Longevity Questions

Transhumanism in a Distant City, [08.05.2025 08:53]
When studying eukaryotic initiation factor 2 (eIF2), researchers face many fundamental and applied questions. Given its central role in protein synthesis, cellular stress response, and potential links to longevity and disease, the following key areas and questions can be identified:

I. Molecular mechanisms of eIF2 functioning:

Structure and dynamics:

247. What are the exact structural changes of eIF2 (and its individual subunits α, β, γ) upon binding to GTP, Met-tRNAiMet, ribosome (40S, 80S), mRNA, and other initiation factors (eIF1, eIF1A, eIF3, eIF5, eIF2B)?

248. How exactly does phosphorylation of the α subunit alter the conformation of eIF2 and its interaction with eIF2B at the atomic level?

249. Are there other, as yet unidentified, post-translational modifications of eIF2 subunits that affect its function?

250. What is the precise stoichiometry and assembly/disassembly dynamics of pre-initiation and initiation complexes involving eIF2?

Interaction with RNA:

251. What are the precise determinants in the structure of the initiator Met-tRNAiMet that are recognized by the γ subunit of eIF2, and how is discrimination from elongator tRNAs ensured?

252. Does eIF2 interact directly with mRNA during scanning, and if so, how?

The GTP/GDP cycle and its regulation (beyond eIF2α phosphorylation):

253. What are the precise kinetic parameters of GTP binding and hydrolysis by eIF2 in different contexts (e.g., at different Mg2+ concentrations, in the presence of different factors)?

254. How is the activity of the guanine nucleotide exchange factor eIF2B itself regulated (beyond its inhibition by phosphorylated eIF2α)?

255. Are there other regulatory proteins or metabolites that affect eIF2B?

II. Regulation of eIF2 activity and the Integrated Stress Response (ISR):

eIF2α kinases and phosphatases:

256. How is the specificity of activation of each of the four kinases (PERK, GCN2, PKR, HRI) achieved by different stress signals?

257. Is there coordination or hierarchy in the activation of these kinases?

258. What is the full spectrum of phosphatases that dephosphorylate eIF2α (besides the well-known PP1/GADD34 and PP1/CReP), and how are their activities and substrate specificities regulated?

259. What are the threshold levels of eIF2α phosphorylation required to initiate different cellular programs (e.g., translational arrest vs. apoptosis induction)?

Selective mRNA translation in ISR:

260. What are the precise molecular mechanisms that allow translation of specific mRNAs (e.g., ATF4, CHOP) under conditions where overall translation is repressed by eIF2α phosphorylation? What role do uORFs (upstream Open Reading Frames) play in these mRNAs?

261. What is the complete translationome when ISR is activated by different stressors and in different cell types?

262. How long can selective translation be sustained under stress, and what determines the transition from an adaptive response to cell death?

ISR context specificity:

263. How do the intensity, duration, and type of stress affect ISR outcome (adaptation, survival, apoptosis, senescence)?

264. Are there tissue-specific or age-specific differences in the regulation and function of the eIF2 pathway and ISR?

III. The role of eIF2 in health, aging, and disease:

Aging and longevity:

265. How do basal eIF2α phosphorylation levels and eIF2α kinase/phosphatase activity change with age in different tissues?

266. Can moderate chronic activation of the ISR (e.g. via low doses of eIF2B inhibitors or eIF2α kinase activators) actually extend healthy life in mammals, and what are the long-term consequences of such interventions?

267. What specific effects of reducing protein synthesis via the eIF2 pathway (improved proteostasis, reduced oxidative stress, energy conservation) contribute most to the potential life extension?

Neurodegenerative diseases:

268. What is the precise role of eIF2 dysregulation and chronic ISR in the pathogenesis of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other neurodegenerative conditions?

269.

Transhumanism in a Distant City, [08.05.2025 08:53]
Is eIF2α phosphorylation a cause or a consequence of protein aggregate accumulation?

Cancer:

270. How do tumor cells adapt the eIF2 pathway to survive stress (hypoxia, nutrient deprivation, chemotherapy)?

271. Can targeting the eIF2 pathway (e.g., inhibiting eIF2α or eIF2B kinases) sensitize cancer cells to therapy?

Metabolic Diseases:

272. How is the eIF2 pathway involved in insulin resistance, type 2 diabetes, and obesity, especially via PERK-mediated ER stress?

Infectious Diseases:

274. How do different viruses and bacteria manipulate the eIF2 pathway (by activating or inhibiting its components) to replicate and evade the immune response?

IV. Therapeutic Potential:

Drug Development:

275. Is it possible to create highly specific and safe molecular modulators (activators or inhibitors) of eIF2α kinases, eIF2α phosphatases, or eIF2B factor?

276. What are the potential therapeutic windows and side effects of modulating eIF2 activity in various diseases?

277. Can eIF2 pathway modulators be used to enhance the effects of existing therapies (e.g. in oncology or in the treatment of viral infections)?