- Email: [email protected]
Live Longer through PHAsting
Cell Metabolism
Previews Is FGF21 a good drug candidate for diabetes, dyslipidemia, and/or obesity? The favorable diabetes and lipid phenotypes are encouraging. The rhesus studies (Kharitonenkov et al., 2007) suggest that these effects are not rodent specific (for example, due to the higher rodent liver PPARa levels or the importance of active brown adipose tissue). On the safety front, the lack of detected hypoglycemia or cell proliferation is important. Thus, this mechanism seems worthy of further investigation. The observations reported in this issue by Badman et al. (2007) and Inagaki et al. (2007) identify FGF21 as an important endocrine hormone helping control adaptation to the fasted state. This provides a previously missing link, downstream of PPARa, by which the liver communicates with the rest of the body in regulating the biology of energy homeostasis.
ACKNOWLEDGMENTS M.L.R. is a full-time employee and shareholder of Merck & Co., Inc.
REFERENCES Badman, M.K., Pissios, P., Kennedy, A.R., Koukos, G., Flier, J.S., and Maratos-Flier, E. (2007). Cell Metab. 5, this issue, 426–437. Cahill, G.F., Jr. (2006). Annu. Rev. Nutr. 26, 1–22. Cryer, P.E., Davis, S.N., and Shamoon, H. (2003). Diabetes Care 26, 1902–1912. Freeman, J.M., Kossoff, E.H., and Hartman, A.L. (2007). Pediatrics 119, 535–543. Goetz, R., Beenken, A., Ibrahimi, O.A., Kalinina, J., Olsen, S.K., Eliseenkova, A.V., Xu, C., Neubert, T.A., Zhang, F., Linhardt, R.J., et al. (2007). Mol. Cell. Biol. 27, 3417–3428. Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007). Cell Metab. 5, this issue, 415–425. Kersten, S., Seydoux, J., Peters, J.M., Gonzalez, F.J., Desvergne, B., and Wahli, W. (1999). J. Clin. Invest. 103, 1489–1498.
Keys, A., Brozek, J., Henschel, A., Mickelsen, O., and Taylor, H.L. (1950). The Biology of Human Starvation (Minneapolis: University of Minnesota Press). Kharitonenkov, A., Shiyanova, T.L., Koester, A., Ford, A.M., Micanovic, R., Galbreath, E.J., Sandusky, G.E., Hammond, L.J., Moyers, J.S., Owens, R.A., et al. (2005). J. Clin. Invest. 115, 1627–1635. Kharitonenkov, A., Wroblewski, V.J., Koester, A., Chen, Y.F., Clutinger, C.K., Tigno, X.T., Hansen, B.C., Shanafelt, A.B., and Etgen, G.J. (2007). Endocrinology 148, 774–781. Lazar, M.A., and Willson, T.M. (2007). Cell Metab. 5, 159–161. Lefebvre, P., Chinetti, G., Fruchart, J.C., and Staels, B. (2006). J. Clin. Invest. 116, 571–580. Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K.P., Goetz, R., Eliseenkova, A.V., Mohammadi, M., and Kuro, O.M. (2007). Proc. Natl. Acad. Sci. USA 104, 7432–7437. Tucker, T. (2006). The Great Starvation Experiment: The Heroic Men Who Starved so That Millions Could Live (New York: Simon & Schuster Free Press).
