The Cell Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity

“…because reactive oxygen species (ROS) are generated as a byproduct of the metabolic activity of the mitochondrial ETC during the production of ATP (Harman, 1956), a decrease in ROS production is the major contributing factor to the long-lived phenotypes of ETC mutants (Feng et al., 2001; Rea and…”

“) is also induced under conditions of protein misfolding, although confined to the ER (Ron and Walter , 2007).”

“We testedwhethermitochondrial reduction resulted in a general upregulation of all protein misfolding pathways by treating hsp-4p::GFP reporter worm strains (Calfon et al., 2002) with cco-1 RNAi.”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“These changes occur coordinately across multiple tissues and organs, in concordance with theories that posit a strong role for the participation of the endocrine system in the regulation of age-related phenotypes (Russell and Kahn, 2007; Tatar et al., 2003).”

“…Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the…”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“RNAi of cco-1 slows development, growth, movement and reduces fecundity (Dillin et al., 2002b).”

“The Mitochondrial Unfolded Protein Response Is Required for ETC-Mediated Longevity In response to a mitochondrial perturbation there exists a stress response mechanism that is communicated to the nucleus to increase the expression of mitochondrial associated protein chaperones, such as HSP-6 andHSP-60, referred to as…”

“These include alteration of signals from the somatic germline which control the aging of nonmitotic tissues (Arantes-Oliveira et al., 2002; Hsin and Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al.”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…et al., 2002; Hsin and Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter…”

“Life-Span Analysis of cco-1 Hairpin Transgenic Animals (A) Wild-type worms allow import of dsRNA from surrounding tissues, but sid-1(qt9) mutant worm can not import dsRNA and RNAi knockdown is no longer systemic but is maintained locally within the tissue in which the dsRNA is produced (Winston et al., 2002).”

“…(Arantes-Oliveira et al., 2002; Hsin and Kenyon, 1999); restoration or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific…”

“…or reduction of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the entire animal to…”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…of insulin/IGF-1 signaling (IIS) in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the entire animal to respond to dietary…”

“A modification to this theory has suggested alternatively that, because reactive oxygen species (ROS) are generated as a byproduct of the metabolic activity of the mitochondrial ETC during the production of ATP (Harman, 1956), a decrease in ROS production is the major contributing factor to the long-lived phenotypes o…”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“…in neuronal or fat tissues (Broughton et al., 2005; Hwangbo et al., 2004; Kapahi et al., 2004; Libina et al., 2003; Wolkow et al., 2000); and genetic manipulations to specific neurons which then alter the capacity for the entire animal to respond to dietary restriction (Bishop and Guarente, 2007).”

“Furthermore, markers of the UPR mt , namely hsp-6p::GFP, have their greatest activation late in larval development at the L4 stage when challenged with mitochondrial stress (Yoneda et al., 2004 ).”

“…promoter driving wild-type sid-1 was injected into rab-3p::cco-1HP transgenic worms to enable knockdown of cco-1 in the neurons by the hairpin transgene and in the intestine by feeding RNAi. ubl-5 knockdown strains were generated with constructs as described (Esposito et al., 2007; Hobert, 2002).”

“ClpP is the homolog of the E.coli ClpP protease located in the mitochondria that plays a role in generating the mitochondrial derived signal to activate DVE-1/UBL-5 stress responsive genes (Haynes et al., 2007).”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“These systems have offered the simplicity of studying tissue-specific expression in organisms in which single-gene mutations can affect longevity, and have been extended to mammalian model systems (Bluher et al., 2003; Conboy et al., 2005; Taguchi et al., 2007).”

“…cco-1 did not affect the response of animals to oxidative stress induced by paraquat in a manner correlated with their longevity phenotype (Table S2), consistent with recent results in worms and flies (Copeland et al., 2009; Doonan et al., 2008; Van Raamsdonk and Hekimi, 2009) (Lee et al., 2002).”

“RNAi of cco-1 slows development, growth, movement and reduces fecundity (Dillin et al., 2002b).”

“…cco-1 did not affect the response of animals to oxidative stress induced by paraquat in a manner correlated with their longevity phenotype (Table S2), consistent with recent results in worms and flies (Copeland et al., 2009; Doonan et al., 2008; Van Raamsdonk and Hekimi, 2009) (Lee et al., 2002).”

“…increased longevity of tissue specific cco-1 hairpin animals did not correlate with the known stress resistance phenotypes associated with other pathways that modulate the aging process (Arantes-Oliveira et al., 2002; Larsen et al., 1995; Lee et al., 1999; Lee et al., 2003; McElwee et al., 2004).”

“…function in nuclear genes encoding electron transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et…”

“cco-1 was chosen because knockdown of this gene results in intermediate phenotypes compared to knockdown of the other ETC genes by RNAi, allowing both positive and negative modulation of longevity to be identified (Dillin et al., 2002b; Lee et al., 2002; Rea et al., 2007).”

