Aging Brain Function Partially Restored With Small Molecule

A single administration partially restores long-term brain function.


Researchers from the University of California, San Francisco have discovered that a small molecule partially restores the cognitive abilities of mice suffering from age-related memory decline [1].

To do this, we need your support. Your charitable contribution tranforms into rejuvenation research, news, shows, and more. Will you help?

A response to damage

As the researchers explain, when neurons detect that something has gone wrong, either through the presence of misfolded proteins (amyloids) or traumatic brain injury, these cells cease to produce all the proteins they need for normal functioning. This mechanism is called the integrative stress response (ISR).

Under normal circumstances, the ISR is supposed to be a transitory, short-term response to stresses. However, as neurons age, these stresses accumulate, and the ISR begins to do more harm than good, preventing these cells from making the proteins they need to function. This prevents the formation of long-term memories, a fact that was discovered as far back as 1962 [2].

Hitting the reset button

In order to disrupt the ISR and restart the protein factories in neurons, the researchers of this study had previously developed an integrated stress response inhibitor (ISRIB), a small molecule that they had successfully tested on a mouse model of traumatic brain injury [3]. One protein that is upregulated in ISR is ATF4, a protein that ISRIB quickly diminishes, allowing for the formation of other, beneficial proteins.

ISRIB administration appears to have multiple beneficial results. For example, it beneficially affects how electricity flows in neurons, it restores mRNA expression to be more like that of young mice, and it partially restores the ability of brains to form memories even three weeks after administration, meaning that a single reset of the ISR has long-lasting effects.


With increased life expectancy, age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition (i) rescues intrinsic neuronal electrophysiological properties, (ii) restores spine density and (iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.


The ISR does not appear to be a direct cause of Alzheimer’s or other proteostasis diseases, it does not seem to be responsible for the failure of new brain cells to form (neurogenesis), and it is probably not responsible for all other sources of age-related cognitive decline. However, as this study shows, it plays an enormous role in the failure of aged brains to form new memories, and ISRIB may offer tremendous hope for elderly people who are attempting to learn new things.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.

All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.

NMN Reduces Systolic Blood Pressure in Clinical Trial

Combining human clinical trial research, cellular analysis, and mouse studies, researchers publishing in the Nature journal Signal Transduction and Targeted...

Rejuvenation Roundup September 2023

On some corners of the Internet, "Spooktober", effectively a month-long Halloween, has just begun. Here at Lifespan.io, though, we talk...

Longevity and DeSci Recap – September 2023

Welcome back to the latest edition of the Longevity and DeSci Recap. Here, you’ll discover the latest interviews, insights, and...

Study: Waist-to-Hip Ratio Predicts Mortality Better Than BMI

A new study suggests that waist-to-hip ratio (WHR) has a more linear correlation with all-cause mortality than either body mass...


[1] Krukowski, K., Nolan, A., Frias, E. S., Boone, M., Ureta, G., Grue, K., … & Walter, P. (2020). Small molecule cognitive enhancer reverses age-related memory decline in mice. bioRxiv.

[2] Flexner, J. B., Flexner, L. B., Stellar, E., Haba, G. D. L., & Roberts, R. B. (1962). Inhibition of protein synthesis in brain and learning and memory following puromycin. Journal of neurochemistry, 9(6), 595-605.

[3] Krukowski, K., Nolan, A., Frias, E. S., Grue, K., Becker, M., Ureta, G., … & Rosi, S. (2020). Integrated stress response inhibitor reverses sex-dependent behavioral and cell-specific deficits after mild repetitive head trauma. Journal of Neurotrauma, 37(11), 1370-1380.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called β€œreal life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
No Comments
Write a comment:


Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.