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In humans, by
the time we are 80 years old our cells have
lost 40-90% of their ability to make new proteins.
In laboratory rats, old adults lose as much
as 80% of their ability to form proteins. Protein
synthesis by the mitochondria of old mice is
only half of that in young mice.
The loss of the ability for
protein synthesis has potentially serious consequences:
1. The protein-forming
machinery fails to replace damaged proteins
in a timely fashion.
2. There is a fall in the activity of proteins,
because they are replaced too slowly when they
wear out.
3. Worn-out proteins accumulate in old cells.
In young cells, special proteins (proteases)
break down worn-out proteins for recycling into
new proteins.
But proteases themselves also
wear out. In young cells, other proteases break
them down in turn, but as we get old failure
of the protein synthesis machinery fails to
replace worn-out proteases.
Failure of protein synthesis
has a domino effect, as it reduces the supply
of new proteins to replace those that wear out.
This causes deterioration of cell structures.
In the aging body, there are dramatic losses
of antioxidant proteins, DNA repair proteins,
and the proteins in the protein-making machinery.
Some scientists speculate that
when an individual reaches an advanced age,
the genes for key proteins "switch off",
and this triggers the final catastrophic acceleration
of the aging process. Switched-off genes are
the ultimate cause of aging. So one approach
is to try and find some drug to switch these
key proteins back "on" again.
We can draw an analogy with
an automobile. When new (young), it runs well.
As time passes, parts wear out and fail. If
we do not replace them, the car shows wear and
tear, and inevitably it eventually stops running
(the life expectancy of U.S. cars is seven years).
But if we continue to replace the car's parts,
it will run forever. By replacing parts, the
car becomes "immortal".
So, the goal of researchers
is to find what switches off genes for key proteins
like DNA repair proteins and anti-oxidant proteins.
By the age of 80 years, you
have less than half the ability to repair DNA,
compared to when you were young.
Details of the reaction of
ROS with proteins is described by Wanagat et.
al. (1999). Metal-catalyzed oxidation of proteins
introduces carbonyl groups (aldehydes and ketones)
to lysine, arginine, proline, or threonine residues
in a site-specific manner (Stadtman, 1992) |
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2004
Nutrition, Metabolism,
and Exercise Laboratory, Donald W. Reynolds
Center on Aging, Slot 806, University
of Arkansas for Medical Sciences, Little
Rock, AR 72205, USA. evanswilliamj@uams.edu
Aging is associated
with remarkable changes in body composition.
Loss of skeletal muscle, a process called
sarcopenia, is a prominent feature of
these changes. In addition, gains in
total body fat and visceral fat content
continue into late life. The cause of
sarcopenia is likely a result of a number
of changes that also occur with aging.
These include reduced levels of physical
activity, changing endocrine function
(reduced testosterone, growth hormone,
and estrogen levels), insulin resistance,
and increased dietary protein needs.
Healthy free-living elderly men and
women have been shown to accommodate
to the Recommended Dietary Allowance
(RDA) for protein of 0.8 g . kg(-1)
. d(-1) with a continued decrease in
urinary nitrogen excretion and reduced
muscle mass. While many elderly people
consume adequate amounts of protein,
many older people have a reduced appetite
and consume less than the protein RDA,
likely resulting in an accelerated rate
of sarcopenia. One important strategy
that counters sarcopenia is strength
conditioning. Strength conditioning
will result in an increase in muscle
size and this increase in size is largely
the result of increased contractile
proteins. The mechanisms by which the
mechanical events stimulate an increase
in RNA synthesis and subsequent protein
synthesis are not well understood. Lifting
weight requires that a muscle shorten
as it produces force (concentric contraction).
Lowering the weight, on the other hand,
forces the muscle to lengthen as it
produces force (eccentric contraction).
