Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway - PubMed (original) (raw)

Comparative Study

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

Pankaj Kapahi et al. Curr Biol. 2004.

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.

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Figures

Figure 1

Figure 1. Regulation of Lifespan by Modulating Genes in the TOR Signaling Pathway

Survival curves on standard laboratory food for male flies obtained after crossing the ubiquitously expressed _da_-GAL4 enhancer trap with various UAS constructs carrying genes in the TOR signaling pathway ([A]–[E] at 29°C, [F] and [G] at 25°C). All logrank test p values are based on comparison of the overexpressor strain with the driver alone. The plus symbol indicates the parental strain w1118. The mean lifespan (days) of the various genotypes were as follows. (A) _da_-GAL4/UAS-dTsc1 (closed squares), 29 days (n=136); +/_da_-GAL4 (driver alone) (open triangles), 26 days (n = 92); +/UAS-dTsc1 (open circles), 25 days (n = 109) (p < 0.0001). (B) _da_-GAL4/UAS-dTsc2 (closed squares), 29 days (n = 112); +/_da_-GAL4 (open triangles), 26 days (n = 92); +/UAS-dTsc2 (open circles), 25 days (n = 118) (p < 0.0001). (C) _da_-GAL4/UAS-dTORFRB (closed squares), 30 days (n = 126); +/_da_-GAL4 (open triangles), 26 days (n = 92); +/UAS-dTORFRB (open circles), 22 days (n = 98) (p < 0.0001). (D) _da_-GAL4/UAS-dS6kKQ (closed squares), 30 days (n = 122); +/_da_-GAL4 (open triangles), 26 days (n = 92); +/UAS-dS6kKQ (open circles), 23 days (n = 115) (p < 0.0001). (E) _da_-GAL4/UAS-dS6kSTDETE (closed squares), 16 days (n = 75); +/_da_-GAL4 (open triangles), 26 days (n = 92); +/UAS-dS6kSTDETE (open circles), 24 days (n = 40) (p < 0.0001). (F) _da_-GAL4/UAS-dTsc2 (closed squares), 69 days (n = 134); +/_da_-GAL4 (open triangles), 58 days (n = 133); +/UAS-dTsc2 (open circles), 56 days (n = 126) (p < 0.0001). (G) _da_-GAL4/UAS-dTORFRB (closed squares), 72 days (n = 112); +/_da_-GAL4 (open triangles), 58 days (n = 133); +/UAS-dTORFRB (open circles), 55 days (n = 128) (p < 0.0001).

Figure 2

Figure 2. Dependence of Lifespan Extension on Overexpression in Specific Tissues

Survival curves, on standard laboratory food, for male flies obtained by crossing various genes in the TOR pathway by using different tissue specific drivers along with appropriate control strains. _gmr_-GAL4 is expressed in the eye, _appl_-GAL4 in the nervous system, 24B-GAL4 and PO188-GAL4 in the muscle and fat tissues, and DJ634-GAL4 and PO163-GAL4 in the fat tissue. All logrank test p values were based on comparison of the overexpressor strain with the driver alone. The plus symbol indicates the parental strain w1118. The mean lifespan at 29°C of the various genotypes were as follows. (A) _gmr_-GAL4/ UAS-dTsc2 (closed squares), 27 days (n = 69); +/_gmr_-GAL4 (open triangles), 31 days (n = 102); +/UAS-dTsc2 (open circles), 27 days (n = 81) (p < 0.01). (B) _appl_-GAL4/ UAS-dTsc2 (closed squares), 33 days (n = 108); +/_appl_-GAL4 (open triangles), 32 days (n = 85); +/UAS-dTsc2 (open circles), 27 days (n = 81) (p < 0.001). (C) 24B- GAL4/UAS-dTsc2 (closed squares), 37 days (n = 107); +/24B-GAL4 (open triangles), 31 days (n = 67); +/UAS-dTsc2 (open circles), 27 days (n = 81) (p < 0.0001). (D) PO188-GAL4/UAS-dTsc2 (closed squares), 35 days (n = 76); +/PO188-GAL4 (open triangles), 24 days (n = 71); +/ UAS-dTsc2 (open circles), 27 days (n = 81) (p < 0.0001). (E) DJ634-GAL4/UAS-dTsc2 (closed squares), 30.6 days (n = 120); +/DJ634-GAL4 (open triangles), 24.6 days (n = 120); +/UAS-dTsc2 (open circles), 25.3 days (n = 118) (p < 0.0001). (F) PO163-GAL4/UAS-dTsc2 (closed squares), 36 days (n = 126); +/PO163-GAL4 (open triangles), 28 days (n = 87); +/UAS-dTsc2 (open circles), 27 days (n = 81) (p < 0.0001). (G) DJ634-GAL4/UAS-dTORFRB (closed squares), 31 days (n = 107); +/DJ634-GAL4 (open triangles), 25 days (n = 120); +/UAS-dTORFRB (open circles), 22 days (n = 98) (p < 0.0001). (H) DJ634-GAL4/UAS-dS6kKQ (closed squares), 31 days (n = 110); +/DJ634-GAL4 (open triangles), 25 days (n = 120); +/UAS-dS6kKQ (open circles), 23 days (n = 115) (p < 0.0001).

Figure 3

Figure 3. Lifespan Extension by dTsc2 Overexpression Is Dependent on the Concentration of Yeast Extract in the Diet

Logrank test was used to calculate the p values. The plus symbol indicates the parental strain w1118. Mean lifespan at 29°C of adult male _da_-Gal4/+ (closed triangles) and _da_-GAL4/UAS-dTSC2 (closed squares) flies were: on 0.1% yeast extract, _da_-Gal4/+, 33 days (n = 125) and _da_-GAL4/UAS-dTSC2, 30 days (n = 164); on 0.3% yeast extract, _da_-Gal4/+, 31 days (n = 139) and _da_-GAL4/UAS-dTSC2, 33 days (n = 138); on 1% yeast extract, _da_-Gal4/+, 30 days (n = 182) and _da_-GAL4/UAS-dTSC2, 34 days (n = 164); on 3% yeast extract, _da_-Gal4/+, 28 days (n = 181) and _da_-GAL4/UAS-dTSC2, 34 days (n = 154); on 9% yeast extract, _da_-Gal4/+, 12 days (n = 150) and _da_-GAL4/UAS-dTSC2, 24 days (n = 156). Mean lifespan differences between flies overexpressing dTsc2 and controls were −9% (p < 0.3), +5% (p < 0.03), +13% (p < 0.0001), +23% (p < 0.0001), and 95% (p < 0.0001) when lifespan was measured on fly food containing 0.1%, 0.3%, 1%, 3%, and 9% yeast extract, respectively.

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