Researchers here show that increased levels of cap-independent translation (CIT) of messenger RNA (mRNA) take place in a diverse set of interventions known to modestly slow aging in mice, suggesting it to be a common phenomenon in these shifts of metabolism towards a slower pace of aging. CIT is a process that in part drives the movement of mRNA, produced from genetic blueprints, into ribosomes for the production of proteins. Since protein levels determine cell behavior, the way in which translation of mRNA into proteins takes place is important. The work here makes a compelling case to link altered CIT levels to mTORC1 inhibition, suggesting that mTOR, already a popular area of study, may play a role in more age-slowing interventions than thought.
Several dietary and pharmacological treatments are known to extend lifespan, including rapamycin (Rapa), acarbose (ACA), and 17-α-estradiol (17aE2). The mechanisms by which these treatments lead to lifespan extension are not well understood. Rapa inhibits the activity of the mammalian target of rapamycin (mTOR), leading at optimal doses to 20%-25% lifespan extension in male and female mice. ACA is an inhibitor of the α-glucosidase hydrolase enzymes and α-amylases, enzymes that digest carbohydrates in the small intestine, leading to reduction in glucose absorption and in peak glucose levels in blood. ACA extends lifespan by around 20% in males and around 5% in female mice. 17aE2 is a non-feminizing steroid that has a reduced affinity for the classical estrogen receptors. 17aE2 has reproducible and robust effects on male median and maximum lifespan, with no lifespan effect in females.
We hypothesized that Rapa, ACA, which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA knockout, and growth hormone receptor knockout mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT).
Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.