by MDI Biological Laboratory
In
new research, Aric N. Rogers, Ph.D., who studies the cellular and
molecular mechanisms of aging at the MDI Biological Laboratory in Bar
Harbor, Maine, has discovered that muscle may be a protected tissue
under conditions of dietary restriction, or DR.
Dietary
restriction, in which calories are restricted without malnutrition, is
one of the most robust anti-aging interventions. When confronted with a
scarcity of nutrients, an organism conserves resources by lowering the
translation, or production, of proteins, which is one of the most
energetically expensive processes in the cell. Proteins serve as the
building blocks for tissues and organs and perform vital physiological
functions.
The conservation of cellular resources through reduced protein translation confers
an evolutionary benefit by allowing the organism to survive so that it
can reproduce when food becomes plentiful. But it comes at the cost of a
reduction in anabolic function, or growth and reproduction.
Working
in the tiny nematode worm C. elegans, Rogers sought to identify the
effects of genetically suppressing protein translation in various
tissues. While skin, nerve and reproductive tissue responded
as expected with enhanced survival and decreased growth and
reproduction, the effect was the opposite in muscle: Instead of being
suppressed, growth and reproduction were accelerated.
C.
elegans is a popular model in aging research because it shares many of
its genes with humans, including those governing nutrient-sensing
pathways, and because its short lifespan allows scientists to rapidly
assess the effects of anti-aging interventions.
The role of foraging
Rogers
theorizes that muscle may be protected under conditions of nutrient
scarcity in order to support the ability of an organism to forage for
food.
"The
usual tradeoff with reduced protein synthesis is increased longevity
for decreased growth and reproductive capacity," Roger said. "But in
muscle tissue, we saw the opposite, which is not what we expected. We
found that muscle tissue is privileged under conditions that are usually
unfavorable for growth and reproduction—that its potential for growth
is protected even when nutrients are scarce."
The
study, entitled "Anabolic Function Downstream of TOR Controls
Trade-offs Between Longevity and Reproduction at the Level of Specific
Tissues in C. elegans," was recently published in the journal Frontiers in Aging.
In addition to Rogers, who is the corresponding author, authors include
first author Amber C. Howard, Ph.D., of Middle Georgia State
University, who was formerly at the MDI Biological Laboratory.
The
results suggest that it may be possible to develop anti-aging drugs
that prolong healthy lifespan without the loss of muscle tissue. They
also offer insight into the mechanisms underlying the
longevity-promoting benefits of exercise and, conversely, the drawbacks
of being the animal model equivalent of a couch potato.
Rogers
theorizes that muscle activity in the form of exercise could send a
signal to the cell that foraging activity is high—in other words, that
nutrients are scarce. Such a signal would launch a systemic
lifespan-enhancing survival and maintenance program that would suppress
growth and reproduction in most tissues, but preserve it in muscle
tissue, in which growth would still be required for purposes of
food-seeking.
The
systemic deactivation of the growth and reproductive program in
response to a high level of muscular activity, he said, could explain a
condition called athletic amenorrhea in which menstruation ceases in
women who exercise excessively, Rogers said.
Conversely, he theorizes, inactivity in muscle tissue,
which is essential for the procurement of food, could be perceived by
the cell as a lack of foraging activity. When coupled with an ample food
supply, this perception could cue the reproductive system that
nutrients in the environment are plentiful—the couch potato scenario—and
that conditions are therefore optimal for growth and reproduction.
"We
believe muscle may send a hormone-like signal that is dependent on
contraction for production and release," he explained. "If an organism
isn't using its muscles, this signal may inform the reproductive system
that foraging activity is low—in other words, that food is
plentiful—and, therefore, that conditions are optimal for making the
next generation, thus redirecting cellular resources toward growth and
reproduction."
Though
Rogers points out that parallels between worms and humans aren't always
valid, he hypothesizes that the inactivity-triggered run-on of a growth
and reproduction program that is no longer relevant after the age of
reproduction, along with the inability of the weakened systems of an
aging body to regulate it, could lead to the "hyper" pathologies of old
age such as cancer, diabetes (high blood sugar) and hypertension.
Ameliorating the negative effects of anti-aging drugs
Over
the past decade, significant research has focused on the anti-aging
potential of a drug called rapamycin, which is considered a DR "mimetic"
because of its ability to suppress protein translation. Like DR,
rapamycin has been shown to extend healthy lifespan in yeast, worms and
flies, and to prevent or delay the onset of age-related degenerative
diseases in mice, which are mammals like humans.
With
rapamycin and other DR mimetics now under intensive study as potential
anti-aging therapies, Rogers believes his discovery of the
tissue-dependent nature of the suppression of protein translation may
point the way to drugs that extend lifespan without the loss of
anabolism, or the ability to replace tissues that occurs when protein
synthesis is turned down, in muscle, thus "extending lifespan without
trade-offs."
One
potential application may be for the treatment of sarcopenia, a
potentially debilitating age-related loss of skeletal muscle that
affects up to 13 percent of people in their 60s and as many as half of
those in their 80s. Because muscle may be spared from the effects of the
suppression of protein translation, Rogers envisions anti-aging
therapeutics that promote longevity while protecting muscle from
atrophying.
"The
MDI Biological Laboratory has focused on the comparative study of
animal models to gain insight into human health for more than 120
years," President Hermann Haller, M.D., said of the research. "Aric's
fascinating discovery in C. elegans that muscle is
protected under conditions of nutrient scarcity, which could lead to
the development of anti-aging drugs without side effects, once again
demonstrates the value of our approach."
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