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 UM-HET3 mouse stock, to avoid effects limited to single inbred backgrounds. However, the intracellular mechanisms regulated by these drugs 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 [4,5,6,7] and prevents many forms of age-dependent pathology, including effects of aging on liver, heart, tendon, and kidney [8]. ACA is an inhibitor of α-glucosidase hydrolase enzymes and a-amylases, enzymes that digest carbohydrates in the small intestine. Thus, mice treated with ACA have a reduction in the pace of glucose absorption and in peak post-prandial glucose levels in blood [9, 10]. ACA extends median lifespan by 22% in males and 5% in females (significant at p = 0.01) and has been shown to have major beneficial effects in glucose homeostasis affecting multiple tissues. ACA exposure also reduces mTOR signaling in liver and kidney tissues [2, 8]. 17aE2 is a non-feminizing steroid that has a reduced affinity for the classical estrogen receptors [2]. 17aE2 has reproducible and robust effects, including an increase in male lifespan, and leads to beneficial effects in muscle and declines in mTOR signaling in males only [8, 11]. 17aE2 does not, however, lead to significant effects on female lifespan. The basis for sexual dimorphism in the effects of 17aE2 on lifespan extension is unknown [3]. Each of these agents is known to modulate the levels of hormones, such as IGF1, and insulin in blood as well as expression of inflammatory cytokines in plasma [12,13,14,15,16,17,18]. Rapa treatments starting at 20 months of age mice have beneficial effect on lifespan similar to those seen in mice exposed to the drug from 9 months of age [19, 20]. In addition, 17aE2 can improve some age-sensitive functions even when treatments are started at 16 months of age [21]. These results suggested that treatments starting in middle age can affect fundamental pathways involved in lifespan extension. mTOR forms two complexes, mTORC1 and mTORC2. Data from our lab have suggested that mTORC1 is diminished by each of these three drugs, whether treatment is started at 6 or at 22 months of age). All three drugs also induce declines in cap-dependent translation and enhanced cap-independent translation (CIT) via enhanced expression of the eukaryotic translation initiation factor 4E-binding protein 1 in liver and kidney tissues [8] (4EBP1). The increases in 4EBP1 have been suggested to have beneficial effects in mice [22, 23]. Our lab has also 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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The data showing similar effects of Rapa, ACA and 17aE2 on mTORC1 and its downstream targets – including stimulation of CIT- [8], suggested other common pathways, such as pathways mediated by AMPK [24] or MAPK pathways [25], might be affected by these agents. This paper focuses on two parallel sets of kinase pathways generally known as the MAPK signaling cascades, one of which is initiated by MEK1 phosphorylation of ERK1/2, and the other of which is initiated by MEK3 phosphorylation of p38-MAPK. The ERK1/2 signaling pathway can respond to extracellular growth factors, including insulin and IGF1 [26]. In liver and kidneys, growth factors activate the ERK1/2 pathway by phosphorylation of the dual specificity mitogen-activated protein kinase-kinase 1 (MEK1) on Serine 217/Threonine 221 (pMEK1), via activation of the RAF signaling and possibly by other non-canonical signals [26]. In turn, activation of MEK1 leads to activation of the mitogen-activated protein kinase 3 (ERK1) and mitogen-activated protein kinase 1 (ERK2) by phosphorylation of threonine 202 (pERK1) and threonine 185 (pERK2) respectively. Activated ERK1/2 then leads to phosphorylation of the MAP kinase-interacting serine/threonine-protein kinases 1 and 2 (MNK1 and 2) at their threonine 197/202 site (pMNK). In mice, MNK1 is a single isoform while MNK2 includes two isoforms, MNK2a and MNK2b; little is known about possible differences in function and expression of these two MNK2 isoforms in mouse tissues [25] One key function of MNK, among many [25], is the phosphorylation of the elongation and initiation factor 4E (eIF4E) at serine 209 (peIF4E). This phosphorylation site is known to control the translation of specific subsets of mRNA. Interestingly, the specific mechanism is not understood, and it is possible that peIF4E may regulate, indirectly, the cap independent translation or CIT, [27]. These relationships are depicted in Fig. 1A. In particular, our previous data have shown that ACA, Rapa and 17aE2 treatments can enhance CIT, via reduction in mTOR signaling [8], suggesting that these drugs might also affect the MEK1 kinase pathway, including MNKs, that leads to eIF4E phosphorylation.
