”…researchers showed rapid restoration of youthful cognitive abilities in aged mice…”
By the University of California, San
Francisco
Decdember 1, 2020 -- Just a few doses of
an experimental drug can reverse age-related declines in memory and mental
flexibility in mice, according to a new study by UC San Francisco scientists.
The drug, called ISRIB, has already been shown in laboratory studies to restore
memory function months after traumatic brain injury (TBI), reverse cognitive
impairments in Down Syndrome , prevent noise-related hearing loss, fight
certain types of prostate cancer , and even enhance cognition in healthy
animals.
In the new study, published December 1,
2020 in the open-access journal eLife , researchers showed
rapid restoration of youthful cognitive abilities in aged mice, accompanied by
a rejuvenation of brain and immune
cells that could help explain
improvements in brain function.
"ISRIB's extremely rapid effects
show for the first time that a significant component of age-related cognitive
losses may be caused by a kind of reversible physiological "blockage"
rather than more permanent degradation," said Susanna Rosi , Ph.D., Lewis
and Ruth Cozen Chair II and professor in the departments of Neurological
Surgery and of Physical Therapy and Rehabilitation Science.
"The data suggest that the aged
brain has not permanently lost essential cognitive capacities, as was commonly
assumed, but rather that these cognitive resources are still there but have
been somehow blocked, trapped by a vicious cycle of cellular stress,"
added Peter Walter , Ph.D., a professor in the UCSF Department of Biochemistry
and Biophysics and a Howard Hughes Medical Institute investigator. "Our
work with ISRIB demonstrates a way to break that cycle and restore cognitive
abilities that had become walled off over time."
Could Rebooting Cellular Protein
Production Hold the Key to Aging and Other Diseases?
Walter has won numerous scientific
awards, including the Breakthrough , Lasker and Shaw prizes, for his
decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in
Walter's lab, works by rebooting cells' protein production machinery after it
gets throttled by one of these stress responses—a cellular quality control
mechanism called the integrated stress response (ISR; ISRIB stands for ISR
InhiBitor).
The ISR normally detects problems with
protein production in a cell—a potential sign of viral infection or
cancer-promoting gene mutations—and responds by putting the brakes on cell's
protein-synthesis machinery. This safety mechanism is critical for weeding out
misbehaving cells, but if stuck in the on position in a tissue like the brain,
it can lead to serious problems, as cells lose the ability to perform their
normal activities, Walter and colleagues have found.
In particular, recent animal studies by
Walter and Rosi, made possible by early philanthropic support from The Rogers
Family Foundation, have implicated chronic ISR activation in the persistent
cognitive and behavioral deficits seen in patients after TBI, by showing that,
in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function
almost overnight.
The cognitive deficits in TBI patients
are often likened to premature aging, which led Rosi and Walter to wonder if
the ISR could also underlie purely age-related cognitive decline. Aging is well
known to compromise cellular protein production across the body, as life's many
insults pile up and stressors like chronic inflammation wear away at cells,
potentially leading to widespread activation of the ISR.
"We've seen how ISRIB restores
cognition in animals with traumatic
brain injury, which in many ways is like a sped-up
version of age-related cognitive decline," said Rosi, who is director of
neurocognitive research in the UCSF Brain and Spinal Injury Center and a member
of the UCSF Weill Institute for Neurosciences. "It may seem like a crazy
idea, but asking whether the drug could reverse symptoms of aging itself was
just a logical next step."
ISRIB Improves Cognition, Boosts Neuron
and Immune Cell Function
In the new study, researchers led by
Rosi lab postdoc Karen Krukowski , Ph.D., trained aged animals to escape from a
watery maze by finding a hidden platform, a task that is typically hard for
older animals to learn. But animals who received small daily doses of ISRIB
during the three-day training process were able to accomplish the task as well
as youthful mice, much better than animals of the same age who didn't receive
the drug.
The researchers then tested how long
this cognitive rejuvenation lasted and whether it could generalize to other
cognitive skills. Several weeks after the initial ISRIB treatment, they trained
the same mice to find their way out of a maze whose exit changed daily—a test
of mental flexibility for aged mice who, like humans, tend to get increasingly
stuck in their ways. The mice who had received brief ISRIB treatment three
weeks before still performed at youthful levels, while untreated mice continued
to struggle.
To understand how ISRIB might be
improving brain function, the researchers studied the activity and anatomy of
cells in the hippocampus, a brain region with a key role in learning and
memory, just one day after giving animals a single dose of ISRIB. They found
that common signatures of neuronal aging disappeared literally overnight:
neurons' electrical activity became more sprightly and responsive to
stimulation, and cells showed more robust connectivity with cells around them
while also showing an ability to form stable connections with one another
usually only seen in younger mice.
The researchers are continuing to study
exactly how the ISR disrupts cognition in aging and other conditions and to
understand how long ISRIB's cognitive benefits may last. Among other puzzles
raised by the new findings is the discovery that ISRIB also alters the function
of the immune system's T cells, which also are prone to age-related
dysfunction. The findings suggest another path by which the drug could be
improving cognition in aged animals, and could have implications for diseases
from Alzheimer's to diabetes that have been linked to heightened inflammation
caused by an aging immune system.
"This was very exciting to me
because we know that aging has a profound and persistent effect on T cells and
that these changes can affect brain function in the hippocampus," said
Rosi. "At the moment, this is just an interesting observation, but it
gives us a very exciting set of biological puzzles to solve.
ISRIB May Have Wide-Ranging Implications
for Neurological Disease
It turns out that chronic ISR activation
and resulting blockage of cellular protein production may play a role in a
surprisingly wide array of neurological conditions. Below is a partial list of
these conditions, based on a recent review by Walter and colleague Mauro
Costa-Mattioli of Baylor College of Medicine, which could potentially be
treated with an ISR-resetting agent like ISRIB:
- Frontotemporal
Dementia
- Alzheimer's
Disease
- Amyotrophic
Lateral Sclerosis (ALS)
- Age-related
Cognitive Decline
- Multiple
Sclerosis
- Traumatic
Brain Injury
- Parkinson's
Disease
- Down
Syndrome
- Vanishing
White Matter Disorder
- Prion
Disease
ISRIB has been licensed by Calico, a
South San Francisco, Calif. company exploring the biology of aging, and the
idea of targeting the ISR to treat disease has been picked up by other pharmaceutical
companies, Walter says.
One might think that interfering with
the ISR, a critical cellular safety mechanism, would be sure to have serious
side effects, but so far in all their studies, the researchers have observed
none. This is likely due to two factors, Walter says. First, it takes just a
few doses of ISRIB to reset unhealthy, chronic ISR activation back to a
healthier state, after which it can still respond normally to problems in
individual cells. Second, ISRIB has virtually no effect when applied to cells actively
employing the ISR in its most powerful form—against an aggressive viral
infection, for example.
Naturally, both of these factors make
the molecule much less likely to have negative side effects—and more attractive
as a potential therapeutic. According to Walter: "It almost seems too good
to be true, but with ISRIB we seem to have hit a sweet spot for manipulating
the ISR with an ideal therapeutic window.
Drug
reverses age-related cognitive decline within days (medicalxpress.com)
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