Experimental Drug Quickly Reduces Age-Related Mental Decline

The compound, known as ISRIB, holds potential for reversing numerous cognitive problems in humans. Mice are used in scientific studies due to having genes that are approximately 85 percent similar to the genes of humans.

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, PhD, 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, PhD, 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, PhD, 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.

Crows Shown to Build Complex Tools from Multiple Separate Parts, Something Only Great Apes and Humans Have Been Shown Doing

Crows continue to prove that they have amazing attributes unique among animals. Crows likely have more to teach humans that study them about cognitive processes, which would aid understanding of the human mind.

Well, we didn’t think it was possible, but we should have had more faith in our feathered corvid friends: crows just got even cooler. Researchers have discovered that crows don’t just use single objects as tools; they can also make them out of multiple parts that are individually useless.

Let that sink in for a moment.

We already knew that corvids – crows and ravens – are capable of reasoning cause and effect, solving multi-step puzzles, planning for the future and even fashioning simple tools out of sticks and paper.

But making compound tools is something that has only ever been observed before in primates – specifically, humans and and great apes.

Even young humans take several years to be able to learn this skill, because cognitively speaking, it’s actually quite complex. It requires the ability to anticipate the properties of objects, and to be able to mentally map the consequences of putting them together prior to doing so.

As such, it’s considered a pretty important milestone when it comes to brain evolution. So observing it in birds is pretty spectacular.

“The finding is remarkable because the crows received no assistance or training in making these combinations, they figured it out by themselves,” said ornithologist Auguste von Bayern of the Max Planck Institute for Ornithology and the University of Oxford.

The team conducted their research on eight New Caledonian crows (Corvus moneduloides), a bird well known for its intelligence.

Almost 1000 New Genes Related to Intelligence Found

The deeper understanding of intelligence allows for it to be recreated, utilized and optimized more effectively. There are certainly more than enough problems in the world — more intelligence could be very helpful in solving them.

Researchers have identified over 1,016 specific genes associated with intelligence, the vast majority of which are unknown to science.

An international team conducted a large-scale genetic association study of intelligence and discovered 190 new genomic loci and 939 new genes linked with intelligence, significantly expanding our understanding of the genetic bases of cognitive function.

Led by statistical geneticist Danielle Posthuma from Vrije Universiteit Amsterdam in the Netherlands, the researchers performed a genome-wide association study (GWAS) of almost 270,000 people from 14 independent cohorts of European ancestry.

All these people took part in neurocognitive tests that measured their intelligence, and when researchers contrast their scores with variations in the participants’ DNA – called single nucleotide polymorphisms (SNPs) – you can see which mutations are associated with high intelligence.

From over 9 million mutations detected in the sample, Posthuma’s team identified 205 regions in DNA code linked with intelligence (only 15 of which had been isolated before), and 1,016 specific genes (77 of which had already been discovered).

According to the team, the genes that make for smartness also look to confer a protective effect to overall cognitive health, with the analysis finding a negative correlation with Alzheimer’s disease, attention deficit/hyperactivity disorder, depressive symptoms, and schizophrenia.

The intelligence genes were however correlated with increased instances of autism, and also longevity, suggesting people with these genetic underpinnings of high intelligence are more likely to live longer.

“Our results indicate overlap in the genetic processes involved in both cognitive functioning and neurological and psychiatric traits and provide suggestive evidence of causal associations that may drive these correlations,” the researchers write.

“These results are important for understanding the biological underpinnings of cognitive functioning and contribute to understanding of related neurological and psychiatric disorders.”

Benefits to Certain Types of Dark Chocolate

Why hasn’t this been studied much before?

New research shows there might be health benefits to eating certain types of dark chocolate. Findings from two studies being presented today at the Experimental Biology 2018 annual meeting in San Diego show that consuming dark chocolate that has a high concentration of cacao (minimally 70% cacao, 30% organic cane sugar) has positive effects on stress levels, inflammation, mood, memory and immunity. While it is well known that cacao is a major source of flavonoids, this is the first time the effect has been studied in human subjects to determine how it can support cognitive, endocrine and cardiovascular health.

Lee S. Berk, DrPH, associate dean of research affairs, School of Allied Health Professions and a researcher in psychoneuroimmunology and food science from Loma Linda University, served as principal investigator on both studies.

“For years, we have looked at the influence of dark chocolate on neurological functions from the standpoint of sugar content — the more sugar, the happier we are,” Berk said. “This is the first time that we have looked at the impact of large amounts of cacao in doses as small as a regular-sized chocolate bar in humans over short or long periods of time, and are encouraged by the findings. These studies show us that the higher the concentration of cacao, the more positive the impact on cognition, memory, mood, immunity and other beneficial effects.”

The flavonoids found in cacao are extremely potent antioxidants and anti-inflammatory agents, with known mechanisms beneficial for brain and cardiovascular health.