GENERAL
I ARTICLE
The Biochemistry of Human Senescence
B Ramachandra Murty
Wi th the passage of time, most organisms show a general decline
in various biochemical and physiological functions and this
results in increased susceptibility to age-associated diseases.
The complexity of the forces operating inside an ageing human
body becomes even more obvious when we ask the simple
question - How old are you?
There are three distinct ways to measure a person's age.
• Chronological age: How old the person is by the calendar.
• Biological age: How old the body is in terms of critical life
signs and cellular processes.
• Psychological age: How old the person feels he/she is
Only the first of these is fixed, yet it is the most unreliable of the
three. A 60 year old may be nearly as healthy as he/she was at 30,
while another may already have the body of a 70 or even 80 year
old. To really know how old a person is, the second measure i.e.,
biological age, comes into play. It reveals how time has affected
the organs and tissues of the individual compared to other
people of the same chronological age.
B Ramachandra Murty is
with the Department of
Biochemistry, PSG
College of Arts and
Science, Coimbatore,
since 1982. His research
interests include
detection, analysis of
amino acid esters and
small peptides from
medicinal plants and
purification of useful
enzymes, from various
sources employing
inexpensive methods.
Free Radicals and Ageing
One of the important tissue components affected by ageing is
collagen, the major protein of the connective tissue. Many physical influences can hasten the ageing of collagen. Some of these
are smoking, excessive exposure to sunlight"vitamin deficiency,
malnutrition and dehydration. Individual collagen molecules
get attached to one another through a process known as cross
linkage. The cause of this is the destructive tendency of free
radicals that attack indiscriminately many vital molecules in the
body including DNA.
Keywords
Ageing, free radicals, anti-oxidants, telomerase.
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GENERAL I ARTICLE
Like sharks roaming in
the sea, free radicals,
in their eagerness to
pair with another
electron, can attack
almost any molecule
and damage it in the
cytoplasm of the cell.
Free radicals are atoms or molecules carrying unpaired electrons. L.ike sharks roaming in the sea, free radicals, in their
eagerness to pair with another electron, can attack almost any
molecule and damage it in the cytoplasm of the cell. In some
instances, free radicals are extremely good to have. For example,
white cells of the immune system use free radicals to attack the
invading bacteria and viruses and kill these invaders.
In 1956, Denham Harman of the University of Nebraska was the
first researcher to theorize that free radicals are an important
cause of ageing at the cellular level. He suggested that the
accumulation of free radical-induced damage to vital molecules
is an important cause of human ageing. Subsequently, Harman
reshaped this theory and proposed that mitochondria are the
major intracellular target of free radical attack that leads to
human ageing.
A number of cell functions decline progressively with age.
Oxidative phosphorylation by mitochondria, synthesis of nucleic
acids, structural and enzymatic proteins, cell receptors and
transcription factors are all reduced. Senescent-cells have a
decreased capacity for uptake of nutrients and for repair of
chromosomal damage. Abnormally lobed nuclei, vacuolated
mitochondria, decreased endoplasmic reticulum and damaged
golgi apparatus are some of the usual features. There is a steady
accumulation of the pigment lipofuscin which represents a product of lipid peroxidation and oxidative damage (free radical
damage).
To protect itself from
damage, every cell
produces enzymes to
degrade, neutralize
and detoxify free
radicals.
To protect itself from damage, every cell produces enzymes to
degrade, neutralize and detoxify free radicals. These free radical
scavengers include various antioxidants such as vitamins C and
E and enzymes such as superoxide dismutase and catalase that
can bind to highly reactive oxygen radicals and render them
harmless before they attack a vulnerable molecule. Although
cells are equipped with well organized anti-oxidative defence
system (ADS), an imbalance between generation of free radicals
and their disposal by antioxidative substances occurs as age
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February 2006
GENERAL I ARTICLE
advances [1]. All these facts suggest that free radical damage is
but one type of imbalance that can occur at the cellular level with
age.
DNA and Ageing
Long thought to be an inert chemical that sits unchanged in the
cell's nucleus, DNA is now known to have a remarkable capacity
for self repair. Under the assault of free radicals and other
'damaging influences, at least five different types of errors can
appear in a DNA strand. If our genes passively accepted such
damage, as every other chemical would, the information coded
on the double helix would get more and more garbled, making
orderly life impossible. But DNA has the ability to repair itself.
It can sense exactly which kind of damage has occurred and with
the help of special enzymes, the appropriate missing links are
spliced back into place. Errors in the efficient repair mechanism
have been linked directly to human ageing. Ifwe graph the life
expectancy of various animals, starting with short lived shrews
and mice and proceeding through cows, elephants and man, the
resulting curve is almost perfectly matched by how well each
animal's DNA can repair itself. Human DNA has the highest
capability to repair itself [2].