Live Longer through PHAsting Arjan B. Brenkman1,* and Boudewijn M.T. Burgering1,* 1
Laboratory of Physiological Chemistry, Division of Biomedical Genetics, University Medical Center Utrecht, Stratenum, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands *Correspondence: [email protected] (A.B.B.), [email protected] (B.M.T.B.) DOI 10.1016/j.cmet.2007.05.009
Dietary restriction provides considerable health benefits and may even increase life span in humans. Panowski et al. (2007) have now identified PHA-4/FoxA as an essential and specific component of DR-induced life-span extension in C. elegans. The notion that life span is subject to the action of genes has become widely accepted. Despite the claims of popular anti-aging pills and creams, dietary restriction (DR) or calorie restriction is the only general nongenetic intervention that has been shown to improve health and increase life span in various model systems. DR differs from starvation and is usually defined as about 30% lower food intake than that of ad libitum feeding. In addition to DR, life span can be extended by reduced insulin/IGF-1 signaling (IIS) and reduced
mitochondrial electron transport chain activity (ECT) (Figure 1) (reviewed in Wolff and Dillin, 2006). A recent study by Panowski et al. (2007) now identifies the C. elegans pha-4 gene as an essential and unique mediator of DR-induced life-span extension. The Dillin lab previously identified suppressor of MEK1 (SMK1) as a regulator of DAF-16, a forkhead transcription factor homologous to mammalian FoxO that mediates IISinduced longevity (Wolff et al., 2006). However, the role of DAF-16 in DR
has remained enigmatic thus far, and surprisingly, it was observed that SMK-1, but not DAF-16, affected DRinduced life span. Because DR uncouples SMK-1 from DAF-16, the authors hypothesized that SMK-1 could regulate another forkhead transcription factor. By systematic screening of all 15 C. elegans forkheads, they identified PHA-4, the homolog of mammalian FoxA (HNF-3). Two independent DR models were used to demonstrate PHA-4 involvement. The classical genetic model for DR uses the mutant
Cell Metabolism 5, June 2007 ª2007 Elsevier Inc. 407
Cell Metabolism
Previews worm eat-2(ad1116), which ex16. PKB/AKT phosphorylation hibits reduced food intake due results in nuclear exclusion to a pharyngeal pumping deand inhibition of FoxA2 tranfect. eat-2 worms lost their scriptional activity (Wolfrum usual life-span extension when et al., 2004). This regulation is PHA-4 was depleted through specific to FoxA2, as FoxA1 RNAi. The second, nongenetic and FoxA3 lack PKB/AKT phosphorylation sites. Thus, it model involves ad libitum feedremains possible that in maming of worms in limiting dilumals, crosstalk between IIS tions of bacteria. Extremes of and DR exists at the level of bacterial concentrations proFoxA2. On a similar note, mamduce short-lived worms, malian target of rapamycin whereas conditions of optimal (mTOR), a key player in nutrient food intake result in life-span sensing, also acts downstream extension, termed bacterial of IIS, and it has been shown DR; this, however, was not the that mTOR depletion extends case for pha-4 mutant worms. life span of Drosophila and C. PHA-4 not only mediates DR elegans in a DAF-16-indepenbut also appears to be specific dent manner, reminiscent of to DR. The long-lived daf-2 muDR (Vellai et al., 2003). Thus, it tants could not be rescued by would be interesting to see pha-4 RNAi, in contrast to dafwhether IIS may crosstalk to 16 RNAi. Also, life span of PHA-4 through mTOR. long-lived ECT mutants (cyc-1 Yeast SIR2, a member of the or isp-1) was not decreased sirtuin family (SIRTs) of deaceby pha-4 RNAi. These observatylases, was the first gene tions show that pha-4 is specifidentified in regulation of DR ically required for DR-induced (Guarente and Picard, 2005). life-span extension and also Surprisingly, life-span extenthat pha-4 RNAi does not insion by SIR2.1 overexpression duce general sickness in in C. elegans requires DAF-16 worms, thereby reducing life (Lin et al., 2002), which would span. be at odds with the lack of Since both PHA-4 and FoxA Figure 1. Mechanisms of Life Span Three main pathways of aging have now been identified: DR DAF-16 involvement in DR. In play a role in development, it (blue box and arrows), IIS (gray box and arrows), and ECT contrast, resveratrol, an