(IM06) Inhibition of Multiple Signaling Pathways May Attenuate mTOR and Promote Healthy Aging in Older Dogs

Abstract:

Background: mTOR is composed of mTORC1, a promotor of cell growth and metabolism, and mTORC2, a regulator of cell proliferation and survival. mTOR dysregulation often increases with age and attenuation of mTOR increases lifespan and slows age-related diseases.Hypothesis: There is increased mTOR activation in leukocytes in aging dogs.Animals: Healthy canines housed in Hill’s animal colony and divided into two groups: young (n = 6, 2-3 yr) and old (n = 6, 10-13 yr).

Methods: Gene expression was assessed from total circulating RNA using Qiagen’s PCR Array- Dog mTOR Signaling. Data were analyzed using the ΔΔCt method.

Results: There was a significant increase in mLST8, RPS6KA1, EIF4EBP2, Akt1, GSK3B, MAPK3, MAPKAP1, a non-significant increase in PIK3CB and MAPK1, but no significant increase in RAPTOR, RICTOR, or DEPTOR in older canines when compared to young.Conclusions and clinical importance: mLST8 plays a key role in phosphorylating mTORC1 effectors including members of S6K and 4EBP families. Attenuating mTORC1-S6K1 or mTORC1-4EBP1 signaling is reported to improve muscle health. Activation of mTORC1 can occur via PI3K/Akt/GSK3 and MAP kinase pathways. Both signaling pathways converge on TSC2 and phosphorylate it to subsequently activate mTORC1. mLST8 is also a component of mTORC2 and MAPKAP1 is a subunit of mTORC2. Components of mTOR complexes and signaling in leukocytes were upregulated in aging dogs and we have previously demonstrated increased level of circulating inflammatory cytokines in aging dogs. Lowering the activation of mTORC1 and mTORC2 through nutrition may be beneficial in reducing age-related inflammatory conditions in canines.