Most Brain Aging Decline Can Be Fixed Overnight

There are two huge aspects to a new antiaging drug. The first aspect is that a large portion of age-related brain decline is not permanent damage. This non-permanent damage is repaired overnight by a new antiaging drug. The Google-back antiaging company, Calico, has licensed the drug.

A new University of San Francisco antiaging 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.

The extremely rapid effects prove that a significant amount of age-related cognitive losses is caused by a kind of reversible physiological blockage rather than more permanent degradation.

ISRIB, discovered in 2013 in Peter 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).

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.

Common signs 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.

ELife – Small molecule cognitive enhancer reverses age-related memory decline in mice

Abstract
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.

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