ИСТИНА

Proteostasis - the balance between protein synthesis and degradation - is one of the key processes affecting lifespan. Its deregulation leads to irreversible changes in the proteome and thus leads to the development of neurodegenerative diseases, cancer, and aging. Many life-prolonging interventions decrease protein synthesis level and improve proteostasis. However, little is known about mRNA-specific translational control upon longevity interventions. We applied ribosome profiling to analyze changes in protein biosynthesis in the liver of mice subjected to four dietary and pharmacological lifespan-extending interventions: 40% caloric restriction, rapamycin (14 ppm), acarbose (1000 ppm), and canagliflozin (180 ppm). Among those, the caloric restriction leads to the most significant changes in gene expression while acarbose, rapamycin, and canagliflozin had only minor effects. Despite the fact that most expression changes occurred on the transcriptional level, we found that certain transcripts (e.g. Srsf11, Noct, Hsd3b7 and mRNAs encoding components of translation apparatus), had altered translation efficiency under caloric restriction. Interestingly, translation response to the interventions in females and males was strikingly different for selected genes. Particularly, Saa1 and Saa2 encoding acute phase response proteins had decreased transcription in female mice under all four interventions while were upregulated in males. A similar pattern was found for genes related to inflammation response. In summary, our results provide first systematic analysis of gene expression changes at the translational level upon lifespan-extending interventions in mice. The study was supported by the Russian Science Foundation (grant RSF 18-14-00291).