For
The First Time: Longevity Modulated Without Disrupting
Life-sustaining Function
Within a hormone-triggered cascade of molecular signals that plays
a crucial for a wide range of physiological functions, researchers
for the very first time have identified a protein that functions
specifically to extend lifespan and youthfulness -- without
disrupting fertility, immunity or the organism's response to
stress.
"In past experiments, meddling with this versatile pathway to
exploit its beneficial effects on aging and life span inevitably
invited a host of problems," says Andrew Dillin, Ph.D., an
assistant professor in the Molecular and Cell Biology Laboratory at
the Salk Institute for Biological Studies and leader of the study,
reported in the March 9 issue of the journal Cell.
The Salk scientists discovered the protein in studies with worms, a
commonly used lab model in genetics; since this signaling cascade
including the newly identified protein is conserved across many
species, including humans, these findings raise the prospect that
one day it might be possible to medically tweak this pathway to
slow aging and improve the quality of life without harmful
consequences to the body.
In humans and other mammals this signaling cascade is known as the
insulin/IGF-1 pathway since it is prompted by insulin and the
closely related insulin-like growth factor-1 or IGF-1. IGF-1 is the
main trigger for childhood growth but continues to exert growth
stimulating effects throughout an individual's life. Insulin, which
is best know for controlling blood glucose levels, has additional
and equally important regulatory functions in the body. In worms,
however, the chain of signals is set in motion when a single
receptor on the cell surface is matched to an insulin-like
signal.
"If you were to interfere with insulin signaling in humans in order
to prolong life, you would induce diabetes right away," cautioned
graduate student and first author Suzanne Wolff. When this pathway
had been clipped in worms, they lived longer than normal, but their
larval development and reproduction were disrupted.
"So, the central question became whether we would be able to
genetically manipulate one element of the pathway without
disrupting its additional functions," said Dillin. "In this regard,
we thought that the life extending function of this pathway would
be elusive, whereas the developmental and reproductive functions
would be more amenable. We were delighted to find that Smk-1 proved
to be specific for the one function we thought the most elusive,"
he added.
Some of Dillin's earlier research had hinted at the possibility
that "specificity" factors may control how and whether insulin and
IGF-1 impact a target gene. Identifying those factors one by one
would allow scientists to separate the different functions of
insulin/IGF-1 signaling and to manipulate them individually without
wreaking havoc on the organism's normal functioning.
Together with the lab of another Salk scientist, Tony Hunter,
Ph.D., Dillin's team identified a protein in the worm
Caenorhabditis elegans that allowed them to do just that. The
protein is encoded by the Smk-1 gene. "Smk-1 is the first known
gene that regulates longevity without affecting other vital
functions of the insulin signaling pathway," said Wolff.
Under favorable conditions, a still unidentified molecule binds to
DAF-2, the worms' equivalent of the insulin/IGF-1 receptor, which
is located at the cell's surface. A cascade of signaling molecules
relays the information deep into the cell till it reaches a protein
called DAF-16. Known as a transcription factor, DAF-16 encodes a
DNA-binding protein that turns on other genes but when DAF-2 is
active, it is unable to enter the cell's nucleus to activate its
target genes.
When environmental conditions turn harsh as a result of
overcrowding and scarce nutrients, for example, DAF-2 signaling
shuts down. No longer marooned outside the nucleus, DAF-16 crosses
into the nucleus, and triggers all the necessary genes to help the
body take care of the stressful situation. But food shortages
aren't the only triggers for the stress program. Others are the
heat that scrambles proteins into toxic clumps and marauding
parasites. Highly reactive molecules known as free radicals also
unleash DAF-16.
If the worms are having a good day in a favorable environment, but
for some reason DAF-2 signaling gets turned off precociously, the
worms reap the benefit of increased stress resistance and double
their lifespan from an average of 20 to 40 days. Except the worms
trade a trim life focused on reproduction for a long life with
fewer progeny and a tendency to halt larval development and enter a
dormant, hibernation-like stage in which they can hang on for
months but don't reproduce.
Unless Smk-1 is missing, that is.
Without Smk-1 to provide guiding assistance, DAF-16 is unable to
slow down the aging process, and the worms die young. "These
mutants are shorter lived because they are unable to respond
appropriately to oxidative stress, but they are just as resistant
to heat stress as wild type worms whose signaling pathways have not
been experimentally manipulated," explained Wolff.
"In the future, we may use this protein as a tool to study the
genetic and metabolic requirements for extending longevity without
causing diverse, wide-ranging effects on the development and
maintenance of the physiological equilibrium in the organism," said
Dillin.
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I don't see why we need to live for so long and can reproduce
endlessly. A torture to Mother Earth.
How much natural resources are we left with now?