BIOCHEMISTRY OF

AGEING

DR.MAHENDRA.
 DEFINITION

Biological process, which causes increased

susceptibility of organism to disease.

Gradual decline in adaptation of an organism to

its normal environment, following the onset of
reproductive maturity
 Effects of ageing

1.Progressive decline in vigor & efficiency

of physiologic functions.

2.Atrophy of most of the organs.

3.Increased vulnerability to infections,

trauma & various immune abnormalities.

4.Increased susceptibility to malignancy.

Life expectancy and life span.

Life expectancy: average number of years a

body is expected to live.

Maximum life span: Greatest age reached by

any member of that species.
Three stages of problem:

1) Biological: Study of molecular, physiological &

structural aspect of cell.

2) Clinical: Study and cure of diseases.

(Geriatrics.)

3) Sociopsychological: Study of problems of old

people. Gerontology)
 THEORIES OF AGEING

1) Programmed Theory.

2) Error theory.
 1)Programmed Theory
Ageing is result of sequential switching on & off
of certain genes.

a) Endocrine theory : acts through hormones to

control pace of ageing.

b) Immunological theory :
A programmed decline in immune functions
leading to increased vulnerability to infections,
ageing & death.
Altered responsiveness of immune system
with age includes :
1) Decreased IL-2 & IL-6 production.

2)Decreased T cell response to IL-2.& mitogen

stimulation.

3) Increased frequency of autoantibody

production.

4) Decreased antibody response to antigenic

stimulation.
 Error theories
A) Wear & tear or age pigment :

• Accumulation of pigment lipofuscin in

cytoplasm of neurons, skeletal & cardiac
muscles.

• Pigment is acid insoluble & rich in per oxidation

products of PUFA.
 Cross-linking

Ageing is due to cross-linking of

macromolecules, nucleic acids & proteins which
are vital for functions of cell.

Succinic acid, pyruvate, silicon, lead,

acetaldehyde, Mn, Ca, Zn are the potential
cross-linkers.
 Somatic mutations
Ageing is due to somatic mutations, which
destroys genes & causes loss of chromosomes
of somatic cells.

These cells do not divide after certain stage of

growth & due to mutations these genes either do
not produce any protein or if they do so ,the
proteins are defective.
With age these mutations accumulate & after
reaching certain levels inactivate the cell.

Therefore no. of functional cells decreases with

age & organism dies when no. of functional cells
decrease below certain levels.
 d) Errors in the proteins :
Two types of proteins:

a) Protein needed for structure (collagen & keratin) & for

metabolism (enzymes).

b) those needed for protein synthesis eg : RNA

polymerase, amino acyl t-RNA synthtase.

Errors in amino acid sequence of enzymes involved in

metabolism , results in decreased or complete loss of
enzyme activity.
Change in amino acid sequence of RNA
polymerase results in synthesis of wrong m-RNA
& proteins.

This effect will continue till whole cell is filled with

wrong proteins, resulting in deterioration of all
functions.

Is error the primary cause of ageing or is it

secondary effect of primary protein, question still
remained unanswered.
 e) The genetic connection :
Cellular differentiation :
 Process by which various cells arise from single cell.

 Due to gene activity these differentiated cells differ in

capacity to synthesize different proteins.

 The proteins expressed by genes carry out multitude of

functions & some of the functions are related to ageing.

 It is the protein product of these genes which are

responsible for longevity or ageing
 f) Free radical theory :
First proposed by Denham Harman.

States that damage caused by oxygen

radical is responsible for many of the
bodily changes that come with ageing.

Free radical have also been implicated in

degenerative disorders including cancer,
atherosclerosis, cataract &
neurodegeneration.
A Free radical is molecule or molecular species,
that contains one or more unpaired electrons &
is capable of independent existence.

Eg : Superoxide,H2O2, hydroxyl singlet O2,

hydroperoxy radical (HOO-), lipid peroxide
radical (ROO-) Nitric oxide (NO-) & peroxynitrite
(ONOO-).
SOURCES :
1) Cellular metabolism :
- Leakage of electrons from ETC.
- Production of H202 or O2- by oxidase enzyme.
Eg. Xanthine oxidase, NADPH oxidase.

- Chain reactions of lipid peroxidation.

- Peroxisomal generation of 02 ,H202.

- Production of nitric oxide from arginine.

- During course of phagocytosis.

- In the oxidation of heme to bile pigments.

- Autoxidation of Fe+2, Cu+2,Ascorbic acid,

glutathione.
- 2) Environmental effects :

- Due to drug metabolism.

- Damage caused by ionising
radiation.
- Photolysis of 02 by light.
- Photoexcitation of organic molecules
- Cigarette smoke.
 Harmful effect of free radicals:

Because of their reactive nature free radical can

provoke inflammation or altered cellular function
through:

1.Lipid peroxidation.

2.Protein modification.

3. DNA modification.
 Lipid peroxidation product:

 React with amino acid mainly CYS, HIS, LYS to

modify protein structure & function.

 Can crosslink lipid in cell membrane interrupting

structure & fluidity.

 Can react with DNA causing mutagenic &

carcinogenic effects.
 2. Protein modification:

- Proteins are major targets of free radical attack

because of their high abundance & because
they are responsible for most of functional
processes.

- Free radical causes oxidation of sulfhydryl gr. &

modification of certain amino acid (met, cys,
His,try)
ROS may damage protein by fragmentation,
crosslinking, & aggregation.