DNA has the ability to
repair itself. It can
sense exactly which
kind of damage has
occurred and with the
help of special
enzymes, the
appropriate missing
links are spliced back
into place.
A second evidence of DNA damage in the ageing process comes
from experiments on replicative ageing. The concept that cells
have a limited capacity for replication was developed from a
simple experimental model for ageing. Normal human fibroplasts
when placed in tissue culture have limited division potential [3].
Cells from children undergo more rounds of replication than
cells from older people. In contrast, cells from patients with
Progeria and Werner syndrome, two rare diseases characterized by
premature ageing, have a markedly reduced in vitro life span.
After a fixed number of divisions, all cells become arrested in a
terminally non-dividing state known as cellular senescence.
Many changes in gene expression occur during cellular ageing
but a key question is which of these are causes and which are
effects [4]. For example some of the proteins that inhibit pro-
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GENERAL I ARTICLE
gression of the cell growth cycle such as the products of the
cyclin-dependent kinese inhibitor genes are over expressed in
aged cells.
How dividing cells can count their divisions is under intensive
investigation. One likely mechanism is that, with each cell
division, there is incomplete replication of chromosome ends
(telomere shortening) which ultimately results in cell cycle
arrest [5,6].
At the tip of each chromosome, there is a non coding, tandemly
repetitive DNA sequence. This is called telomere. These telomeric
sequences are not fully copied during DNA synthesis prior to
mitosis. As a result, a single strand tail of DNA is left at the tip
of each chromosome and with each cell division, the telomeres
are shortened (Figure 1). Eventually the telomeres are so short
that DNA polymerase is unable to engage in the sub-telomeric
start positions for replication, which signals cell cycle arrest.
Most somatic cells lack telomerase, the enzyme that regenerates
telomeres. In humans it is only in germ cells and in embryos
that telomeres are replicated by the enzyme telomerase. Conversely in immortal cancer cells, telomerase is reactivated and
telomeres are not shortened, suggesting that telomere elongation might be an important step in tumor formation [7].
Telomeric shortening
Telomeric shortening could explain the replication limit of
cells. This is supported by the finding that telomeric length
decreases with the age of the individual from which the chromosomes are obtained.
could explain the
replication limit of
The Hormone Connection
cells. This is
supported by the
finding that telomeric
length decreases
with the age of the
individual.
In the late 1980's, Jay Glaser researched on a very intriguing
steroid called dehydroepiandrosterone (DHEA), a precursor of
the stress hormones like glucocarticoids and other steroid hormones. It was found that cortisol (a glucocorticoid) levels go up
markedly in patients awaiting surgery, it stays up the day after
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GENERAL I ARTICLE
Mitosis x 100
Mitosis x 100
Cells with telomerase ego Germ cells
Mitosis x 100
Figure 1. Telomerase, telomeres and replicative capability. Most somatic cells
lack te/omerase, the enzyme that regenerates telomeres. Therefore te/omeres shorten with each cell
division until chromosomal
copying becomes impossible. Some neoplastic cells
and germ cells express
te/omerase activity and
thereby have extended replicative capacity.
Mitosis x 100
Cells without telomerase ego Somatic cells
surgery, with a slight elevation in DHEA. Two weeks later
cortisol level is still up but DHEA has fallen, supporting the
theory that the DHEA reservoir was depleted by stress.
Glucocorticoids are secreted by the adrenal glands as part of the
heightened arousal demand of the body under stress. They
initiate the breakdown of glycogen in the liver and muscle,
making available glucose that the body can use when needed.
When glycogen is used up, the same glucocorticoids initiate
break-down of proteins.
Glucocorticoids
The logical conclusion was that if one can keep the DHEA levels
up, the body must be able to resist stress and with fewer stress
reactions, ageing should be retarded.
The best known of the glucocorticoids, cortisol, plays a hidden
role in the ageing of certain animals. A well known example is
the Pacific salmon. After hatching, young salmon spends its first
are secreted by the
adrenal glands as
part of the
heightened arousal
demand of the
body under stress.
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GENERAL
Proponents of a
biological ageing clock
have tracked the
body's internal
biorhythms to a tiny
cluster of neurons in
the hypothalamus,
known as the super
chiasmatic nucleus
(SeN).
Figure 2. Structures of
some chemical substances associated with ageing.
