The Theory Of Aging - Ayu

“The link between genes and lifespan is

unquestioned. The simple observation that

some species live longer than others-

humans live longer than dogs, tortoises

longer than mice- is one convincing piece of

evidence”- The National Institute of Aging-

Compiled by: Ayu Yussof

WHAT IS AGING?

Everyone intuitively knows what ‘aging’ means, but it is quite difficult to give the exact

definition of aging. These are some of the widely accepted definitions of aging:

Aging is inevitable physiological changes occurring in organisms over time. It

ultimately ‘leads to death naturally as one gets old along with gradual dysfunctions of

all organs in the organisms’. Aging is the direct cause of diseases and death in humans.

Along with growth, aging proceeds once human are born. Based upon aging, many

physiological phenomena such as reduction in the number of cellular tissues, a

decrease of the metabolic rate, an increase of diseases and loss of adaptability take

place. The progression of aging is a degenerative change associated with biological

characteristics rather than being determined by environmental factors and ultimately

indicates that the probability of death is rapidly increasing. The environmental factors

that are relevant to lifestyle including stress, exercise, smoking and exposure to

sunlight either accelerate the progression of aging.

The processes that occur during life which culminate in changes that decreased an

individual’s ability to handle biological challenges.

The gradual and spontaneous changes that occur in maturation from infant to young

adult. These changes create a normal physiologic decline seen in middle and late

adulthood.

Aging is initiated based on genetic and environmental factors that operate from the

time of birth of organisms. Aging induced several physiological phenomena such as

reduction of cell counts, deterioration of tissues proteins, tissue atrophy, a decrease of

the metabolic rate, reduction of body fluids and calcium metabolism abnormalities.

This phenomena leads to several vital impairments such as cardiopulmonary,

neurological, endocrine function, as well as motor function impairments. Therefore,

the exposure to risk factors including hypertension, smoking, hyperlipidemia, glucose

metabolism impairment, obesity, food, lifestyle, alcohol and stress induced multiple

diseases in various body system e.g.

- Nervous central system: Along with aging, the number of cerebral nerve cells is

reduced by approximately 20% in cerebral blood flow. The size of the brain is

then reduced slightly and some neurons are lost in selected part of the brain such

as locus ceruleus, subsantia nigra, hippocampus, caudate nucleus, putamen and

cerebral cortex. However, there are no sufficient studies showing that the

functions of the brain are markedly impaired due to aging.

Dementia, degenerative diseases, stroke, cataract and hearing loss.

- Neuroendocrine system: It has been well known that the loss of some neurons is

accompanied in the neuroendocrine system by aging.

hormone imbalance

- Cardiopulmonary system: hypertension, arteriosclerosis, heart failure,

arrhythmias and pulmonary emphysema.

- Digestive system: Stomach ulcer and diverticulum.

- Metabolic system: Diabetes


- Renal system: Kidney failure

- Skeletal system: Osteoporosis and degenerative arthritis

THEORIES OF AGING

“The link between genes and lifespan is unquestioned. The simple observation that some

species live longer than others- humans live longer than dogs, tortoises longer than mice-

is one convincing piece of evidence”- The National Institute of Aging-

All aging begins with genetics

Aging changes the biochemical and physiological processes in the body

Cell and molecular biologists examine and propose theories to explain the aging

process

- What causes aging?

- How can you manipulate aging, thus prolong life?

THE MAIN CATEGORIES IN THEORY OF AGING.

1. Programmed theories: Aging has a biological timetable or internal biological clock

- The programmed theories imply that aging follows a biological timetable,

perhaps a continuation of the one that regulates childhood growth and

development. This regulation would depend on changes in gene expression

that affect the system responsible for maintenance, repair and defense

responses.

2. Error theories

- Aging is the result of internal or external assault that damage cells or organs

so they can no longer function properly.

- The error theories emphasize environmental assaults to living organisms that

induce cumulative damage at various levels as the cause of aging.