“Together, UBL-5 and DVE-1 respond to mitochondrial perturbation to increase expression of mitochondrial chaperones, including hsp-6 and hsp-60 (Benedetti et al., 2006).”

“These changes occur coordinately across multiple tissues and organs, in concordance with theories that posit a strong role for the participation of the endocrine system in the regulation of age-related phenotypes (Russell and Kahn, 2007; Tatar et al., 2003).”

“…an inverted repeat of the cco-1 cDNA under the control of well-characterized promoters expressed in neurons (unc-119 and rab-3) (Maduro and Pilgrim, 1995; Nonet et al., 1997), intestine (ges-1) (Aamodt et al., 1991), and body-wall muscle cells (myo-3) (Miller et al., 1986; Okkema et al., 1993).”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“elegans, Drosophila, andmice delay the aging process (Copeland et al., 2009; Dell’Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“Life-span analyses were performed with rde-1(ne219) mutant animals in which rde-1 was restored by tissue-specific expression of wild-type rde-1 cDNA (Qadota et al., 2007). rde-1 was rescued in transgenic lines under the control of the lin-26 hypodermal promoter, the hlh-1 body wall muscle promoter,…”

“elegans, mitochondria undergo a period of dramatic proliferation during the L3/L4 stage (Tsang and Lemire, 2002).”

“…RNAi does not result in the detrimental phenotypes observed when bacterial feeding RNAi against other components of the ETC is administered undiluted, such as severe developmental delay and lethality (Copeland et al., 2009; Gems and Doonan, 2008; Van Raamsdonk and Hekimi, 2009; Yang et al., 2007).”

“…promoter driving wild-type sid-1 was injected into rab-3p::cco-1HP transgenic worms to enable knockdown of cco-1 in the neurons by the hairpin transgene and in the intestine by feeding RNAi. ubl-5 knockdown strains were generated with constructs as described (Esposito et al., 2007; Hobert, 2002).”

“…an inverted repeat of the cco-1 cDNA under the control of well-characterized promoters expressed in neurons (unc-119 and rab-3) (Maduro and Pilgrim, 1995; Nonet et al., 1997), intestine (ges-1) (Aamodt et al., 1991), and body-wall muscle cells (myo-3) (Miller et al., 1986; Okkema et al., 1993).”

“For example, exposure of the intestine to bacterially expressed dsRNA results in the dsRNA entering through the intestinal lumen but eliciting knockdown in other cells, such as the muscle and hypodermis (Jose et al., 2009).”

“A modification to this theory has suggested alternatively that, because reactive oxygen species (ROS) are generated as a byproduct of the metabolic activity of the mitochondrial ETC during the production of ATP (Harman, 1956), a decrease in ROS production is the major contributing factor to the long-lived phenotypes o…”

“…an inverted repeat of the cco-1 cDNA under the control of well-characterized promoters expressed in neurons (unc-119 and rab-3) (Maduro and Pilgrim, 1995; Nonet et al., 1997), intestine (ges-1) (Aamodt et al., 1991), and body-wall muscle cells (myo-3) (Miller et al., 1986; Okkema et al., 1993).”

“…transport chain (ETC) components in yeast, C. elegans, Drosophila, and mice delay the aging process (Copeland et al., 2009; Dell'Agnello et al., 2007; Dillin et al., 2002b; Feng et al., 2001; Hansen et al., 2008; Kirchman et al., 1999; Lapointe et al., 2009; Lee et al., 2002; Liu et al., 2005).”

“…is not surprising given the roles of dve-1 in growth and development and the embryonic lethality observed for homozygous dve-1 mutant animals (Burglin and Cassata, 2002; Haynes et al., 2007 suppressed longevity in the same manner as dve-1, suggesting that these RNAi treatments were…”

“…RNAi does not result in the detrimental phenotypes observed when bacterial feeding RNAi against other components of the ETC is administered undiluted, such as severe developmental delay and lethality (Copeland et al., 2009; Gems and Doonan, 2008; Van Raamsdonk and Hekimi, 2009; Yang et al., 2007).”

“Hormetic reactions may trigger a mitochondrial defensive response both in the same tissue in which mitochondria are defective and even in distant tissues, as shown in C. elegans (Durieux et al., 2011).”

“A non-cell-autonomous mitochondrial regulatory pathway was also reported in C. elegans: a tissuespecific RNA interference-mediated knockdown of cytochrome c oxidase subunit in neurons causes a local cellular stress response in neurons that is also communicated to the gut (Durieux et al., 2011).”

“In fact, in C. elegans, conditions of increased ROS generation such as ETC dysfunction, loss of sod-2, PQ treatment, and reduced glucose metabolism were shown to promote longevity (Schulz et al., 2007; Durieux et al., 2011; Wang and Hekimi, 2015).”