activawas important to separate de(orange box and arrows). DR and IIS signal to members of tor of SIRTs, increases life span velopmental effects from those the forkhead transcription factor family (PHA-4/FoxA and DAF-16/FoxO, respectively). The deacetylase SIR2 regulates in a DAF-16-independent manof life span. Thus, Panowski DAF-16 and has been shown to deacetylate FoxO. Because ner (Viswanathan et al., 2005). et al. (2007) applied pha-4 DR requires both PHA-4/FoxA and SIR2, the possibility exists This pathway could potentially RNAi at the adult stage only or that SIR2 also deacetylates PHA-4/FoxA (indicated by dashed line and question mark). PKB/AKT has been shown to regulate involve PHA-4, and it would induced adult-specific loss of both FoxO and FoxA2 and may represent a specific point of be interesting to see whether pha-4 using temperature-sencrosstalk between DR and IIS in mammalian cells. FurtherPHA-4 is potentially deacetysitive alleles. Both approaches more, mTOR may similarly crosstalk with DR or signal directly lated by SIRTs (Figure 1). How showed that PHA-4 affects life to mitochondria. PHA-4/FoxA and DAF-16/FoxO alter glucose and lipid metabolism, thereby shifting mitochondrial activity. It SIRTs discriminate between span independently of its deis suggested now that this may induce differential SOD exacting on DAF-16/FoxO and/ velopmental function. DR inpression and, in conjunction with altered metabolism, may be or PHA-4/FoxA following DR duces FoxA (Wolfrum et al., responsible for life-span extension. ECT may proceed along a type of retrograde pathway in which directly altered and resveratrol remains to be 2004) and PHA-4 expression. mitochondrial activity results in changed ROS metabolism established, but differential Therefore, the authors generand, consequently, differential regulation of SODs and altered sensitivity toward upstream ated transgenic pha-4 worms glucose and lipid metabolism (dashed orange arrows). signals as shown for IIS regulato analyze whether PHA-4 is tion of FoxA and FoxO could be sufficient for life-span extension. malian FoxA and FoxO regulate glucoIntriguingly, only in the background of neogenic genes such as PEPCK and a possibility (Wolfrum et al., 2004). The ‘‘free radical theory’’ proposes daf-16 null mutants did pha-4 overex- G6P. pression induce longevity, suggesting Of the three mammalian FoxA aging to be the consequence of accuthat pha-4 and daf-16, although clearly isoforms FoxA1, FoxA2, and FoxA3, mulating damage caused by reactive in separate genetic pathways, could FoxA2 is regulated by the insulin/ oxygen species (ROS). Thus, in the be partially redundant. This idea is PKB/AKT signaling axis, similar to simplest deduction, lowering ROS supported by the fact that both mam- FoxO, the human homolog of DAF- reduces damage and consequently 408 Cell Metabolism 5, June 2007 ª2007 Elsevier Inc.
Cell Metabolism
Previews would increase life span. Although some controversies exist, especially with respect to the relationship between altered metabolism and ROS generation, many studies indeed establish a correlation between ROS and life span. C. elegans expresses five genes encoding superoxide dismutases (SODs), which convert superoxide into peroxide, and of these, sod-3 mediates IIS-induced life-span extension. Interestingly, Panowski et al. (2007) observe differential SOD regulation by DR and IIS. DR specifically regulates sod-2 and -4, and this is PHA-4 dependent, whereas IIS specifically regulates sod-3, which is DAF-16 dependent. Regulation of sod-1 and -5 is common to both DR and IIS. Since SODs probably show cell-type-specific expression and are also differentially localized within cells, this differential SOD increase by DR as compared to IIS indicates different locations and/or mechanisms of ROS generation following DR or IIS. Therefore, it can be concluded that altered metabolism toward mitochondrial respiration following DR (Lin et al., 2002) or lowered IIS requires a change in stress maintenance but that the molecular components thereof depend on the nature of the metabolic switch. This illustrates that stress regulation is not an independent trait for life-span regulation but rather a sine qua non and therefore intricately linked to specific metabolic shifts causing life-span
