Abstract
Inhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age-associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate-specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.
Highlights
Rapamycin is an FDA-approved compound that robustly extends the lifespan of yeast, worms, flies, and mice (Powers et al, 2006; Bjedov et al, 2010; Miller et al, 2011; Robida-Stubbs et al, 2012)
We examined mTOR signaling in the livers of HET3 mice (Lamming et al, 2013) as well as available tissues from DBA/2 inbred mice and F344 rats obtained from the NIA Aged Rodent Tissue Bank
We conducted our study of mTOR signaling in mouse aging in C57BL/ 6J.Nia mice from the NIA Aged Rodent Colony, a widely used mouse resource
Summary
Rapamycin is an FDA-approved compound that robustly extends the lifespan of yeast, worms, flies, and mice (Powers et al, 2006; Bjedov et al, 2010; Miller et al, 2011; Robida-Stubbs et al, 2012). MTORC1 signaling may be optimal during development, but inappropriately high for the maintenance of health later in life, and rapamycin acts to repress this overactive mTORC1 signaling (Blagosklonny, 2009). In both of these conceptual models, mTORC1 signaling in the aged may drive much of the pathophysiology of aging. Dietary regimens that extend lifespan, such as calorie restriction and protein restriction, are associated with reduced mTORC1 signaling (Lamming & Anderson, 2014; Solon-Biet et al, 2014; Lamming et al, 2015)
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