I ARTICLE
four years at sea before it is mysteriously guided thousands of
miles to the exact fresh water lakes where it was born. After a
heroic journey upstream, mature salmon spawns and almost
immediately dies. What causes the fish to age overnight into
feeble, spent creatures is not sheer exhaustion but an internal
ageing clock, that bides its time until spawning and then releases
a rush of cortical hormone in massive amounts from the adrenal
glands. Cortisol is a potent stress hormone in all animals. In
salmon it is a death hormone.
Many biologists speculate that the human body also contains an
ageing clock. If it does, it must be much more variable than that
in the salmon for humans die at extremely wide ranging ages.
Proponents of a biological ageing clock have tracked the body's
internal biorhythms to a tiny cluster of neurons in the hypothalamus, known as the super chiasmatic nucleus (SCN). No
Dehydroepiandrosterone (DHEA)
o
OH
HO
OH
o
o
Cortisol
Dopamine
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RESONANCE I February 2006
GENERAL
I ARTICLE
larger than a pencil point, this clump of neurons regulates the
body's sense of time. Finding the body's biological clock did not
solve the mystery of ageing because hypothalamus is connected
to the rest of the brain, the endocrine system and the immune
system. Any or all of these could be involved in the ageing
process.
At this point it is appropriate to mention the role of 'melatonin'
a hormone secreted by the pineal gland. Chemically melatonin is
N -acetyl-5-methoxy tryptamine and was first identified by Lerner
and coworkers in 1985 [10]. Melatonin is implicated in ageing
because it has well demonstrated antioxidant functions. The
hormone has been shown to participate in the antioxidant defence system (ADS) both as a free radical scavenging antioxidant
and as a preventive antioxidant.
According to Massion [9], melatonin is psychosensitive; various
types of meditation and yoga have been shown to enhance
endogenous melatonin levels. Since both meditation and melatonin share several physiological effects like decrease in anxiety,
stress, heart rate and blood pressure, the beneficial effects of
meditation have been attributed to stimulation of pineal gland
function and augmented melatonin secretion.
Disorders of the Aged
Cardiovascular Changes
It is often said that we are as old as our arteries, suggesting that
arterial disease, which certainly increases with age, is the usual
cause of all the clinical signs of old age. Arterial degeneration,
particularly atherosclerosis, is the commonest cause of debility
and death in developed countries (see article by Piste and Patil
in this issue). It may also be logical to think that many diseases
might also have their roots in a progressively diminishing supply of oxygen and nutrients to cells.
A very common cause of ageing is a progressive increase in blood
pressure called idiopathic hypertension. In this condition the
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February 2006
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GENERAL
Hypertension is a
physiological attempt
to overcome
resistance and to
maintain the essential
perfusion pressure to
peripheral tissues.
I ARTICLE
initial pathologic changes appears to be a permanent increase in
small vessel resistance. Hypertension is a physiological attempt
to overcome resistance and to maintain the essential perfusion
pressure to peripheral tissues. Unfortunately the increased blood
pressure has detrimental effects in large vessels such as increased atheroma.
Skin Changes
At a gross level, the elderly are identifiable from their wrinkled
skin and sagging facial muscles. Biochemically the skin contains
less collagen and less elastin. Both of these proteins are produced
by fibroplasts. As already mentioned, research carried out on
fibroplasts in culture has shown that cells cultured from young
individuals are more capable of divisions than the cells derived
from elderly individuals. On full assessment it was found that
wrinkling is most pronounced on the sun-exposed areas of the
skin, which may be attributed to the effect of ultraviolet light on
skin.
Osteoarticular Changes
Elderly individuals are often stooped and susceptible to fractures. Many post menopausal women and elderly men have some
degree of bone loss. In most cases this is due to osteoporosis in
which the bone matrix is mineralized as normal but the trabeculae are thinned. This results in fractures from relatively minor
trauma.
It is now becoming clear that the development of osteoporosis in
old age is much more common in those who were inactive or who
had diets low in calcium or vitamin D during youth. Epidemiological evidence is accumulating that many classic features of
old age are controlled in this way by things that happen during
the youth of the individual. An example is the development of
valvular heart disease in the elderly due to episodes of rheumatic
fever in youth.
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GENERAL
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Impaired Immunity
The relative weakening of the immune system in old age can
result in the recurrence of infections that were contracted many
years before and remained dormant. For example, tuberculosis
may erupt again in the elderly, particularly if they are on immuno
suppressive drugs as a therapeutic measure against cancer. Similarly the chicken pox virus can emerge from its hiding place in
the nerve ganglia in old age. Decreased efficiency of the immune
system is also the major cause of development of various types of
cancers in aged individuals.
