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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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