PROGRAMMED VS. ERROR THEORIES

PROGRAMMED THEORIES ERROR THEORIES

1. Programmed senescence theory

2. Endocrine theory

3. Immunology Theory

Wear and tear theory

Rate-of-living theory

Cross-linking theory

Free radical theory

Error Catastrophe theory

Somatic mutation theory

Hayflick’s Cellular Clock Theory


PROGRAMMED THEORIES

1. PROGRAMMED SENESCENCE THEORY

Senescence can be defined as a process by which organisms proceed through a

physical deterioration of the body. It is a complex biological process in which changes

at molecular, cellular and organ levels result in an escalating, inexorable and

ineluctable decrease of the body’s ability to respond appropriately to internal and/or

external stressors (Chodzko-Zajko & Ringel, 1987). Senescence is a degenerative

process by which a cell loses its ability to divide, grow and function. This loss of

function ultimately ends in death.

Example:

i. Telomeric Theory:

- Telomerase are specialized DNA sequences at the end of chromosome.

**They shorten with each cell division.

**When the telomeres become too short, the cell enters the senescence stages.

- In the normal process of DNA replication, the end of the chromosome is not

copied exactly, which leaves an unreplicated gap.

The enzyme; telomerase fills the gap by

attaching bases to the end of the

chromosomes.

As long as the cells have enough

telomerase to do the job, they keep the

telomeres long enough to prevent any

important information from being lost

as they go through each replication.

- With time, telomerase levels

decrease.

- With decreasing telomerase levels,

the telomeres become shorter and

shorter.


2. ENDOCRINE THEORY

Biological clocks act through hormones to control the pace of aging. Hormones

effects growth, metabolism, temperature, inflammation and stress.

Examples: Menopause

- Decreased level of estrogen and progesterone

- Hot flushes, insomnia

3. IMMUNOLOGIC THEORY

A programmed declined in the immune system leads to an increased vulnerability to

disease, aging and death.

Examples: Decreased T cells (helper cells) in adults

- Increased diseases in older adults

- Increased autoimmune diseases in adults

ERROR THEORIES

1. WEAR AND TEAR THEORY

Years of damage to cells, tissues and organs eventually wear them out, killing both

them and the body.

Example: Wearing out the skeletal system such as osteoarthritis

Wear and tear can be viewed as a result of aging and not the cause of it.

2. RATE-OF-LIVING THEORY (Pearl, 1928)

“Human possessed a finite amount of some vital substance. When that substance is

consumed, we die.”

The greater an organism’s basal metabolic rate, the shorter the life span.

Free radicals or other metabolic by-product play a role in senescence.

Example: Animal with the most rapid metabolism tend to have the shortest lifespan,

i.e, birds have a shorter lifespan than human.

Studies examining the relationship between metabolic rates and longevity have

produces inconsistent results, limiting the usefulness of this theory.

3. CROSS-LINKING THEORY (Dr. Johan Bjorksten, 1968)

The accumulation of cross-linked proteins damages cells and tissue, slowing down

bodily processes.

Example: Non-enzymatic glycosylation reactions occur when glucose molecules

attach to proteins causing a chain of chemical reactions resulting in a structural

change to the proteins.

- Loss of flexibility of connective tissue

- Microvascular changes in arteries


4. FREE RADICAL THEORY (Dr. Denham Harman, 1954)

Free radical is a term used to describe any molecule that differs from conventional

molecules which possessed a free electron, a property that makes it react with other

molecules I highly volatile and destructive ways.

In a conventional molecule, the electrical charge is balanced. Electrons come in pairs

so that their electrical energies cancel each other out. Atoms that are missing electrons

combine with atoms that have extra electrons, creating a stable molecule with evenly

paired electrons and a neutral electrical charge.

The free radical, on the other hand, has an extra negative charge. This unbalanced

electrical energy tends to make the free radical attach itself to other molecules as it

tries to steal a matching electron to attain electrical equilibrium. By doing so, they

created more free radicals and extensive bodily damage.

Free radicals attack the structure of our cell membranes, creating metabolic waste

products, including substances known as lipofuscins (aging spots). These lipofuscins

in turn interfere with the cells’ ability to repair and reproduce themselves. They

disturb DNA & RNA synthesis, interfere with synthesis of protein, deplete energy

level

The free radical "grabs" electron from any molecule in its vicinity

it does this because electrons like to exist in pairs.

When it 'grabs' an electron from another molecule, it damages the other molecule.