Organ A trophy
Many body organs in the elderly are reduced in size and are
abnormally brown. This condition is called 'brown atrophy'.
The heart and liver are affected more commonly. The brown
appearance is caused by excessive amounts oflipofucsin, a granular brown intracellular pigment, often referred to as 'wear and
tear' pigment because of its supposed association with excessive
usage of an organ.
Suggested Reading
[1]
[21
[3]
[4]
[5]
[6]
Neurodegenerati'Ve Changes
[7]
Alzheimer's disease that leads to rapid neurodegeneration, was
discovered as early as 1906 by Alois Alzheimer, a prominent
investigator and physician in Munich. He dissected the body of
a 55 year old woman, who had been mentally deteriorating for
three years before her death. In her brain Alzheimer found
visible damage that could not be explained as normal ageing:
Twisted, tangled nerves and hardened deposits of chemical
plaque were found. It took nearly seventy years for the importance of Alzheimer's discovery to be fully grasped.
[8]
[9]
[10]
In recent years, recognition of Alzheimer's disease has increased
dramatically. The illness affects about 50 to 60 % of all these who
exhibit Senile Dementia. Dementia is the medical term for the
host of symptoms associated with the general term senility;
T Finkel andNJ Holbrook,
Oxidants, oxidative stress
and the biology of ageing,
Nature, Vo1.408, p. 239,
2000.
B A Gilchrest and V A
Bohr, Aging processes,
DNA damage and repair,
FASEB. J, No.H, p. 322,
1997.
L Hayflick and P S Moorhead, The serial cultivation of human diploid cell
strains, Exp. Cell, Res,
Vo1.25, p. 585, 1961.
jR Smith and OM PereiraSmith, Replicative senescence: Implications for
invirro ageing-tumor suppression,Science, Vo1.273,
p.63,1996.
E H Blackburn, Switching
and signaling atthe telomere, Cell, Vo1.106, p. 661,
2001.
jMYWongandKCollins,
Telomere maintenance
and disease, Lancet,
Vo1.362, p. 983, 2003.
SAStewartandRA Weinberg, Senescence: does it
all happen at the ends? 00cogene, Vo1.21 p.627,2002.
P S Trimiras, inHormones
and ageing, Eds P S Timiras, WDQuayandAVernadakis, CRC Press, Boca
Raton, pp. 3-22,1995.
S Venkatramanujan, in
Melatonin, oxidative
stress and ageing, Current
Science, Vo1.76,No.10,pp.
46-53,1999.
A V Massion,j Teasandj
R Herbert, in Melatonin in
psychiatric and neoplastic
disorder, Eds. M Shafii and
SS Sham, American Psychiatric Press, Washington DC, pp.261-294, 1998.
--------~-------RESONANCE I February 2006
25
GENERAL
Although many
remedies have been
advanced for the
prevention and delay
of this disease,
Alzheimer's is
I
ARTICLE
forgetfulness, confusion, disorientation, short attention span,
irritability and decreased intelligence are the major symptoms.
It has been described as the worst of all diseases, not just for what
it does to the victim, but for its devastating effects on families
and friends. It begins with the loss of learned skills, arithmetic
and typing and progresses to a total shutting down of the mind.
presently incurable.
Much speculation has been offered regarding the cause of this
disease, a rare 'slow virus' that takes decades to mature, a defect
in the immune system that causes the victims own antibodies to
attack the brain, increased accumulation of aluminium in the
neurons, but none of these causes has been proved. Although
many remedies have been advanced for the prevention and delay
of this disease, Alzheimer's is presently incurable. After the
onset of the disease, medical care is limited to tranquilizing or
sedating the patient.
Another dreaded disease of old age is Parkinson's disease, a
neurological disorder that produces uncontrollable muscle movements and drastic slowing down of bodily motions such as
walking, eventually resulting in a body so stiff that the patient
cannot move at all. Parkinson's disease has been traced to an unexplained depletion of a critical brain chemical called dopamine,
that functions as a neurotransmitter in the brain. L-DOPA, a
precursor of dopamine is often used in the treatment of
Parkinson's disease as it can cross the blood-brain barrier, whereas
dopamine cannot. However L-DOPA can only offer symptomatic relief to PD patients. Research on new therapies are currently going on.
Summary
Address for Correspondence
B Ramachandra Murty
Department of Biochemistry
PSG College of Arts and
Science
Coimbatore 641 014, India.
Email:[email protected]
With controlled diet, exercise including yoga and meditation,
the ageing process can be to some extent slowed down. However,
immortality is biochemically impossible to achieve in natural
organisms, including bacteria.
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