If you want to be sprite like a 20-year-old while in your 50s, raise your hand. You can all put your hands down now. That dream is closer than you think.

Three takeaways to tell your friends:

• The spatial learning abilities of older mice were no different from young mice one week after receiving a new treatment.¹
• Both male and female mice saw improvements in cognitive functions following the treatment.¹
• The probability of a neuron firing in older mice was rescued to levels indistinguishable from young mice following treatment.¹

Cognitive deficiency is a big part of aging. Accessing memories and learning new information becomes more difficult with age, even without the presence of neurodegenerative disease. This has been shown in both humans² and mice.³ Thanks to effective research, we may have a treatment for age-related cognitive decline, the Integrated Stress Response (ISR).

Since its discovery in the early 2000s, the ISR has been a coordinated expression of specific genes in response to stressful events within a cell.⁴ However, as of 2020, the stakes skyrocketed. In science, when you have an idea based on evidence, that’s a hypothesis. The researchers behind today’s article hypothesized that the ISR is responsible for age-related cognitive decline. To test this hypothesis, they inhibited the ISR with an ISR inhibitor (ISRIB). This blockage of the ISR culminated in the discovery of a drug, ISRIB, that reverses age-related cognitive decline.

Given that the ISR is a coordinated expression of specific genes, researchers from this study compared levels of these genes in young, old, and ISRIB-treated old mice. A major upregulated gene in the ISR is ATF4.⁵ As expected, in older mice, there was significantly more ATF4 present. However, there was no statistical difference in the levels of ATF4 in the young mice and the older mice treated with ISRIB.¹ That was true for both male and female mice.

Two cognitive tests were performed on the mice to control the possibility of stress caused by one of the tasks. To test spatial learning and memory, mice are placed in a radial arm water maze.⁶ Imagine a cylindrical pool, except part of it is blocked off. There’s an open circle in the middle with eight individual arms extending to the edge allowing access for the mouse to swim. Placed at the end of one of those arms is a platform, where the mouse is saved from the water. Mice are trained on the location of the platform, using spatial cues set up in the room. The test involves recording the number of “errors” mice perform. Errors are when a mouse enters an arm that does not contain the platform.

ISRIB treatment occurs for three consecutive days then the radial arm water maze is run on day four. While searching for the platform, young mice averaged one error, and older mice averaged three errors.¹ However, old mice treated with ISRIB only recorded two errors.¹ Without the administration of additional treatment, the same older mice previously treated with ISRIB conducted the radial arm water maze a week later. This time the older mice averaged one error, equating their spatial learning to the young mice.¹ Female mice also saw an improvement in error scores a week after ISRIB treatment ceased.¹

To remove the stress of swimming, mice are placed in a delayed-matching-to-place (DMP).⁷ DMP tests both spatial learning and working memory. Mice are placed on a circular platform containing forty circles where one opens to an escape tunnel. After learning the location of the escape tunnel based on spatial clues around the room, the mouse is returned to its cage (delayed) and ready to be tested. For this test, the time mice search for the tunnel is recorded. This way, the longer the mouse spent searching, the weaker the memory capabilities of that mouse.

Since ISRIB continued to improve the cognitive abilities of older mice one week after treatment, the researchers used the same mice for the DMP three weeks following treatment. Still, the old mice previously treated with ISRIB took significantly less time to find the escape tunnel.¹ The ISRIB continues to improve age-related cognitive decline weeks after the three-day treatment of ISRIB.

The other results in this paper are remarkable, but I’ll let you dive in as it’s a very well-written paper. Although, if it’s too complex for you, here are other findings from ISRIB use:

• In old mice treated with ISRIB, a neuron’s probability of firing is returned to levels similar to young mice.¹
• In old mice treated with ISRIB, the number of connection-receiving centers on neurons increased.¹
• Three inflammatory genes involved in age-related cognitive decline⁸ were indistinguishably expressed between young mice and ISRIB-treated old mice.¹
• A marker present on white blood cells, while raised in old mice, was comparable between young mice and ISRIB-treated old mice.¹

As evident, the findings are astounding, and, to nobody’s surprise, clinical trials have begun. With our ever-elongating lifespans, spread the word! Your brain can stay as sharp as a 20-year-olds!

Experimental factors to consider…

The ISRIB was administered by injection directly into the mouse’s abdomen. Young mice were 20-30 human years old, and older mice were older than 56 human years old.

REFERENCES

1. Krukowski K, Nolan A, Frias ES, Boone M, Ureta G, Grue K, et al. Small molecule cognitive enhancer reverses age-related memory decline in mice. Elife. 2020;9.
2. Kramer AF, Hahn S, Gopher D. Task coordination and aging: explorations of executive control processes in the task switching paradigm. Acta Psychol (Amst). 1999;101(2-3):339-78
3. Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659-63.
4. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374-95.
5. Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol. 2004;167(1):27-33.
6. Buresova O, Bures J, Oitzl MS, Zahalka A. Radial maze in the water tank: an aversively motivated spatial working memory task. Physiol Behav. 1985;34(6):1003-5.
7. Feng X, Krukowski K, Jopson T, Rosi S. Delayed-matching-to-place Task in a Dry Maze to Measure Spatial Working Memory in Mice. Bio Protoc. 2017;7(13).
8. Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014;346(6205):89-93.