Some of the molecules that may be damaged by free radicals are fats, proteins, and

DNA (both in the nucleus and in mitochondria).

If membrane fats are attacked, then you get the breakdown of the cell membrane. If it

is red blood cell membrane, you get hemolysis.

If proteins are attacked, you get the breakdown of proteins, which may result in the

loss of biological function and the accumulation of ‘catastrophic’ compounds.

If DNA is attacked, you will get a mutation that may cause aging or cancer.

However, free radicals do not go unchecked. The body has multi-layers of defense

system that reacts and detoxifies the damaging radicals. The defenses include:

- Natural antioxidants in the body, such as bilirubin.

- Enzymes such as superoxide dismutase (SOD), catalase & glutathione

peroxidase.

- Dietary antioxidants such as beta carotene and vitamins C and E.

Under normal conditions, the body natural defense mechanisms prevent most of the

oxidative damage from occurring. The free radical theory of aging proposes that, little

by little, small amounts of damage accumulation contribute to the deterioration of

tissues and organs.

5. HAYFLICK LIMIT: CELLULAR CLOCK THEORY

Dr. Leonard Hayflick & Dr Paul Moorhead discovered that human cells have a

limited capacity to reproduce themselves in culture of dividing. This limitation is

believed to be determined by the length of cell’s telomeres. It was believed by

scientists that telomere shortening is the answer to human aging process. However, in

human not all types of tissue contain actively replicating cells. Example, brain cells

and muscle cell of the heart does not have replicating activity. The scientists conclude

that while telomeres may contribute to aging but does not govern it.


1. MOLECULAR THEORIES

Codon restriction – Accuracy of mRNA translation is impaired due to inability to

decode codon in mRNA.

Error catastrophe (Dr. Leslie Orgel, 1963)

- Fidelity of gene expression decline with age, resulting in increased fraction of

abnormal proteins.

- Any damage to the enzyme systems that synthesize proteins in the body

results in faulty protein synthesis.

- The faulty proteins continue to accumulate in the cell until they reach a level

that damages the cells, tissues and organ. When enough damage accumulates,

this may result in cell malfunctioning (aging) leading to death.

Somatic mutation (Dr. Leo Szilard, 1959)

- Accumulation of molecular damage, primarily to DNA / genetic material.

- Genetic mutation occur and accumulate with age in the somatic cell causing

the cell to:

Deteriorate

Malfunction

- Accumulation of mutations result in:

Damage to the DNA: the theory states that aging is an imbalance between

DNA’s ability to repair itself and accumulating DNA damage.

When the damage exceeds repair, the cell malfunctions and this can lead to

senescence.

Dysdifferentiation – Gradual accumulation of random molecular damage impairs

regulation of gene expression.

Gene regulation – Aging caused by changes in gene expression regulating both

aging & development.

Biological Theories Of Aging

Molecular theories

Cellular theories

System theories

Evolutionary theories


2. CELLULAR THEORIES

Wear & tear – Accumulation of normal injury.

Free radical – Oxidative metabolism produces highly reactive free radicals that

subsequently damage proteins and DNA (B. Ames, 10 and R. Melhom, 12)

Apoptosis – programmed cell death resulting from genetically determined events

or genomes crisis (J. Campisi, 11)

Senescence – Phenotypes of aging are caused by an increased in frequency of

senescent cells. Senescence may be the result from telomere loss (replicative

senescence) or cell stress (cellular senescence)

3. SYSTEM THEORIES

Rate of living – Assumes a fixed amount of metabolic potential for every living

organisms (live fast, die young)

Neuroendocrine (Prof. Vladimir Dilman of Petrov Institute of Oncology, St.

Petersberg, Russia, 1983) – Alteration in neuroendocrine control of homeostasis

results in age-related physiological changes. (P.S Timiras, F. Yaghmaie, 35)

Immunologic – Well documented decline of immune function with age results in

increased incidence of disease. (H. Stemberg, 25+26)

4. EVOLUTIONARY THEORIES

Disposable soma – somatic cells are maintained only to ensure continued

reproductive success; following reproduction the soma is disposable.

Life span theory – Different organisms vary dramatically in their lifespan.