extension. Indeed, MnSOD mimetics do not extend life span of otherwise wild-type C. elegans (Keaney et al., 2004). This further implies that, since different stress maintenance programs combine with different life-span interventions, the full range of different stress-resistance phenotypes (thermotolerance, paraquat, DNA damage etc.) will be not always be observed in long-lived animals. Multiple examples exist of long-lived C. elegans that do not show resistance to all types of exogenous stresses (reviewed in Wolff and Dillin, 2006). Consequently, it is unlikely that one unified downstream genetic program exists that conveys life-span extension for DR, IIS, and altered mitochondrial activity. Finally, in mammalian cells, exogenous stress increases expression of SODs, underlining their role in altered stress conditions. However, this also illustrates that ROS not only is a damage factor in aging but also has a signaling function. Peroxide generated by SODs, although potentially damaging, can also act as a signaling molecule due to its relative long halflife. Consistent with this, DAF-16/ FoxO regulation by the peroxide-regulated stress kinase JNK extends life span in C. elegans and Drosophila (Oh et al., 2005; Wang et al., 2005). Thus, life-span extension may depend not only on lowered ROS but also on the signaling ability of ROS. Understanding the metabolic and ROS re-
quirements by which PHA-4 regulates life span will eventually bring us closer to a central question in aging research: If we wish, can we extend our own lives? REFERENCES Guarente, L., and Picard, F. (2005). Cell 120, 473–482. Keaney, M., Matthijssens, F., Sharpe, M., Vanfleteren, J., and Gems, D. (2004). Free Radic. Biol. Med. 37, 239–250. Lin, S.J., Kaeberlein, M., Andalis, A.A., Sturtz, L.A., Defossez, P.A., Culotta, V.C., Fink, G.R., and Guarente, L. (2002). Nature 418, 344– 348. Oh, S.W., Mukhopadhyay, A., Svrzikapa, N., Jiang, F., Davis, R.J., and Tissenbaum, H.A. (2005). Proc. Natl. Acad. Sci. USA 102, 4494– 4499. Panowski, S.H., Wolff, S., Aguilaniu, H., Durieux, J., and Dillin, A. (2007). Nature, in press. Published online May 2, 2007. 10. 1038/nature05837. Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A.L., Orosz, L., and Muller, F. (2003). Nature 426, 620. Viswanathan, M., Kim, S.K., Berdichevsky, A., and Guarente, L. (2005). Dev. Cell 9, 605–615. Wang, M.C., Bohmann, D., and Jasper, H. (2005). Cell 121, 115–125. Wolff, S., and Dillin, A. (2006). Exp. Gerontol. 41, 894–903. Wolff, S., Ma, H., Burch, D., Maciel, G.A., Hunter, T., and Dillin, A. (2006). Cell 124, 1039–1053. Wolfrum, C., Asilmaz, E., Luca, E., Friedman, J.M., and Stoffel, M. (2004). Nature 432, 1027–1032.
Cell Metabolism 5, June 2007 ª2007 Elsevier Inc. 409
Previews Is FGF21 a good drug candidate for diabetes, dyslipidemia, and/or obesity? The favorable diabetes and lipid phenotypes are encouraging. The rhesus studies (Kharitonenkov et al., 2007) suggest that these effects are not rodent specific (for example, due to the higher rodent liver PPARa levels or the importance of active brown adipose tissue). On the safety front, the lack of detected hypoglycemia or cell proliferation is important. Thus, this mechanism seems worthy of further investigation. The observations reported in this issue by Badman et al. (2007) and Inagaki et al. (2007) identify FGF21 as an important endocrine hormone helping control adaptation to the fasted state. This provides a previously missing link, downstream of PPARa, by which the liver communicates with the rest of the body in regulating the biology of energy homeostasis.
ACKNOWLEDGMENTS M.L.R. is a full-time employee and shareholder of Merck & Co., Inc.
REFERENCES Badman, M.K., Pissios, P., Kennedy, A.R., Koukos, G., Flier, J.S., and Maratos-Flier, E. (2007). Cell Metab. 5, this issue, 426–437. Cahill, G.F., Jr. (2006). Annu. Rev. Nutr. 26, 1–22. Cryer, P.E., Davis, S.N., and Shamoon, H. (2003). Diabetes Care 26, 1902–1912. Freeman, J.M., Kossoff, E.H., and Hartman, A.L. (2007). Pediatrics 119, 535–543. Goetz, R., Beenken, A., Ibrahimi, O.A., Kalinina, J., Olsen, S.K., Eliseenkova, A.V., Xu, C., Neubert, T.A., Zhang, F., Linhardt, R.J., et al. (2007). Mol. Cell. Biol. 27, 3417–3428. Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007). Cell Metab. 5, this issue, 415–425. Kersten, S., Seydoux, J., Peters, J.M., Gonzalez, F.J., Desvergne, B., and Wahli, W. (1999). J. Clin. Invest. 103, 1489–1498.
