The mammalian target of rapamycin (mTOR) signaling pathway regulates growth and metabolism in response to the availability of nutrients. The mTOR pathway is highly conserved, and a homologue of the central component of the pathway, the mTOR protein kinase, is found in most eukaryotes, including yeast, worms, flies, plants, mice, and humans. mTOR is a member of two distinct complexes, mTORd and mTORC2, each of which regulates distinct cellular targets. Recent studies have demonstrated that inhibition of TOR signaling can extend the lifespan of yeast, worms, and flies. However, the mechanism behind this effect is unknown, and it is not yet known if decreased mTOR signaling will promote longevity in mammals. Inhibition of mTOR signaling has been proposed to mimic the effects of calorie restriction, an intervention which promotes health and longevity in many organisms, and may therefore be of therapeutic value in the treatment of diabetes, neurodegeneration and other age-related diseases. In this proposal, I outline studies that I will undertake to better understand the effects of decreased mTOR signaling on mammalian health and aging. I will examine stress resistance, which often correlates with longevity, in a tissue culture model using mouse embryonic fibroblasts derived from mTOR, Raptor (a component of mTORCI), and Rictor (a component of mTORC2) heterozygous knockout mice. Using mice heterozygous for mTOR, Raptor, or Rictor, I will examine the role of both mTORCI and mTORC2 signalling in stress resistance and aging. Populations of these heterozygous knockout mice will be allowed to age, and biomarkers of longevity, including insulin levels and glucose tolerance, will be assessed. Standard RNA microarrays and analysis of protein samples will be used to analyze the role of mTORCI and mTORC2 signaling in aging and longevity. Finally, conditional tissue specific knockouts of Raptor and Rictor will be examined for their ability to regulate resistance to a high-fat diet. Inhibition of the mammalian target of rapamycin (mTOR) signalling extends longevity in lower organisms, and has been proposed to mimic the effects of calorie restriction, an intervention that promotes health and longevity in mammals. Inhibition of mTOR signalling may therefore be of therapeutic value in the treatment of diabetes, cancer, neurodegeneration and other age-related diseases. This proposal seeks to determine if inhibition of mTOR signalling does promotes health and longevity in mammals, and to determine the mechanism behind this effect.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AG032833-03
Application #
7983432
Study Section
Special Emphasis Panel (ZRG1-F05-J (20))
Program Officer
Finkelstein, David B
Project Start
2008-12-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
3
Fiscal Year
2011
Total Cost
$51,326
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Soliman, Mohamed A; Abdel Rahman, Anas M; Lamming, Dudley W et al. (2014) The adaptor protein p66Shc inhibits mTOR-dependent anabolic metabolism. Sci Signal 7:ra17
Lamming, Dudley W; Ye, Lan; Katajisto, Pekka et al. (2012) Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335:1638-43
Robida-Stubbs, Stacey; Glover-Cutter, Kira; Lamming, Dudley W et al. (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15:713-24
Yilmaz, Ömer H; Katajisto, Pekka; Lamming, Dudley W et al. (2012) mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486:490-5
Ye, Lan; Varamini, Behzad; Lamming, Dudley W et al. (2012) Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front Genet 3:177
Lamming, Dudley W; Sabatini, David M (2011) A radical role for TOR in longevity. Cell Metab 13:617-8