daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans

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• IsDAF-16::GFP animals are more stress resistant and longer-lived than control anima

• we show that nematodes carrying an integrated DAF-16::GFP transgene grow and reproduce more slowly yet are more stress resistant and longer lived than controls carrying the integration marker alone.

• nuclear localization of the DAF-16::GFP fusion protein responds to environmental inputs as well as genetic

• Environmental stresses, such as starvation, heat, and oxidative stress, cause rapid nuclear localization of DAF-16

• DAF-16::GFP is inhibited from entry into the nucleus by daf-2 and akt-1/akt-2,

• daf-16 is negatively regulated by an insulin-like signaling pathway in C. elegans and is required for dauer formation

• three different transcripts: a1, a2, and b, which encode a putative transcription factor with a fork head or winged helix DNA binding domai

• the fusion protein is predominantly unlocalized and is strongly expressed in many neuronal cells

• DAF-16 effects on growth and fertility

• es, such as resistance to UV, only the integrated strain showed significant resistance.

• the integrated strain performed better, suggesting that it is beneficial if all cells carry the transgene

• Insulin/IGF signaling in mammals inhibits DAF-16-like proteins predominantly through the action of the serine-threonine kinase AKT/PKB, which phosphorylates specific serine/threonine residues on DAF-16-like proteins

• inhibition of daf-2, a homolog of the insulin receptor [16], results in nuclear localization of DAF-16::GFP

• Simultaneous inhibition of both akt-1/akt-2 by RNAi resulted in nuclear localization of DAF-16::GF

• Juglone, a known oxidative stressor, also resulted in nuclear localization

• . Interestingly, ExDAF-16::GFP confers strongest resistance to those conditions that result in strong nuclear localization, such as heat, while little if any resistance is seen to conditions that do not cause nuclear localization of DAF-16::GFP, such as UV

• When conditions are unfavorable, growth and reproduction are reduced, cellular repair and maintenance are favored, life span is lengthened, and DAF-16 is found in the nucleus

• Finally, aging clearly can be slowed in response to interventions that change the ability of the organism to deal with stress

• Our results suggest that DAF-16 may have evolved as a switch to alter the allocation of resources in response to a changing environment. Under favorable conditions, DAF-16 remains in the cytoplasm, favoring rapid reproduction and growth at the expense of stress resistance and longevity. When conditions are unfavorable, DAF-16 moves to the nucleus and functions to delay reproduction and growth, while increasing stress resistance and longevity