tests

Fewer tumours

More resistance to carcinogens

Less oxidative damage

Slower formation of collagen cross links

Fewer free radicals

Lower mean blood glucose level