Editors' ChoiceAging

Brain rejuvenation by inhibiting stress response

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Science Translational Medicine  16 Dec 2020:
Vol. 12, Issue 574, eabf7740
DOI: 10.1126/scitranslmed.abf7740

Abstract

Age-related cognitive decline can be reversed with small molecule inhibition of the stress response pathway.

Aging is an inevitable process for all living creatures. With increased life expectancy, age-related cognitive decline such as Dementia or Alzheimer’s disease, is a burgeoning global problem. Accumulation of misfolded proteins occurs during aging, and this leads to the chronic activation of the integrated stress response (ISR), an evolutionarily conserved protein homeostatic program activated by endoplasmic reticulum stress. Drug-like small molecules ISR inhibitors (ISRIB) have been shown to rescue traumatic brain injury–induced behavioral and cognitive deficits; whether similar approach could also reduce age-related cognitive impairments is unclear.

In this paper, Krukowski et al. extend the use of ISRIB to rapidly reverse spatial memory deficits and ameliorate working memory in preclinical models of aging in mice. With just three daily injections of ISRIB, aged mice were able to perform better in a radial arm water maze. These ISRIB-treated aged mice also showed improved cognitive performance in delayed-matching-to-place paradigm 18 days after ISRIB treatment. These effects were not seen in control young mice, suggesting that the ISRIB-induced improvements are age-dependent.

At the cellular level, ISRIB was able to rescue intrinsic neuronal electrophysiological properties as shown by whole cell patch clamping and restore spine density measured by confocal imaging. Quantitative PCR analysis performed on hippocampi obtained from ISRIB-treated animals demonstrated a reduction in interferon (IFN)-related inflammatory molecules and T-cell markers to concentrations similar to young animals.

These results suggest that the aged brain might still maintain essential cognitive capacities but is perhaps trapped in a viscous cycle of cellular stress. Pharmacological attenuation of ISR presents as a promising strategy to break that cycle and restore cognitive abilities that have walled off over time.

However, these ISRIB-mediated neuronal and immune effects were tested only in male mice. Further work is required to investigate if these restorative effects can also be observed in females. Importantly, it remains to be seen if ISRIB is able to produce similar effects in larger animals physiologically more similar to humans.

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