The Brain-Boosting Potential of Experimental Drug ISRIB: Blocking Stress Response Pathway Reverses Age-Related Cognitive Decline
When exposed to stressful situations — infections, nutrient deficiencies, or misfolded proteins, to name a few — human and animal cells activate a network of signals to help adapt to the insult. This evolutionary quality control system — coined the integrated stress response (ISR) — attempts to bring the cell back into balance, or homeostasis. Although this is a beneficial system, overactivation of the ISR pathway occurs with increasing age and is linked to cognitive decline. In a recent study published in eLife, Krukowski and colleagues looked at the effects of inhibiting this stress response on memory and cognition in aged mice.
The aging brain: how cellular changes compromise cognition
With age, several critical aspects of brain health deteriorate, leading to progressive cognitive decline. This degradation includes deficits in various forms of memory, including spatial, working, and episodic memory. Briefly, spatial memory involves remembering details about your environment and spatial location, working memory holds short-term information to guide decision-making, and episodic memory recalls experiences from the past. The hippocampus — an area of the brain essential for learning and forming new memories — is especially vulnerable to age-related deficits. Hippocampal neurons’ activity change with age as the brain cells experience subdued excitability in response to stimuli. Neuron excitability is beneficial, as it maintains homeostasis of the cells; reduced excitability is linked to memory loss.
Another factor involved with age-related cognitive decline is reduced dendritic spine density, which are small projections coming off the ends of dendrites, the branch-like area off the ends of neurons that receive signals from other cells, acting like an antenna. The dendritic spine branches off the dendrite at certain areas, forming sites for synapses to grow. As synapses allow for two nerve cells to communicate with each other, the proper structure and density of them are thought to play an essential role in memory formation.
Misfolded proteins miss the mark
One of the hallmarks of aging is an accumulation of misfolded proteins and disrupted protein synthesis — known as a loss of proteostasis. These misfolded proteins can aggregate in the brain, clumping together to cause brain damage and cognitive decline. When the ISR notices these misfolded proteins, it halts all protein synthesis. While this helps reduce a potential buildup of dysfunctional proteins, chronic overactivation of this system is linked to brain cell dysfunction and memory loss.
Previous research from the same authors of this study found that inhibiting the ISR with a small compound called ISRIB (“integrated stress response inhibitor”) reversed cognitive decline in mice with traumatic brain injuries within days. Discovered in 2013, the now-patented ISRIB essentially reboots the stress response pathway, allowing for normal protein synthesis to continue. In this December 2020 study, Krukowski and colleagues now used the same compound to see if temporarily blocking the ISR pathway could improve memory and cognition in naturally aged mice.
Resetting the stress response rejuvenates the brain
The researchers compared three groups of mice: young mice of 3-6 months, aged 19-month old control mice (approximately 60 in human years), and aged 19-month old mice who received ISRIB treatment. The ISRIB treatment was short-term, with just three days of daily injections of the compound. From there, the team tested various aspects of cognition, memory, and neuronal health over the next month.
Several proteins indicate if the ISR is overactivated, including ATF4 and eIF2, which regulate the adaptation of cells to stress factors. When these proteins are elevated, the ISR is thought to be in full swing. Concurrently, these proteins are increased in the aging brain. After the aged mice received ISRIB treatment, their ATF4 and eIF2 levels significantly dropped to levels comparable to the young mice. These protein changes indicate that ISRIB effectively reset the ISR pathway.
Next, the team looked at changes in memory, using tests that measure cognitive decline by assessing spatial, working, and episodic memory. In the first test, the researchers trained the mice to find a hidden platform within a water-filled maze, relying on their spatial memory of the environment to escape. Without ISRIB treatment, the aged mice averaged three errors on the test, while young mice averaged one error. After ISRIB treatment, the aged mice significantly improved their memory, reducing their errors to just two.
In a second test, the mice were scored on their ability to find their way out of a maze, with the maze’s exit changing each time. Three weeks after ISRIB treatment, the mice had improved scores on these tests that measured their short term (working) and situational (episodic) memory — essentially testing mental flexibility. Even 18 days post-treatment, the mice still exhibited improved working and episodic memory, indicating that short-term ISR inhibition can lead to long-lasting results. Although they didn’t reach “young” memory status, these results suggest that temporarily blocking ISR could partially reverse age-related memory loss.
At the level of cells, ISRIB reversed age-related declines in brain cell function, including increasing neuron excitability to young levels and reducing dendritic spine loss. As expected, the aged and non-treated mice had drastically lower dendritic spine density than young mice; ISRIB treatment ameliorated this loss, improving both neuron structure and function in older mice.
As just three days of ISRIB treatment rapidly mitigated cognitive decline and brain cell function, these results suggest that memory loss and age-related brain abnormalities may not be permanent. Rather than completely eliminating the response pathway, ISRIB simply reboots it to a healthier and more youthful state. So, transient inhibition of the stress response (and its subsequent cessation of protein synthesis) may reverse the deterioration of the brain and cognition.
Is ISRIB the next brain-boosting miracle drug?
If these results translate to humans, cognitive decline and memory loss related to age or injury may soon be a thing of the past. As clinical trials have yet to be performed on ISRIB, it’s difficult to determine if the impressive results seen in mice will copy over to humans. One important caveat that needs to be studied more extensively is whether or not interfering with this critical internal mechanism causes adverse effects. Fortunately, the animal studies so far have shown no significant side effects, perhaps due to the short duration of ISR inhibition. While it’s too soon to tell if ISRIB is the next brain-boosting miracle drug — and too soon to tell if it’s completely safe — this small compound holds promise for the millions affected by memory loss.
Krukowski K, Nolan A, Frias ES, et al. Integrated Stress Response Inhibitor Reverses Sex-Dependent Behavioral and Cell-Specific Deficits after Mild Repetitive Head Trauma. J Neurotrauma. 2020;37(11):1370-1380. doi:10.1089/neu.2019.6827
Krukowski K, Nolan A, Frias ES, et al. Small molecule cognitive enhancer reverses age-related memory decline in mice. Elife. 2020;9:e62048. Published 2020 Dec 1. doi:10.7554/eLife.62048
Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374-1395. doi:10.15252/embr.201642195