Keys, A., Brozek, J., Henschel, A., Mickelsen, O., and Taylor, H.L. (1950). The Biology of Human Starvation (Minneapolis: University of Minnesota Press). Kharitonenkov, A., Shiyanova, T.L., Koester, A., Ford, A.M., Micanovic, R., Galbreath, E.J., Sandusky, G.E., Hammond, L.J., Moyers, J.S., Owens, R.A., et al. (2005). J. Clin. Invest. 115, 1627–1635. Kharitonenkov, A., Wroblewski, V.J., Koester, A., Chen, Y.F., Clutinger, C.K., Tigno, X.T., Hansen, B.C., Shanafelt, A.B., and Etgen, G.J. (2007). Endocrinology 148, 774–781. Lazar, M.A., and Willson, T.M. (2007). Cell Metab. 5, 159–161. Lefebvre, P., Chinetti, G., Fruchart, J.C., and Staels, B. (2006). J. Clin. Invest. 116, 571–580. Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K.P., Goetz, R., Eliseenkova, A.V., Mohammadi, M., and Kuro, O.M. (2007). Proc. Natl. Acad. Sci. USA 104, 7432–7437. Tucker, T. (2006). The Great Starvation Experiment: The Heroic Men Who Starved so That Millions Could Live (New York: Simon & Schuster Free Press).
Live Longer through PHAsting Arjan B. Brenkman1,* and Boudewijn M.T. Burgering1,* 1
Laboratory of Physiological Chemistry, Division of Biomedical Genetics, University Medical Center Utrecht, Stratenum, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands *Correspondence: [email protected] (A.B.B.), [email protected] (B.M.T.B.) DOI 10.1016/j.cmet.2007.05.009
Dietary restriction provides considerable health benefits and may even increase life span in humans. Panowski et al. (2007) have now identified PHA-4/FoxA as an essential and specific component of DR-induced life-span extension in C. elegans. The notion that life span is subject to the action of genes has become widely accepted. Despite the claims of popular anti-aging pills and creams, dietary restriction (DR) or calorie restriction is the only general nongenetic intervention that has been shown to improve health and increase life span in various model systems. DR differs from starvation and is usually defined as about 30% lower food intake than that of ad libitum feeding. In addition to DR, life span can be extended by reduced insulin/IGF-1 signaling (IIS) and reduced
mitochondrial electron transport chain activity (ECT) (Figure 1) (reviewed in Wolff and Dillin, 2006). A recent study by Panowski et al. (2007) now identifies the C. elegans pha-4 gene as an essential and unique mediator of DR-induced life-span extension. The Dillin lab previously identified suppressor of MEK1 (SMK1) as a regulator of DAF-16, a forkhead transcription factor homologous to mammalian FoxO that mediates IISinduced longevity (Wolff et al., 2006). However, the role of DAF-16 in DR
has remained enigmatic thus far, and surprisingly, it was observed that SMK-1, but not DAF-16, affected DRinduced life span. Because DR uncouples SMK-1 from DAF-16, the authors hypothesized that SMK-1 could regulate another forkhead transcription factor. By systematic screening of all 15 C. elegans forkheads, they identified PHA-4, the homolog of mammalian FoxA (HNF-3). Two independent DR models were used to demonstrate PHA-4 involvement. The classical genetic model for DR uses the mutant
Cell Metabolism 5, June 2007 ª2007 Elsevier Inc. 407
Cell Metabolism
Previews worm eat-2(ad1116), which ex16. PKB/AKT phosphorylation hibits reduced food intake due results in nuclear exclusion to a pharyngeal pumping deand inhibition of FoxA2 tranfect. eat-2 worms lost their scriptional activity (Wolfrum usual life-span extension when et al., 2004). This regulation is PHA-4 was depleted through specific to FoxA2, as FoxA1 RNAi. The second, nongenetic and FoxA3 lack PKB/AKT phosphorylation sites. Thus, it model involves ad libitum feedremains possible that in maming of worms in limiting dilumals, crosstalk between IIS tions of bacteria. Extremes of and DR exists at the level of bacterial concentrations proFoxA2. On a similar note, mamduce short-lived worms, malian target of rapamycin whereas conditions of optimal (mTOR), a key player in nutrient food intake result in life-span sensing, also acts downstream extension, termed bacterial of IIS, and it has been shown DR; this, however, was not