Abstract
BackgroundRapamycin (Rapa), acarbose (ACA), and 17α-estradiol (17aE2, males only) have health benefits that increase lifespan of mice. Little is known about how these three agents alter the network of pathways downstream of insulin/IGF1 signals as well as inflammatory/stress responses.ResultsACA, Rapa, and 17aE2 (in males, but not in females) oppose age-related increases in the MEK1- ERK1/2-MNK1/2 cascade, and thus reduce phosphorylation of eIF4E, a key component of cap-dependent translation. In parallel, these treatments (in both sexes) reduce age-related increases in the MEK3-p38MAPK-MK2 pathway, to decrease levels of the acute phase response proteins involved in inflammation.ConclusionEach of three drugs converges on the regulation of both the ERK1/2 signaling pathway and the p38-MAPK pathway. The changes induced by treatments in ERK1/2 signaling are seen in both sexes, but the 17aE2 effects are male-specific, consistent with the effects on lifespan. However, the inhibition of age-dependent p38MAPK pathways and acute phase responses is triggered in both sexes by all three drugs, suggesting new approaches to prevention or reversal of age-related inflammatory changes in a clinical setting independent of lifespan effects.
Highlights
Rapamycin (Rapa), acarbose (ACA), and 17α-estradiol (17aE2, males only) have health benefits that increase lifespan of mice
This paper focuses on two parallel sets of kinase pathways generally known as the MAPK signaling cascades, one of which is initiated by mitogen-activated protein kinase-kinase 1 (MEK1) phosphorylation of Mitogen-activated protein kinase 3 (ERK1)/2, and the other of which is initiated by mitogen-activated protein kinase kinase 3 (MEK3) phosphorylation of p38-MAPK
We find that the MEK3 pathway, leading to acute phase proteins (APPs) production. is down-regulated by all three agents in both sexes, but that the MEK1 pathway, leading to Eukaryotic translation initiation factor 4E (eIF4E) phosphorylation, while down-regulated by Rapa and ACA in both sexes, is inhibited by 17-α Estradiol (17aE2) in male mice but not in females
Summary
Rapamycin (Rapa), acarbose (ACA), and 17α-estradiol (17aE2, males only) have health benefits that increase lifespan of mice. Several dietary and pharmacological treatments extend mouse lifespan, including rapamycin (Rapa, [1]) and acarbose [ACA, [2]] in both sexes, and 17α-estradiol in males only [17aE2, [2, 3]]. These longevity experiments were done using the genetically heterogeneous UMHET3 mouse stock, to avoid effects limited to single inbred backgrounds. Our lab has found that Rapa, ACA and 17aE2 treatments can enhance mTORC2 signaling in liver [11], but the implication of this mTORC2 effect for the aging process is not understood
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