With the aging population growing, age-associated cognitive decline has increasingly become a concern. A detrimental neurological process called the integrated stress response (ISR) takes hold during aging and contributes to age-related cognitive decline.

A new study from Rosi and colleagues from UC San Francisco published December 1 in the open-access journal eLife demonstrated that administering a drug that inhibits the ISR restored youthful cognitive abilities in older mice. The drug called the integrated stress response inhibitor (ISRIB) also rejuvenated neurons, possibly explaining the observed 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,” stated Susanna Rosi, Ph.D., a professor in the Neurological Surgery and Physical Therapy and Rehabilitation Science Departments at UC San Francisco and a lead author of the study in a press release.

Age-Induced ISR Activation Impairs Neuron Function

The ISR typically detects problems with protein production in cells stemming from viral infections, cancer-causing gene mutations, or misfolded proteins that accumulate during aging. In response to these incursions, the cell puts the brakes on protein production. This mechanism can weed out dysfunctional cells, but with age, its increased activation in a tissue like the brain can lead to age-related cognitive decline as cells lose their abilities to function normally.

The Experimental Drug ISRIB Resets the Age-Induced Brain Stress Response

When the researchers administered ISRIB, it reset the ISR in the brains of aged mice. They saw this after injecting ISRIB daily for three consecutive days in aged mice and examining the effects 18 days later. Typically, levels of the protein ATF4 increase with ISR, and administering the experimental molecule ISRIB reversed age-induced elevation in ATF4 protein levels. When they examined ATF4 levels 18 days after ISRIB injections, the researchers found a persistent reduction in ATF4 protein levels.

(Krukowski et al., 2020 | eLife) ISRIB treatment reduced the activation of the integrated stress response (ISR) that blocks protein production in the brain during aging. Levels of the protein marker for the ISR called ATF4 increased in older mice, and injecting older mice with ISRIB reversed this effect.

Injecting mice with ISRIB also reversed age-induced spatial learning and memory impairments. The researchers assessed how ISRIB influences age-related cognitive defects by comparing the performance of young and old mice in a water maze. In this test of spatial memory, mice are repeatedly and randomly placed into a pool of opaque water and have to find a hidden platform. This pool has spatial cues around it that the mice can learn to use to find the platform. For the study, the mice had two days to learn how to use the spatial cues to locate a platform hidden under opaque water before being tested. While young animals averaged just one error before successfully locating the escape platform, older animals averaged three errors. But after receiving ISRIB, the aged mice averaged two errors before finding the escape platform, indicating that the aged mice had improved memory of the escape platform location with ISRIB administration. Importantly, these improvements persisted weeks after the mice received ISRIB.

(Krukowski et al., 2020 | eLife) Aged mice have improved memory one week after ISRIB administration. After two days of training, young mice navigated a water maze with an average of one error, while older mice navigated it with an average of three errors. Treating older mice with ISRIB and training them for two days on the task resulted in an average of two errors, suggesting that ISRIB restores learning and memory capabilities in aged mice.

ISRIB Reversed Age-Related Changes to Neurons 

ISRIB treatment reversed age-related changes in neurons from a brain region associated with learning and memory, the hippocampus, which could explain the improvements in memory. A single ISRIB injection the day before examination of electrical activity in neurons resulted in improved neuron excitability from aged mice. Additionally, cellular structures linked to communication between neurons called dendritic spines increased in density in aged mice following ISRIB treatment.

(Krukowski et al., 2020 | eLife) ISRIB treatment allays age-associated changes in neuron structure in a region of the brain associated with learning and memory, the hippocampus. The left figure shows an increased density of dendritic spines (labeled with white dots), cellular structures that aid in communication between neurons. The right figure illustrates the density of dendritic spines in young, old, and old mice treated with ISRIB. Dendritic spine density diminished in aged mice compared to young, however, ISRIB treatment reversed these age-related reductions.

The researchers think that the ISR activation and resulting blockage of cellular protein production may play a critical role in a wide array of neurological conditions. For these reasons, ISRIB could potentially treat numerous conditions like frontotemporal dementia, Alzheimer’s disease, and traumatic brain injury.

Future Directions for Utilizing ISRIB

“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,” said Peter Walter, Ph.D., another author of the study and professor in the UC San Francisco Department of Biochemistry and Biophysics in the press release. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

ISRIB has been licensed to Calico, a company located in South San Francisco that explores the biology of aging. Other pharmaceutical companies are also using the idea of targeting ISR to treat diseases, according to Peter Walter, Ph.D. “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,” said Walter in the press release.