the that mTOR depletion extends case for pha-4 mutant worms. life span of Drosophila and C. PHA-4 not only mediates DR elegans in a DAF-16-indepenbut also appears to be specific dent manner, reminiscent of to DR. The long-lived daf-2 muDR (Vellai et al., 2003). Thus, it tants could not be rescued by would be interesting to see pha-4 RNAi, in contrast to dafwhether IIS may crosstalk to 16 RNAi. Also, life span of PHA-4 through mTOR. long-lived ECT mutants (cyc-1 Yeast SIR2, a member of the or isp-1) was not decreased sirtuin family (SIRTs) of deaceby pha-4 RNAi. These observatylases, was the first gene tions show that pha-4 is specifidentified in regulation of DR ically required for DR-induced (Guarente and Picard, 2005). life-span extension and also Surprisingly, life-span extenthat pha-4 RNAi does not insion by SIR2.1 overexpression duce general sickness in in C. elegans requires DAF-16 worms, thereby reducing life (Lin et al., 2002), which would span. be at odds with the lack of Since both PHA-4 and FoxA Figure 1. Mechanisms of Life Span Three main pathways of aging have now been identified: DR DAF-16 involvement in DR. In play a role in development, it (blue box and arrows), IIS (gray box and arrows), and ECT contrast, resveratrol, an activawas important to separate de(orange box and arrows). DR and IIS signal to members of tor of SIRTs, increases life span velopmental effects from those the forkhead transcription factor family (PHA-4/FoxA and DAF-16/FoxO, respectively). The deacetylase SIR2 regulates in a DAF-16-independent manof life span. Thus, Panowski DAF-16 and has been shown to deacetylate FoxO. Because ner (Viswanathan et al., 2005). et al. (2007) applied pha-4 DR requires both PHA-4/FoxA and SIR2, the possibility exists This pathway could potentially RNAi at the adult stage only or that SIR2 also deacetylates PHA-4/FoxA (indicated by dashed line and question mark). PKB/AKT has been shown to regulate involve PHA-4, and it would induced adult-specific loss of both FoxO and FoxA2 and may represent a specific point of be interesting to see whether pha-4 using temperature-sencrosstalk between DR and IIS in mammalian cells. FurtherPHA-4 is potentially deacetysitive alleles. Both approaches more, mTOR may similarly crosstalk with DR or signal directly lated by SIRTs (Figure 1). How showed that PHA-4 affects life to mitochondria. PHA-4/FoxA and DAF-16/FoxO alter glucose and lipid metabolism, thereby shifting mitochondrial activity. It SIRTs discriminate between span independently of its deis suggested now that this may induce differential SOD exacting on DAF-16/FoxO and/ velopmental function. DR inpression and, in conjunction with altered metabolism, may be or PHA-4/FoxA following DR duces FoxA (Wolfrum et al., responsible for life-span extension. ECT may proceed along a type of retrograde pathway in which directly altered and resveratrol remains to be 2004) and PHA-4 expression. mitochondrial activity results in changed ROS metabolism established, but differential Therefore, the authors generand, consequently, differential regulation of SODs and altered sensitivity toward upstream ated transgenic pha-4 worms glucose and lipid metabolism (dashed orange arrows). signals as shown for IIS regulato analyze whether PHA-4 is tion of FoxA and FoxO could be sufficient for life-span extension. malian FoxA and FoxO regulate glucoIntriguingly, only in the background of neogenic genes such as PEPCK and a possibility (Wolfrum et al., 2004). The ‘‘free radical theory’’ proposes daf-16 null mutants did pha-4 overex- G6P. pression induce longevity, suggesting Of the three mammalian FoxA aging to be the consequence of accuthat pha-4 and daf-16, although clearly isoforms FoxA1, FoxA2, and FoxA3, mulating damage caused by reactive in separate genetic pathways, could FoxA2 is regulated by the insulin/ oxygen species (ROS). Thus, in the be partially redundant. This idea is PKB/AKT signaling axis, similar to simplest deduction, lowering ROS supported by the fact that both mam- FoxO, the human homolog of DAF- reduces damage and consequently 408 Cell Metabolism 5, June 2007 ª2007 Elsevier Inc.