The net result is that free radical injury may

result in loss of biological activity of proteins.
 3. DNA modification :
Free radical induced DNA damage includes :
- strand break.

- DNA- protein crosslink.

- large range of base & sugar modification.

Hydroxyl radical is most prominent in development of base
& sugar modification.

DNA damage also occurs through reactive nitrogen

species undergoing mainly nitration & deamination of
purines.

The net result is increased risk of mutagenesis &

carcinogenesis.

Oxidative damage is repaired by cellular repair system &

DNA base damage is by base excision repair.
 Antioxidants :

1. Enzymatic : SOD, Catalase, glutathione

peroxidase & reductase.

2. Nutrient : B-carotene, A-tocopherol, ascorbate

& selenium.

3. Metabolic : glutathione, bilirubin,

transferrin, ceruloplasmin, uric acid.
Antioxidants & ageing Gerbils :

High levels of antioxidants can slow the ageing

process.

Study of PBN or N-tert-butyl-alpha-

phenylnitrone in Gerbils support this hypothesis .

At NIA, Richard Cutler found high levels of SOD

in longer lived animals.
Insertion of extra copies of SOD gene into fruit
flies extend life span by 5 to 10%.

Higher levels of SOD & Catalase seen in long-

lived nematodes.

Current studies are exploring role of vitamin C &

E in reducing heart diseases.
 Glucose cross-linking:
Non-enzymatic glycosylation.

Glycation triggers a chain of reaction

that ends in protein binding together or cross-
linking, altering their biological roles.

AGEs seems to toughen tissues & may cause

deterioration a/w ageing.
AGEs linked to stiffening of connective tissues,
hardened arteries, loss of nerve function & less
efficient kidneys.
Macrophages:

- Combat glycation.

- Macrophages detects AGEs, engulf them & once

broken down the AGEs are dumped into the
blood steam & are filtered out & eliminated by
kidneys.

- Similar to antioxidant, this system is not perfect

& AGEs overcome our only defenses against
them with age.
Researchers say that, the efficiency of kidneys
decreases with age & macrophages become
less active while the levels of AGEs increases.
 DNA REPAIR :
DNA undergoes continual damage.

Oxygen radicals, UV light,& other agents

damages DNA in the form of deletions, or
destroyed sections & mutations, or changes in
sequence of DNA bases.

Repair process may be major factor in ageing,

health,& longevity.
DNA damage accumulation leads to
malfunctioning genes, proteins, cells.

Animals ability to repair DNA damage is directly

related to life span of its species .

Humans repair DNA more quickly & efficiently.

Most efficient repair seen in sperm & egg cells.

Photo-ageing damages collagen & elastin.

These proteins declines with age.

In ageing process turnover of keratinocytes slows

down & in photo- ageing, they are damaged.

Melanocytes decline with ageing & are killed in

photoageing.
Mitochondrial DNA is injured at much greater
rate than nuclear DNA.

Mitochondrial DNA damage increases

exponentially with age.
Telomeres :

- Protects genetic encoding from becoming a

short sequence during replication.

- Tail at the end of every chromosome that gets

shorter as the cell divides.

-When telomeres become too short their function

is disrupted & cell stops dividing.
 Telomerases :

- Enzyme responsible for restoring lost telomeric

sequence in cells. So cell can divide indefinitely.

- Mostly found in sperm & egg cells.

 Heat shock proteins :
Produced when cells are exposed to various stresses.

Their expression can be triggered by exposure to toxic

substances such as heavy metals & chemicals & even
by behavioral & psychological stress.

HSP declines with age.

Old animals placed under stress shows lower levels of

HSP-70 than young animals
Researchers found a striking decline in HSP-70
production as cell approaches senescence.

Exact role of HSP – not yet clear.

HSP known to help the cell disassemble &

dispose of damaged proteins & to facilitates the
making & transport of new proteins.
Hormones & research on ageing

1. Estrogen :
- used in HRT to relieve discomfort
of menopause.
- produced by ovaries
- slows the bone thinning process
 2. Growth hormone :
- Produced by pituitary gland.

- Plays a role in body composition & muscle &

bone strength.

- Released through GHRH.

- Works by stimulating production of IGF.

- All three are under study for their potential to

strengthen muscle & bones.
3.Melatonin :
- Produced by pineal gland.

- Regulates various seasonal changes in body.

- Declines during ageing & trigger

changes in endocrine system.
4. Testosterone :

- Produced by testes.

- Declines with age.

- Under investigation for its ability to

strengthen muscles & prevent
frailty & disability.
5. DHEA : (Dehydroepiandrosterone).

- Produced in adrenal gland.

- Precursor to testosterone & estrogen.

-Under study for its effects on ageing

& potential to prevent cancer & multiple sclerosis.
 Role of dopamine receptors in
ageing

Changes a/w ageing are due to loss of particular

chemical receptor in the brain.

Researchers studied the effect of ageing on

dopamine, which modulates the communication
between areas in brain that are involved with
movement, cognition, motivation & reward.
Investigators measured both the levels of
dopamine receptors & brain glucose
metabolism.

They found that ageing correlated with a loss of

dopamine receptors & that these losses were
associated with a decline in activity in frontal
region.

They concluded that the decline in cognitive

abilities & higher propensity for depression in
elderly is due to losses of brain dopamine
receptors.
 Macular degeneration of eye :

Normally cornea is transparent & avascular.

Contains chemical –VEGF-A that promotes

angiogenesis.

Researcher identified protein VEGFR-1 which

blocks the blood vessel growth.