Obviously aging negatively affects the duration of life since it increases the risk of

death. These intrinsic, maladaptive effects of aging, unchecked by selection, are,

however, not the only factors affecting the length of life. Independent of whether

aging occurs or not, reproductive lifespan can evolve adaptively in response to

selection for increased reproductive success (Stearns 1992)

Mutation accumulation – Mutations that affect health at older ages are not selected.

According to Medawar ‘s MA hypothesis (1946, 1952); if the effects of a

deleterious mutation were restricted to late ages, when reproduction has largely

stopped and future survival is unlikely, carriers of the negative mutation would

have already passed it on to the next generation before the negative late-life


effects would become apparent. In such situation, natural selection would be weak

and ineffective at eliminating such mutation and over evolutionary time such

effectively neutral mutation would accumulate in the population by genetic drift,

which in turn would lead to the evolution of aging.

Antagonistic pleiotropy – Genes that are beneficial at younger ages are deleterious

at older ages. George C. Williams (1957) argued Medawar’s MA hypotheses; if it

is true that selection cannot counteract deleterious effects at old age, he argued,

then mutations or alleles might exist that have opposite, pleiotropic effects at

different ages: genetic variants that are on one hand exhibit beneficial effects on

fitness early in life, when selection is strong, but on the other hand have

deleterious effects late in life, when selection is already weak. This hypotheses is

known today as the AP hypothesis for the evolution of aging (Rose 1991, Flatt &

Promislow 2007, Figure 3B)

ERIC ERIKSON’S THEORY: FULL LIFE DEVELOPMENT THEORY

The 1st psychological theorist to develop a personality theory that extends to old

age.

Erikson’s approach in perspective is influential and comprehensive; it covers

entire life span. He believed that not everyone passes through stages at the same

time.

Psychological Theories Of

Aging

Full-life development theories

(Erikson's Theory)

Mature-life theory

1. Robert Peck's

2. Neugarten's Theory


STAGE PSYCHOSOCIAL CRISIS BASIC VIRTUE AGE

1 Trust vs Mistrust Hope 0 - 1 ½

2 Autonomy vs Shame Will 1 ½ - 3

3 Initiative vs Guilt Purpose 3 – 5

4 Industry vs Inferiority Competency 5 – 12

5 Ego Identity vs Role Confusion Fidelity 12 – 18

6 Intimacy vs Isolation Love 18 – 40

7 Generativity vs Stagnation Care 40 – 65

8 Ego Integrity vs Despair Wisdom 65+

ROBERT PECK’S: MATURE LIFE THEORY

STAGE 1

EGO DIFFERENTIATION

VS

WORK-ROLE PERFORMANCE

For those who invested heavily in their

careers, finding other ways to affirm self-

worth through family, friendship, and

community life.

STAGE 2

BODY TRANSCENDENCE

VS

BODY PREOCCUPATION

Surmounting physical limitations by

emphasizing the compensating rewards of

cognitive, emotional and social powers.

STAGE 3

EGO TRANSCENDENCE

VS

EGO PREOCCUPATION

As contemporaries die, facing the reality of

death constructively through efforts to make

life more secure, meaningful, and gratifying

for younger generations.

BERNICE NEUGARTEN’S: MATURE LIFE THEORY

A person must remain as active as possible.

Age-graded expectations for life event


SUMMARY

1. MAIN CATEGORIES IN AGING

2. CLASSIFICATION OF AGING THEORIES

BIOLOGICAL THEORIES OF AGING PSYCHOLOGICAL THEORIES OF AGING

Molecular Theories

Cellular Theories

Evolutionary Theories

System Theories

FULL DEVELOPMENT THEORIES

- Eric Erikson’s Theories

MATURE-LIFE THEORIES

- Robert Peck’s Theories

- Bernice Neugarten’s Theories

Programmed Theories

• Programmed Senescence Theories

• Endocrine Theories

• Immunology Theories

Error Theories

• Wear & Tear Theories

• Rate-of-Living Theories

• Cross-Linking Theories

• Free Radical Theories

• Error Catastrophe Theories

• Somatic Mutation Theories

• Hayflick's Cellular Clock Theories

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The Theory Of Aging - Ayu