These lengthening muscle contractions
have been shown to produce ultrastructural
damage (microscopic tears in contractile
proteins muscle cells) that may stimulate
increased muscle protein turnover. This
muscle damage produces a cascade of
metabolic events which is similar to
an acute phase response and includes
complement activation, mobilization
of neutrophils, increased circulating
an skeletal muscle interleukin-1, macrophage
accumulation in muscle, and an increase
in muscle protein synthesis and degradation.
While endurance exercise increases the
oxidation of essential amino acids and
increases the requirement for dietary
protein, resistance exercise results
in a decrease in nitrogen excretion,
lowering dietary protein needs. This
increased efficiency of protein use
may be important for wasting diseases
such as HIV infection and cancer and
particularly in elderly people suffering
from sarcopenia. Research has indicated
that increased dietary protein intake
(up to 1.6 g protein . kg(-1) . d(-1))
may enhance the hypertrophic response
to resistance exercise. It has also
been demonstrated that in very old men
and women the use of a protein-calorie
supplement was associated with greater
strength and muscle mass gains than
did the use of placebo.
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2002
Department
of Biochemistry, School of Pharmaceutical
Sciences, Toho University, Funabashi,
Chiba, 274-8510 Japan.
Many reports have been
published on the effects of lifelong
dietary restriction (DR) on a variety
of parameters such as life span, carcinogenesis,
immunosenescence, memory function, and
oxidative stress. There is, however,
limited available information on the
effect of late onset DR that might have
potential application to intervene in
human aging. We have investigated the
effect of DR initiated late in life
on protein and protein degradation.
Two months of DR in 23.5-month-old mice
significantly reduced heat-labile altered
proteins in the liver, kidney, and brain.
DR reversed the age-associated increase
in the half-life of proteins, suggesting
that the dwelling time of the proteins
is reduced in DR animals. In accordance
with this observation, the activity
of proteasome, which is suggested to
be responsible for degradation of altered
proteins, was found increased in the
liver of rats 30 months of age subjected
to 3.5 months of DR. Thus, DR can increase
turnover of proteins, thereby possibly
attenuating potentially harmful consequences
by altered proteins. Likewise, DR in
old rats reduced carbonylated proteins
in liver mitochondria, although the
effect was not observed in cytosolic
proteins. Fasting induced apoA-IV synthesis
in the liver of young mice for efficient
mobilization of stored tissue fats,
while it occurred only marginally in
the old. DR for 2 months from 23 months
of age partially restored inducibility
of this protein, suggesting the beneficial
effect of DR. Taking all these findings
together, it is conceivable that DR
conducted in old age can be beneficial
not only to retard age-related functional
decline but also to restore functional
activity in young rodents. Interestingly,
recent evidence that involves DNA array
gene expression analysis supports the
findings on the age-related decrease
in protein turnover and its reversion
by late-onset DR.
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Department
of Medicine, University of Rochester,
Rochester, New York 14642, USA.
Sarcopenia, the decline
in muscle bulk and performance associated
with normal aging, is an important component
of frailty in the elderly. The gradual
loss of both motor nerves and muscle
fibers during senescence appears to
be the major problem. Atrophy (especially
in fast-twitch fibers) and impaired
function of the surviving cells also
contribute to sarcopenia. Although skeletal
muscle has the capacity to regenerate
itself, this process is not activated
by the gradual age-related loss of muscle
fibers. The endocrine, autocrine, and
paracrine environment in old muscle
is less supportive of protein synthesis,
reinnervation of muscle fibers, and
satellite cell activation, proliferation,
and differentiation. Lifelong exposure
of DNA to free radical damage results
in accumulation of somatic mutations
in nerves and muscle fibers. Reduced
protein synthesis leads to atrophy,
and slower fractional protein turnover
contributes to longer retention of proteins
that may have been damaged by free radicals.
Many genes are differentially expressed
in young and old muscle, but additional
research is needed to determine which
of these genes have a significant role
in the pathogenesis or adaptation to
sarcopenia.
