TOR, DIETS and LIFESPAN

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Bartholomew Powers
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1 A small story about the TOR gene

2 Rapamycin: The wonder drug from Easter Island

3 Rapamycin: The wonder drug from Easter Island with the many uses: Anti fungal Immunosuppressant Anti cancer Anti aging???

4 Question: How do you find the target of rapamycin (or drug X) in yeast? Answer: Isolate a mutant yeast that is resistant to rapamycin (or drug X). Identify and sequence the mutant gene that confers resistance to rapamycin (or drug X).

5 Rapamycin inhibits a protein kinase complex

6 The TOR kinase complex (Yip et al, Mol Cell 38: , 2010)

7 The TOR kinase complex +Rapamycin A major target for cancer therapy

8 Figure?1 Nutrient Sensing and Metabolism Pathways AMP activated kinase (AMPK) is activated by energy stress and promotes catabolic pathways to produce ATP while switching off ATP consuming anabolic pathways. In contrast, mammalian target of rapamycin comp... Hai Xin Yuan, Yue Xiong, Kun Liang Guan Nutrient Sensing, Metabolism, and Cell Growth Control Molecular Cell Volume 49, Issue

9 Figure?1 Nutrient Sensing and Metabolism Pathways AMP activated kinase (AMPK) is activated by energy stress and promotes catabolic pathways to produce ATP while switching off ATP consuming anabolic pathways. In contrast, mammalian target of rapamycin comp... Hai Xin Yuan, Yue Xiong, Kun Liang Guan Nutrient Sensing, Metabolism, and Cell Growth Control Molecular Cell Volume 49, Issue

10 (From

11 IS ANY OF THAT RELATED TO AGING?

12 By far, the highest risk factor of most cancers is.

13 By far, the highest risk factor of most cancers is.aging!! (Source: WHO)

15 But is aging modifiable?

16 Q: How many times can a cell divide? A: If you can count, you get the replicative lifespan.

17 Aging in yeast

19 (n)

21 Nature 460: (2009) Rapamycin extends lifespan in mice

22 On the WHO list of core drugs Very safe, over the counter No previous link with aging pathways

23 Ibuprofen extends RLS Fraction Viable YPD (25.8, 640) YPD + 0.2mM Ibu (30.3, 640) Age (Generations)

24 Ibuprofen extends RLS Fraction Viable YPD (25.8, 640) YPD + 0.2mM Ibu (30.3, 640) Age (Generations) Off target effect (no COX in yeast)

25 How does ibuprofen delay yeast aging?

26 Evaluating diets for maximal healthspan

27 Evaluating diets for maximal healthspan The Geometric Framework Approach (see

30 (From

32 858 mice 25 diets, fed at libitum 4 variables Protein (5 60%) Fat (16 75%) Carbohydrates (16 75%) Energy (8 17 Kj/g) Monitoring at late middle age & end of life (From Solon Biet et al, Cell Metabolism, 2014)

33 Half maximal nutrient intake Keeps going up, Fat intake largely unregulated (From Solon Biet et al, Cell Metabolism, 2014)

34 They are not after energy per se. Intake is regulated by protein (and to some extent carbohydrate) content. (From Solon Biet et al, Cell Metabolism, 2014)

36 The moral of this graph Eating high fat food will not satisfy you and make you eat less (From Solon Biet et al, Cell Metabolism, 2014)

37 But why do the crickets march?

State-dependent changes in cannibalism (A) in field-collected Mormon cricket nymphs after 5 h of pretreatment on either one of four synthetic diets (P, C, PC, or O; n = 20)

38 State-dependent changes in cannibalism (A) in field-collected Mormon cricket nymphs after 5 h of pretreatment on either one of four synthetic diets (P, C, PC, or O; n = 20) (B) or grass seed heads with or without a separate source of 0.25 M NaCl (n = 50) (C) by National Academy of Sciences Stephen J. Simpson et al. PNAS 2006;103:

39 As long as fat intake is low High Protein Low food intake ( Atkins scenario) (From Solon Biet et al, Cell Metabolism, 2014)

40 (From Solon Biet et al, Cell Metabolism, 2014)

41 (From Solon Biet et al, Cell Metabolism, 2014)

42 As long as fat intake is low High Protein Low food intake ( Atkins scenario) But is it good for you (From Solon Biet et al, Cell Metabolism, 2014)

43 (From Solon Biet et al, Cell Metabolism, 2014)

44 (From Solon Biet et al, Cell Metabolism, 2014)

45 Looking good but living longer (From Solon Biet et al, Cell Metabolism, 2014)

46 (From

Dietary effects on body composition, glucose metabolism, and longevity are modulated by skeletal muscle mitochondrial uncoupling in mice

Aging Cell (2011) 10, pp122 136 Doi: 10.1111/j.1474-9726.2010.00648.x Dietary effects on body composition, glucose metabolism, and longevity are modulated by skeletal muscle mitochondrial uncoupling in