longer than normal. This lack of lifespan extension was particularly unexpected because mi-tochondrial respiration is widely assumed to influence aging in an ongoing manner during adulthood through the generation of reactive oxygen species (8, 20). Our findings bring this assumption into question. Caloric restriction during adulthood extends lifespan and has been proposed to act by decreasing the rate of respiration (21, 22). However, our finding that lifespan extension caused by respiratory-chain RNAi requires inhibition during development suggests that caloric restriction in animals, as in yeast (23), extends lifespan in another way. The same holds for insulin/IGF-1 signaling, which functions exclusively during adulthood to influence C. elegans lifespan (19). In conclusion, we propose that C. elegans possesses a regulatory system that senses, interprets, and remembers the rate of mito-chondrial respiration during development. Under normal conditions, this system establishes normal rates of growth, behavior, and aging. However, if the rate of respiration is low, this system reduces the animal's growth rate and body size, as well as its rates of behavior and aging. It is possible that the rate of respiration during development is sufficient to specify the rate at which the animal lives its entire life; alternatively, the adult animal may make reference to contempora-neous rates of respiration, which, in turn, are influenced by mitochondrial activity during development. The low-density lipoprotein receptor (LDL-R) is a typical example of a multidomain protein, for which in vivo folding is assumed to occur vectorially from the amino terminus to the carboxyl terminus. Using a pulse-chase approach in intact cells, we found instead that newly synthesized LDL-R molecules folded by way of "collapsed" intermediates that contained non-native disulfide bonds between distant cys-teines. The most amino-terminal domain acquired its native conformation late in folding instead of during synthesis. Thus, productive LDL-R folding in a cell is not vectorial but is mostly posttranslational, and involves transient long-range non-native disulfide bonds that are isomerized into native short-range cysteine pairs.

The germ line of the nematode Caenorhabditis elegans influences life-span; when the germ-line precursor cells are removed, life-span is increased dramatically. We find that neither sperm, nor oocytes, nor meiotic precursor cells are responsible for this effect. Rather life-span is influenced by the proliferating germ-line stem cells. These cells, as well as a downstream transcriptional regulator, act in the adult to influence aging, indicating that the aging process remains plastic during adulthood. We propose that the germ-line stem cells affect life-span by influencing the production of, or the response to, a steroid hormone that promotes longevity.

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The two parts of the Caenorhabditis elegans reproductive system, the germ cells and the somatic reproductive tissues, each influence the life span of the animal. Removing the germ cells increases longevity, and this life span extension requires the somatic gonad. Here we show that the somatic gonad and the germ cells make distinct contributions to life span determination. The life span increase produced by loss of the germ cells requires the DAF-16/FOXO transcription factor. In response to germ-cell removal, DAF-16 accumulates in nuclei. We find that the somatic gonad is not required for DAF-16 nuclear accumulation or for the increased stress resistance that is produced by germ-cell removal. The somatic gonad is required, however, for expression of specific DAF-16 target genes. DAF-16 is known to be activated by reduced insulin/IGF-1 signaling in C. elegans. In certain insulin/IGF-1-pathway mutants, the somatic gonad is not required for germ-cell removal to extend life span. Our genetic experiments suggest that these mutations reduce insulin/IGF-1 signaling below a critical threshold level. At these low levels of insulin/IGF-1 signaling, factors normally provided by the somatic gonad are no longer needed for germ-cell removal to increase the expression of DAF-16 target genes.

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