EVANSTON,
Ill. --- When does aging really begin? Two Northwestern University scientists
now have a molecular clue. In a study of the transparent roundworm C. elegans,
they found that adult cells abruptly begin their downhill slide when an animal
reaches reproductive maturity.
A
genetic switch starts the aging process by turning off cell stress responses
that protect the cell by keeping important proteins folded and functional. The
switch is thrown by germline stem cells in early adulthood, after the animal
starts to reproduce, ensuring its line will live on.
While the studies were conducted in worms, the findings have implications for humans, the researchers report. The genetic switch and other components identified by the scientists as playing a role in aging are conserved in all animals, including humans, offering targets for future study. (C. elegans has a biochemical environment similar to that of humans and is a popular research tool for the study of the biology of aging and as a model of human disease.)
Knowing
more about how the quality control system works in cells could help researchers
one day figure out how to provide humans with a better cellular quality of life
and therefore delay degenerative diseases related to aging, such as
neurodegenerative diseases.
“Wouldn’t
it be better for society if people could be healthy and productive for a longer
period during their lifetime?” said Richard I. Morimoto, the senior author of the
study.
“I am very interested in keeping the quality control systems optimal as
long as we can, and now we have a target. Our findings suggest there should be
a way to turn this genetic switch back on and protect our aging cells by
increasing their ability to resist stress.”
Morimoto
is the Bill and Gayle Cook Professor of Molecular Biosciences and director of
the Rice Institute for Biomedical Research in
Northwestern’s Weinberg College of Arts and Sciences.
He also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern
University.
The
study, built on a decade of research, will be published in the July 23 issue of
the journal Molecular Cell. Johnathan Labbadia, a postdoctoral fellow in
Morimoto’s lab, is the first author of the paper.
In
C. elegans, the decline begins eight hours into adulthood -- all the switches
get thrown to shut off an animal’s cell stress protective mechanisms. Morimoto
and Labbadia found it is the germline stem cells responsible for making eggs
and sperm that control the switch.
In
animals, including C. elegans and humans, the heat shock response is essential
for proper protein folding and cellular health. Aging is associated with a
decline in quality control, so Morimoto and Labbadia looked specifically at the
heat shock response in the life of C. elegans.
“We
saw a dramatic collapse of the protective heat shock response beginning in
early adulthood,” Morimoto said.
Morimoto
and Labbadia found the genetic switch occurs between two major tissues in an
organism that determine the future of the species: the germline and the soma
(the body tissues of the animal, such as muscle cells and neurons). Once the
germline has completed its job and produced eggs and sperm -- necessary for the
next generation of animals -- it sends a signal to cell tissues to turn off
protective mechanisms, starting the decline of the adult animal.
“C.
elegans has told us that aging is not a continuum of various events, which a
lot of people thought it was,” Morimoto said.
“In
a system where we can actually do the experiments, we discover a switch that is
very precise for aging,” he said. “All these stress pathways that insure
robustness of tissue function are essential for life, so it was unexpected that
a genetic switch is literally thrown eight hours into adulthood, leading to the
simultaneous repression of the heat shock response and other cell stress
responses.”
Using
a combination of genetic and biochemical approaches, Morimoto and Labbadia
found the protective heat shock response declines steeply over a four-hour
period in early adulthood, precisely at the onset of reproductive maturity. The
animals still appear normal in behavior, but the scientists can see molecular
changes and the decline of protein quality control.
In
one experiment, the researchers blocked the germline from sending the signal to
turn off cellular quality control. They found the somatic tissues remained
robust and stress resistant in the adult animals.
“This
was fascinating to see,” Morimoto said. “We had, in a sense, a super
stress-resistant animal that is robust against all kinds of cellular stress and
protein damage. This genetic switch gives us a target for future research.”
The
research was supported by grants from the National Institutes of Health, the
Ellison Medical Foundation and the Daniel F. and Ada L. Rice Foundation and a
postdoctoral fellowship to Johnathan Labbadia from the ALS Association.
The
title of the paper is “Repression of the Heat Shock Response Is a Programmed
Event at the Onset of Reproduction.”