Autophagy is a means of recycling cells' old, broken, or unneeded
parts so that their components can be re-used to make new molecules or
be burned for energy.
Biologists have known for decades that enduring a short period of
mild stress makes simple organisms and human cells better able to
survive additional stress later in life. Now, scientists at Sanford
Burnham Prebys Medical Discovery Institute (SBP) have found that a
cellular process called autophagy is critically involved in providing
the benefits of temporary stress.
‘Brief exposure to mild heat stess helps alleviate protein aggregation. This finding could lead to new approaches to slow the advance of neurodegenerative diseases such as Huntington's.’
The study, published today in Nature Communications
, creates new avenues to pursue treatments for neurological disorders such as Huntington's disease.
The process had previously been linked to
longevity, in no small part because of research led by Malene Hansen, associate professor at SBP and senior author of the study. The
new results suggest that long life and stress resistance are connected
at the cellular level.
"We used C. elegans
- tiny roundworms used to study
fundamental biology - to test the importance of autophagy in becoming
stress resistant," says Caroline Kumsta, staff scientist in
Hansen's lab and lead author of the study. "They're a great model system
because they're transparent, so you can easily observe what goes on
inside them, most of their genes and molecular signaling pathways have
functional counterparts in humans, and they only live a few weeks, which
greatly facilitate measuring their lifespans."
Kumsta and colleagues incubated worms at 36 °C, significantly above
the temperature they are usually kept at in the laboratory, for one
hour. After this short heat exposure - a mild form of stress that
improves the organism's survival - autophagy rates increased throughout
the worms' tissues. When they exposed these heat-primed worms to
another, longer heat shock a few days later, worms that were deficient
in autophagy failed to benefit from the initial mild heat shock, as
observed in heat-primed worms with intact autophagy.
The researchers reasoned that a mild heat stress might also improve
the worms' ability to handle another condition that worsens with
age - buildup of aggregated proteins, which is stressful for cells. To
test this hypothesis, Kumsta used worms that model Huntington's disease,
a fatal inherited disorder caused by neuronal proteins that start to
stick together into big clumps as patients age, leading to degeneration
throughout the brain. Exposing worms that make similar sticky proteins
in different tissues to a mild heat shock reduced the number of protein
aggregates, suggesting that a limited amount of heat stress can reduce
toxic protein aggregation.
"Our finding that brief heat exposure helps alleviate protein
aggregation is exciting because it could lead to new approaches to slow
the advance of neurodegenerative diseases such as Huntington's," says
Hansen. "The results may also be relevant to Alzheimer's and
Parkinson's, which are similarly caused by clumping-prone proteins."
"This research raises many exciting questions," adds Hansen. "For
example, how does induction of autophagy by a mild heat stress early on
make cells better able to survive heat later - what's the cellular
memory? There's a lot to follow up on."
"A lot of people ask us if this means they should start going to the
sauna or do hot yoga," jokes Kumsta. "That may not be an entirely bad
idea - epidemiological studies do indicate that frequent sauna use is
associated with longer life. But we have a lot more research to do to
figure out whether that has anything to do with the beneficial induction
of autophagy by heat stress that we see in C. elegans
Kumsta recently received a promotion from postdoc to staff scientist in recognition of her leadership of this study.