Cell Metabolism
Previews would increase life span. Although some controversies exist, especially with respect to the relationship between altered metabolism and ROS generation, many studies indeed establish a correlation between ROS and life span. C. elegans expresses five genes encoding superoxide dismutases (SODs), which convert superoxide into peroxide, and of these, sod-3 mediates IIS-induced life-span extension. Interestingly, Panowski et al. (2007) observe differential SOD regulation by DR and IIS. DR specifically regulates sod-2 and -4, and this is PHA-4 dependent, whereas IIS specifically regulates sod-3, which is DAF-16 dependent. Regulation of sod-1 and -5 is common to both DR and IIS. Since SODs probably show cell-type-specific expression and are also differentially localized within cells, this differential SOD increase by DR as compared to IIS indicates different locations and/or mechanisms of ROS generation following DR or IIS. Therefore, it can be concluded that altered metabolism toward mitochondrial respiration following DR (Lin et al., 2002) or lowered IIS requires a change in stress maintenance but that the molecular components thereof depend on the nature of the metabolic switch. This illustrates that stress regulation is not an independent trait for life-span regulation but rather a sine qua non and therefore intricately linked to specific metabolic shifts causing life-span
extension. Indeed, MnSOD mimetics do not extend life span of otherwise wild-type C. elegans (Keaney et al., 2004). This further implies that, since different stress maintenance programs combine with different life-span interventions, the full range of different stress-resistance phenotypes (thermotolerance, paraquat, DNA damage etc.) will be not always be observed in long-lived animals. Multiple examples exist of long-lived C. elegans that do not show resistance to all types of exogenous stresses (reviewed in Wolff and Dillin, 2006). Consequently, it is unlikely that one unified downstream genetic program exists that conveys life-span extension for DR, IIS, and altered mitochondrial activity. Finally, in mammalian cells, exogenous stress increases expression of SODs, underlining their role in altered stress conditions. However, this also illustrates that ROS not only is a damage factor in aging but also has a signaling function. Peroxide generated by SODs, although potentially damaging, can also act as a signaling molecule due to its relative long halflife. Consistent with this, DAF-16/ FoxO regulation by the peroxide-regulated stress kinase JNK extends life span in C. elegans and Drosophila (Oh et al., 2005; Wang et al., 2005). Thus, life-span extension may depend not only on lowered ROS but also on the signaling ability of ROS. Understanding the metabolic and ROS re-
quirements by which PHA-4 regulates life span will eventually bring us closer to a central question in aging research: If we wish, can we extend our own lives? REFERENCES Guarente, L., and Picard, F. (2005). Cell 120, 473–482. Keaney, M., Matthijssens, F., Sharpe, M., Vanfleteren, J., and Gems, D. (2004). Free Radic. Biol. Med. 37, 239–250. Lin, S.J., Kaeberlein, M., Andalis, A.A., Sturtz, L.A., Defossez, P.A., Culotta, V.C., Fink, G.R., and Guarente, L. (2002). Nature 418, 344– 348. Oh, S.W., Mukhopadhyay, A., Svrzikapa, N., Jiang, F., Davis, R.J., and Tissenbaum, H.A. (2005). Proc. Natl. Acad. Sci. USA 102, 4494– 4499. Panowski, S.H., Wolff, S., Aguilaniu, H., Durieux, J., and Dillin, A. (2007). Nature, in press. Published online May 2, 2007. 10. 1038/nature05837. Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A.L., Orosz, L., and Muller, F. (2003). Nature 426, 620. Viswanathan, M., Kim, S.K., Berdichevsky, A., and Guarente, L. (2005). Dev. Cell 9, 605–615. Wang, M.C., Bohmann, D., and Jasper, H. (2005). Cell 121, 115–125. Wolff, S., and Dillin, A. (2006). Exp. Gerontol. 41, 894–903. Wolff, S., Ma, H., Burch, D., Maciel, G.A., Hunter, T., and Dillin, A. (2006). Cell 124, 1039–1053. Wolfrum, C., Asilmaz, E., Luca, E., Friedman, J.M., and Stoffel, M. (2004). Nature 432, 1027–1032.
Cell Metabolism 5, June 2007 ª2007 Elsevier Inc. 409