Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

Authors: Kapahi P; Zid BM; Harper T; Koslover D; Sapin V; Benzer S
Year: 2004
Journal: Current biology : CB
Abstract: In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.


Created on Nov. 6, 2012, 11:54 a.m. and lastly updated on Nov. 29, 2012, 4:07 p.m.
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Reduction of nutrients in the diet extends the lifespan in flies [14-16].

The fat body in Drosophila acts as a nutrient sensor, which uses TOR signaling to generate humoral signal that modulates insulin signaling and growth in peripheral tissues [22].

TOR deficiency in nematode extends the lifespan [23].

Ubiquitously overexpression of UAS constructs (via the daughterless (da)-GAL-4 driver) containing dTSC1 or dTSC2 extends mean lifespan at 29°C by 14% and 12%, respectively.

Ubiquitous overexpression of the dominant-negative form of dS6K extends the lifespan.

Overexpression of dTsc2 and dTOR(FRB) at 25°C lead to a 20% and 26% increase in mean lifespan, respectively.

Overexpression of dTsc2 via a UAS promoter in the eye using the driver gmr-GAL4 or in the nervous system by using appI-GAL4 does not extend the lifespan. Using the drivers 24BGAL4 and PO188-GAL4, enhancer traps that are predominantly expressed in the muscle and fat results in mean lifespan extension of 27% and 37%, respectively, at 29°C.

Using DJ634-GAL4 to overexpress the dominant-negative form of TOR (UAS-dTOR(FRB)) or of S6k (UAS-UAS-dS6K(KQ)) also led to mean lifespan increases of 30% and 29%, respectively at 29°C.

Overexpression of the dominant-negative form of S6k protects flies from the deleterious effects of rich food.

Lifespan extension by TOR deficiency in C. elegans is not suppressible by a daf-16 mutation [23]. TOR mutant animals do not further extend lifespan in a daf-2 background [23],

TOR mutation does not further extend the lifespan of daf-2 mutants, but longevity conferred by TOR deficiency is not suppressed by daf-16 mutation

Lifespan extension by chico is semidominant [13]. Dominant effect on lifespan are observed with Inr, EcR, Indy and Rpd3, but their effect on lifespan can be uncoupled from other phenotypes such as decundity, stress resistance, or lipid accumulation.

DR in mice protects against age-related tumorgensis [38, 39].

Reduction of daf-2 levels in C. elegans nervous system is sufficient to extend lifespan [40, 41]. Lifespan extension due to mutations in IIS or germline ablation in C. elegans are dependent on daf-16 activity in the intestine (the fat-storage tissue in C. elegans) [41].

FIRKO mice live 18 longer [43].

Juvenile hormone and ecdysone are two endocrine signals that are implicated in regulating lifespan in conjunction with the insulin pathway in Drosophila [4].

This paper was retracted due to errors found in labeling of samples (Current Biology, Volume 14, Issue 19, 5 October 2004, Page 1789) [].

Species: Fruit fly

Experiments: 3
  • Figure 1. Regulation of Lifespan by Modulating Genes in the TOR Signaling Pathway
  • Figure 2. Dependence of Lifespan Extension on Overexpression in Specific Tissues
  • Figure 3. Lifespan Extension by dTsc2 Overexpression Is Dependent on the Concentration of Yeast Extract in the Diet

  • Interventions:
  • Tsc1 overexpression
  • gig overexpression
  • Dominant negative Tor
  • Constitutive active S6k overexpression
  • Dominant-negative S6k

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