Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity

By Dudley Lamming, Lan Ye, P. Katajisto, M. Goncalves, M. Saitoh, Deanna M Stevens, James G. Davis, A. Salmon, Arlan Richardson, R. Ahima and 3 more. Science, 2012

1,153 citations recorded by the source corpus.

Dissecting Rapamycin Responses Long-term treatment of mice and other organisms with the drug rapamycin extends life span. But, at the same time, the drug disrupts metabolic regulation and the action of the hormone insulin. Lamming et al. (p. 1638; see the Perspective by Hughes and Kennedy) dissected the action of rapamycin in genetically modified mice and found, encouragingly, that these two actions of rapamycin can be separated. Rapamycin inhibits a protein kinase complex known as mTORC1, and this appears to provide most of the life-lengthening effects of the drug. However, rapamycin also acts on a related complex known as mTORC2, and it is the disruption of mTORC2 action that produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin. The effect of the drug rapamycin on life span can be separated from its effects on metabolism. Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.

Subfields: Aging

View Paper: https://www.semanticscholar.org/paper/2181e4591ba22522bb8c4e0c636b0d54cd273b1e

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Citations in the corpus

Cellular Senescence: A Translational Perspective (2017, background): “For example, rapamycin can induce insulin resistance through acting on the TORC2 complex (Lamming et al., 2012), cataract formation, and other effects.”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “169 – 171 Altogether, these studies have proved that extended life span was highly dependent on nutritional condition (glucose, fat, and protein metabolism) and a close association with the mTOR pathway.”
Canonical Nlrp3 inflammasome links systemic low grade inflammation to functional decline in aging (2013, neutral): “Notably, enhanced lifespan in mice treated with rapamycin is associated with amelioration of few aging phenotypes and also leads to several detrimental effects, such as increased cataract formation, testicular degeneration, and reduced insulin sensitivity (Lamming et al., 2012; Neff et al., 2013).”
The hallmarks of aging. (2013, background): “Genetically modified mice with low levels of mTORC1 activity but normal levels of mTORC2 have increased lifespan (Lamming et al., 2012), and mice deficient in S6K1 (a main mTORC1 substrate) are also long-lived (Selman et al., 2009).”
TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO (2012, background): “elegans evidence indicated that rapamycin interferes with TORC2 in addition to TORC1 in vivo (Figure 6), also in agreement with recent observations in the mouse (Lamming et al., 2012).”
mTOR is a key modulator of ageing and age-related disease (2013, background): “Hormonal cues can stimulate IIS, which can increase longevity through PI(3)K and AKT mediation of the FOXO family of transcription factors.”
mTOR signaling in growth control and disease (2012, background): “A new study also indicates that chronic rapamycin treatment impairs whole-body insulin sensitivity at least by disrupting the integrity of mTORC2 and by blocking the ability of mTORC2-Akt to inhibit hepatic gluconeogenesis (Lamming et al., 2012).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “This result is explained at least in part by the fact that prolonged rapamycin treatment also inhibits mTORC2 signaling in vivo (Lamming et al., 2012).”