The parallel MEK3 kinase cascade responds to extracellular inflammatory factors, such as TNF, IL6 and cytokines, as well as to intracellular stress signaling stimuli [25], such as DNA damage [28]. Activation of this pathway is therefore very complex, depending on the tissue and specific receptor(s) triggered. However, many of these stressors and inflammatory factors converge on the activation of dual specificity mitogen-activated protein kinase kinase 3 (MEK3) by phosphorylation on serine 186 [pMEK3, [25]]. The activation of MEK3 leads to a cascade of events that includes the activation of members of the p38-MAPK kinase family by phosphorylation on threonine 180 [pp38, [25]]. Examples include MAPK11 (p38α) and MAPK14 (p38β). In turn, phosphorylated p38 kinases can phosphorylate and activate a myriad of substrates, including the MAP kinase-activated protein kinase 2 (MK2) at threonine 334 [pMK2, [29]]. MK2 activation has been implicated in many inflammatory and stress processes [29] as well as in the phenomenon of cell senescence [30, 31]. In this context, there are data suggesting that rapamycin can reduce the production of harmful secreted products from senescent cells by reducing the activity of MK2 [30, 31]. In vitro, MK2 is present in two isoforms, MK2-short and MK2-long. The MK2-long isoform is generated by in frame alternative 5′ UTR translation from the same mRNA transcript that encodes the MK2-short isoform [32]. It is unclear what processes govern the relative levels of each isoform [32], but both isoforms can be phosphorylated by p38. Current evidence suggests that the MK2-short form, but not the MK2-long form, may regulates downstream proinflammatory responses [32].
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Downstream targets of the p38/MK2 cascade are extensive [33] and include elements of the DNA repair machinery [34], cellular senescence [35] and the mRNA binding proteins regulating mRNA level proinflammatory cytokines [36]. Inflammatory mediators, such as IL-6, are known to regulate the expression of the acute phase response proteins or APPs [37]. In human and mouse, proinflammatory cytokines and related stress events are transient and difficult to quantify at the protein level, but APPs are abundant and stable proteins that have protective effects. High levels of APPs are considered markers of a proinflammatory or stress phenotype, in mice and humans, that if unchecked would lead to long-term tissue damage [38, 39]. These APPs include serum amyloid P-component (SAP), Alpha-1-acid glycoprotein 1 (ORM1), the serpin family of protease inhibitors [Alpha-1-antitrypsin 1-4 protease inhibitor 1-4 (Serpin A1d) and Alpha-1-antitrypsin 1-5 (Serpin A1e)], as well as Heme oxygenase 1 and 2 (HMOX1/2) and several caspases, such as caspase 6 (Cas6) and caspase 3 (Cas3). These relationships are depicted in Fig. 1 B. To see if the beneficial effects of ACA, Rapa, and 17aE2 might involve a reduction in tissue damage and inflammatory injury, we initiated a study of the effects of age and drug effects on the p38MAPK signals that lead to changes in the levels of APPs.
Recently, we have found that ACA and Rapa, in both sexes, and 17aE2 (in males only) can reduce mTORC1 signaling, suggesting that pathways upstream of mTOR may be affected by these drugs, potentially including mediators of IGF-1 and insulin signaling [8] or other extracellular factors that often act via one of the MAPK (MEK1 or MEK3) cascades. In this report we document the effects of these three agents on two such kinase cascades. We find that the MEK3 pathway, leading to APP production. is down-regulated by all three agents in both sexes, but that the MEK1 pathway, leading to eIF4E phosphorylation, while down-regulated by Rapa and ACA in both sexes, is inhibited by 17aE2 in male mice but not in females. Thus, the pattern of sexual dimorphism in lifespan extension parallels the outcome of MEK1 signals, but not MEK3 signals. Anti-inflammatory effects of interference by these drugs on inflammatory signals might potentially generate health benefits in both sexes.
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