Priority Research Paper Volume 14, Issue 6 pp 2442—2461
Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice
- 1 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- 2 University of Michigan Geriatrics Center, Ann Arbor, MI 48109, USA
- 3 Paul F. Glenn Center for Biology of Aging Research, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Received: January 5, 2022 Accepted: March 6, 2022 Published: March 19, 2022
https://doi.org/10.18632/aging.203959How to Cite
Copyright: © 2022 Shi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.