Literature
ISRIB and Aging: A Comprehensive Review of Current Research Findings
Does ISRIB Really Reverse Aging?
Current State of Research
As of the latest knowledge update in January 2022, the claim that ISRIB (Integrated Stress Response Inhibitor) directly reverses aging remains speculative. ISRIB has shown promising results in improving cognitive functions in mice, but its long-term effects on aging in humans are still under investigation. More comprehensive research is required to establish its safety and efficacy for reversing aging.
Understanding ISR and eIF2B Regulation
The integrated stress response (ISR) is a key cellular pathway that is activated in response to various environmental and pathological conditions such as proteostasis defects, nutrient deprivation, viral infections, and oxidative stress. ISR aims to restore cellular homeostasis by reprogramming gene expression.
The sensing of different stresses is accomplished by four specialized kinases: PERK, GCN2, PKR, and HRI. These kinases converge at the phosphorylation of a single serine residue on the eukaryotic translation initiation factor 2 (eIF2). The phosphorylation of eIF2 plays a pivotal role in regulating protein synthesis. In particular, eIF2α is heavily phosphorylated during the ISR process.
The Role of eIF2α Kinases in Aging and Neurodegeneration
Previous studies have shown that the regulation of eIF2α phosphorylation is crucial in the pathogenesis of neurodegenerative diseases. For instance, the phosphorylation of eIF2α is known to decrease phospho-CREB (p-CREB) levels and increase the production of β-amyloid (Aβ) proteins, which are neurotoxic and a hallmark of Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative conditions.
ISRIB Studied in Mouse Models
A significant breakthrough was reported in 2020 when a compound called ISRIB was tested for its effects on the memory decline in aging mice. The Small molecular cognitive enhancer reverses age-related memory decline in mice study, published in eLife, demonstrated that ISRIB could reverse age-related cognitive decline in mice. ISRIB acts as a PERK inhibitor, regulating the phosphorylation of eIF2α to activate eIF2B. This activation counters the ISR activation, leading to improved cognitive function.
PKR and Memory Enhancement
PKR (Patrician kinase RNA-activated) is another kinase involved in the regulation of eIF2α phosphorylation. The PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice study showed that inhibiting PKR could rescue memory deficits and reduce the expression of ATF4 mRNA in apoE4 mice. Additionally, research has shown that the absence of PKR enhances learning and memory by increasing network excitability and late-phase long-term potentiation (L-LTP) in the hippocampus.
Conclusion and Future Prospects
While ISRIB shows great potential in addressing cognitive decline and age-related memory issues, the exact mechanisms and long-term effects in human subjects remain to be fully elucidated. Future research focusing on long-term studies and clinical trials will provide more conclusive data on the efficacy and safety of ISRIB in the context of aging and neurodegeneration.