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2001
Physiological
Research Center, Pennsylvania State
University, University Park 16801, USA.
Skeletal muscle proteins
are constantly being synthesized and
degraded, and the net balance between
synthesis and degradation determines
the resultant muscle mass. Biochemical
pathways that control protein synthesis
are complex, and the following must
be considered: gene transcription, mRNA
splicing, and transport to the cytoplasm;
specific amino acyl-tRNA, messenger
(mRNA), ribosomal (rRNA) availability;
amino acid availability within the cell;
the hormonal milieu; rates of mRNA translation;
packaging in vesicles for some types
of proteins; and post-translational
processing such as glycation and phosphorylation/dephosphorylation.
Each of these processes is responsive
to the need for greater or lesser production
of new proteins, and many states such
as sepsis, uncontrolled diabetes, prolonged
bed-rest, aging, chronic alcohol treatment,
and starvation cause marked reductions
in rates of skeletal muscle protein
synthesis. In contrast, acute and chronic
resistance exercise cause elevations
in rates of muscle protein synthesis
above rates found in non-diseased rested
organisms, which are normally fed. Resistance
exercise may be unique in this capacity.
This chapter focuses on studies that
have used exercise to elucidate mechanisms
that explain elevations in rates of
protein synthesis. Very few studies
have investigated the effects of aging
on these mechanisms; however, the literature
that is available is reviewed.
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1985
Department of Molecular
Pharmacology and Toxicology, University
of Southern California, 1985 Zonal Avenue,
Los Angeles, California 90033, USA.
The purpose of this
study was to determine (1) whether oxidative
damage to plasma proteins in mice and
rats, accrued during aging and manifested
as carbonyl modifications, was selective
or random, and (2) whether the putative
carbonylated proteins could be used
as markers of oxidative stress and aging.
The total protein carbonyl content of
the plasma significantly increased with
age in mice but not in rats. Immunostaining
of mouse plasma proteins, resolved by
SDS-PAGE to localize carbonyls, revealed
that only two specific proteins exhibited
an age-associated increase in carbonylation.
These proteins with molecular weights
of 68 and 75 kDa, were identified as
albumin and transferrin, respectively.
In the rat, albumin and a 167-kDa protein,
alpha1-macroglobulin (alpha-1M), showed
significant age-dependent accrual of
carbonylation. In the plasma of middle
age Rhesus monkeys, in addition to albumin,
a 54-kDa protein showed carbonylation.
However, neither transferrin nor alpha-1M
were carbonylated in the plasma of Rhesus
monkey. Albumin was the only protein
that showed carbonylation in all the
three species examined. Results of this
study indicate that age-associated increase
in protein carbonylation is a selective
and not a random phenomenon. However,
the set of proteins that become carbonylated
differs in different species. (c)2002
Elsevier Science.
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1984
The rate of protein
synthesis was measured in isolated mitochondria
from Drosophila melanogaster and from
the livers and kidneys of C57BL/6J mice
of increasing ages. Over the life-span
of the organisms, the synthesis of mitochondrial
proteins decreased to a level which
was less than half the original rate.
Concomitant with this decrease, the
amount of mitochondria which could be
isolated from the organisms declined
by about 30%. Thus, the separate translational
system of mitochondria exhibited an
age-related decrease in activity which
was in addition to the decrease already
observed in the cytoplasmic ribosomal
system.
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1980
The cell-free protein
synthetic activity of the postmitochondrial
supernatant isolated from whole brain
of 6- to 32-month-old male Fischer F344
rats was compared. Protein synthesis
decreased 56% from 6 to 32 months of
age. The decrease in cell-free protein
synthesis was not due to an age-related
increase in RNase activity. Although
monomeric ribosomes (ribosomes stripped
of mRNA) isolated from the brains of
older rats were less active in polyuridylic
acid directed polyphenylalanine synthesis,
the fidelity of polyuridylic acid translation
by monomeric ribosomes did not decrease
with increasing age.
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