Rates of Behavior and Aging Specified by Mitochondrial Function During Development

Abstract

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.

A salicylic acid derivative extends the lifespan of Caenorhabditis elegans by activating autophagy and the mitochondrial unfolded protein response

“…It has been shown previously that altering the expression of some subunits of the mitochondrial complexes that mediate the oxidative phosphorylation within the inner membrane of the mitochondria could significantly extend the lifespan of C. elegans (Dillin et al, 2002; Lee et al, 2003). Interestingly, these interventions were then found to trigger the mitochondrial unfolded protein response (UPR mit ) that contributes to the observed lifespan extension (Durieux, Wolff, & Dillin, 2011).…”

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…In a paradoxical way, in yeast (Delaney et al., 2013), worms (Dillin et al., 2002), flies (Owusu‐Ansah, Song & Perrimon, 2013), and mice (Liu et al., 2005), suppression of mitochondrial ETC function increases lifespan (Dell'agnello et al., 2007; Durieux, Wolff & Dillin, 2011). While counterintuitive, these findings are supported by reports demonstrating that upregulation of mitochondrial stress response contributes to enhanced longevity in the long‐lived mitochondrial mutants (Durieux et al., 2011; Kirchman, Kim, Lai & Jazwinski, 1999).…”

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

“…Although metabolic rate tends to scale with temperature in exothermic animals (Tribe and Bowler 1968), metabolic rate clearly does not determine lifespan (Yen et al 2004). Work in flies, worms, and mice has shown that metabolism and longevity are not always correlated (Arking et al 1988;Dillin et al 2002;Holloszy and Smith 1986;Houthoofd et al 2002;Hulbert et al 2004). The effects of cold temperature on an organism are more complicated than usually appreciated.…”

“…Excluding complex II, RNAi of any complex of the electron transport chain increases the lifespan of worms (Curran and Ruvkun 2007;Dillin et al 2002). The complete mechanism by which mitochondrial mutations extend lifespan has not been elucidated, but evidence has suggested that it does not require daf-16 and is partially dependent on aak-2 (Dillin et al 2002). A specific mutant, clk-1, has been shown to extend lifespan (Wong et al 1995), possibly through its preferential usage of complex II instead of complex I (Kayser et al 2004).…”