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Long-Lived Drosophila with Overexpressed dFOXO in Adult Fat Body

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Science  16 Jul 2004:
Vol. 305, Issue 5682, pp. 361
DOI: 10.1126/science.1098219

Abstract

Reduced activity of the insulin/insulin-like growth factor signaling (IIS) pathway increases life-span in diverse organisms. We investigated the timing of the effect of reduced IIS on life-span and the role of a potential target tissue, the fat body. We overexpressed dFOXO, a downstream effector of IIS, in the adult Drosophila fat body, which increased life-span and reduced fecundity of females but had no effect on male life-span. The role of FOXO transcription factors and the adipose tissue are therefore evolutionarily conserved in the regulation of aging, and reduction of IIS in the adult is sufficient to mediate its effects on life-span and fecundity.

Reduced activity of the insulin/insulin-like growth factor signaling (IIS) pathway extends life-span in the worm, fly, and mouse and can also lower fecundity (13). How the evolutionarily conserved effects of IIS on these traits are mediated is not understood. IIS affects not only life-span and fecundity of the adult fruit fly Drosophila melanogaster, but also growth in the pre-adult period. We examined whether the adult phenotypes of altered IIS in Drosophila are a consequence of effects of lowered IIS in the adult or the pre-adult period, whether a downstream component of this pathway modulates life-span and fecundity, and whether altered signaling in a particular adult tissue can mediate these effects of altered IIS.

In the worm Caenorhabditis elegans, reducing function of the IIS receptor DAF-2 by RNA interference during development affects only adult fecundity, whereas reducing function during adulthood affects only life-span (2), suggesting that effects of IIS on fecundity and life-span are independent. A key target of IIS is a forkhead transcription factor, FOXO, that is inactivated by IIS in the worm, fly, and mouse (4). The worm ortholog, DAF-16, is necessary for life-span increase in response to mutations in IIS (5), and its overexpression extends life-span (6).

To investigate whether overexpression of the fly ortholog of DAF-16, dFOXO, during adulthood is sufficient to increase life-span and reduce fecundity, dFOXO was expressed in the adult fat body (7), the fly equivalent of the mammalian liver and white adipose tissue. Induced expression of dFOXO in the fat body from the onset of adulthood increased life-span and reduced fecundity of female flies by 20 to 50% and by 50%, respectively (Fig. 1) (8, 9) and increased resistance to paraquat in females (10). No effect on life-span was seen in male flies (10).

Fig. 1.

Life-span and fecundity experiments. (A to C) Survival experiments on flies given either +RU486 (+dFOXO, solid circles) or –RU486 (–dFOXO, open circles) food. [(A) and (B)] Results of overexpression of an insert of dFOXO on chromosome 3 (replicates), showing survival of w;S1106/+;dFOXO/+ females. (A) Median life-span (m) and percent change between treatments: –RU486, m = 36; +RU486, m = 51; +41.6% change (P < 0.0001). (B) Median life-span and percent change between treatments: –RU486, m = 32; +RU486, m = 39; +21.8% change (P < 0.0001). (C) Results of overexpression of an independent insert of dFOXO on chromosome 2, showing survival of w;S1106/dFOXO;+/+ females. Median life-span and percent change between treatments: –RU486, m = 25; +RU486, m = 38; +52% change (P < 0.0001). (D) Fecundity of w;S1106/+;dFOXO/+ females given +RU486 (hatched) and –RU486 (open) food. Mean and standard error bars are shown. *, P < 0.05; **, P < 0.0001.

DAF-16 activity in either the worm intestine (11), which is also its adipose tissue, or the nervous system (11) is sufficient for some life-span extension by altered IIS. The functions of the Drosophila fat body include many of the metabolic activities of the mammalian liver and also fat storage. In the mouse, deletion of the insulin receptor in white adipose tissue results in a lean, long-lived adult (13). Adipose tissue is therefore consistently implicated as important in mediating extension of life-span by altered IIS in three model organisms. The role of FOXO factors in regulating aging is hence conserved between C. elegans and Drosophila, suggesting that transcriptional targets of FOXO that regulate aging may also be conserved. Furthermore, the ability of lowered IIS, confined to adult adipose tissue, to extend life-span is conserved over the evolutionary distance between the worm and fly.

Supporting Online Material

www.sciencemag.org/cgi/content/full/1098219/DC1

Materials and Methods

Fig. S1

References and Notes

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