Integrated Stress Response (ISR)

•Pre-clinical— ISRIB studies in mouse cognition

What it is

The ISR is a four-kinase, one-substrate signalling hub:

Kinase	Activated by
PERK	ER stress (unfolded proteins in ER)
GCN2	Amino-acid starvation, UV
HRI	Heme depletion, oxidative stress, mitochondrial dysfunction
PKR	Viral dsRNA

All four phosphorylate the same substrate — eIF2α — which inhibits general protein synthesis while paradoxically permitting selective translation of ATF4 and a stress-adaptation gene programme.

Why it matters in aging

• Sustained ISR activation impairs synaptic plasticity and memory.
• ISR activation rises with age in brain and other tissues.
• ISR-inhibitor compounds (ISRIB and analogs) restored memory in aged mice in landmark Walter-lab studies.
• Cross-talk with mTOR: ISR represses cap-dependent translation while mTOR promotes it — together they govern the balance between growth and stress response.

Cross-talk

• mtUPR: HRI sensing of mitochondrial dysfunction overlaps with mtUPR signalling.
• mTORC1: opposing forces on global translation.
• Inflammation: chronic ISR activation amplifies NF-κB.
• Autophagy: ATF4 turns on autophagy genes.

Pharmacology

• ISRIB (integrated-stress-response inhibitor) — small molecule reversing eIF2α-P inhibition; pre-clinical only.
• Salubrinal — opposite direction (PP1 inhibitor that prolongs eIF2α phosphorylation).
• Several pharma companies have ISR-modulator programs (e.g. Calico has reported interest).

Related entries

Loss of proteostasis, mtUPR, mTOR, Cognitive decline.