FRAMING FOR ACTION. The evidence we
have for enhancing climate resilience of ecosystems places direct responsibility on governments to ensure implementation. However, investment will only happen if costs of refraining from activities that undermine resilience are distributed in ways that lead to effective action. Realizing such incentive schedules may be challenging. However, there are three specific reasons that building a safe operating space for ecosystems by controlling local stressors is more conducive to immediate action than global control of greenhouse gases. From global to local commons. Potential incentives for local protection are much stronger than those to supply the global public good of abating greenhouse gas emissions (18), for the same reason that countries tend to favor adaptation over mitigation. Mitigation requires global collective action and is vulnerable to free riding, whereas adaptation can be done unilaterally, with benefits accruing almost exclusively to the country doing the adaptation. However, iconic ecosystems also provide a global public good. This is why they are on the World Heritage list in the first place. In some cases, the local interventions can result in substantial global mitigation. For instance, slowing down Amazon deforestation made Brazil a global leader in climate change mitigation (16).
From high to low uncertainty. Perceived uncertainty has often paralyzed policy (19), and experimental evidence suggests that uncertainty about climate change tipping points undermines efforts to avoid crossing a dangerous threshold (20). There is less uncertainty on the ecosystem level than on the global level when it comes to effects of management options. From negative to positive framing. Gloom-and-doom perceptions may backfire to block action. Terms such as “extreme events” and “catastrophic transitions” may express the urgency of the matter. However, social experiments reveal that accounts of disastrous future effects of climate change can invoke cognitive dissonance that causes many people to disbelieve climate change altogether. This response disappears if a feasible approach to take action and abate the problems is presented simultaneously (21). A positive, action-oriented framing of a safe operating space for the world’s iconic ecosystems may help stimulate societal consensus that climate change is real and should be addressed. ■ REFERENCES AND NOTES
1. M. Scheffer, S. Carpenter, J. A. Foley, C. Folke, B. Walker, Nature 413, 591 (2001) 2. J. Rockström et al., Ecol. Soc. 14, 32 (2009). 3. R. P. Kelly et al., Science 332, 1036 (2011). 4. M. Holmgren, M. Hirota, E. H. Van Nes, M. Scheffer, Nat. Clim. Change 3, 755 (2013). 5. B. Moss et al., Inland Waters 1, 101 (2011). 6. S. Kosten et al., Glob. Change Biol. 18, 118 (2012). 7. T. P. Hughes et al., Science 301, 929 (2003). 8. T. P. Hughes et al., Curr. Biol. 17, 360 (2007). 9. Y. Malhi et al., Science 319, 169 (2008). 10. K. J. Feeley, S. Joseph Wright, M. N. Nur Supardi, A. R. Kassim, S. J. Davies, Ecol. Lett. 10, 461 (2007). 11. P. M. Brando et al., Proc. Natl. Acad. Sci. U.S.A. 111, 6347 (2014). 12. C. Guardiola-Albert, C. R. Jackson, Wetlands 31, 907 (2011). 13. D. R. Bellwood, T. P. Hughes, C. Folke, M. Nyström, Nature 429, 827 (2004). 14. A Great Barrier Reef Marine Park, Great Barrier Reef Outlook Report 2014: In Brief (Great Barrier Reef Marine Park Authority, Townsville, Queensland, 2014). 15. D. Normile, L. Dayton, Science 346, 683 (2014). 16. D. Nepstad et al., Science 344, 1118 (2014) 17. J. Ferreira et al., Science 346, 706 (2014). 18. E. Ostrom, J. Burger, C. B. Field, R. B. Norgaard, D. Policansky, Science 284, 278 (1999). 19. N. Oreskes, E. M. Conway, Merchants of Doubt: How a Handful of Scientists Obscured the Truth on Issues from Tobacco Smoke to Global Warming (Bloomsbury Press, New York, 2010). 20. S. Barrett, A. Dannenberg, Nat. Clim. Change 4, 36 (2014). 21. M. Feinberg, R. Willer, Psychol. Sci. 22, 34 (2011). ACKNOWLEDGMENTS
M.S. is supported by a European Research Council advanced grant and Spinoza award. C.F. is supported by the Stellenbosch Institute for Advanced Study. S.R.C.’s research is supported by NSF. A.J.G. was supported by a WIMEK research fellowship and S.K. by Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Veni grant 86312012. M.S., C.F., and S.R.C. are also at the South American Institute for Resilience and Sustainability Studies. This work was carried out under the program of the Netherlands Earth System Science Centre (NESSC). 10.1126/science.aaa3769
SCIENCE sciencemag.org
STEM CELLS
Holding your breath for longevity A nutrient-sensing protein is important for the health of hematopoietic stem cells during aging By Alejandro Ocampo and Juan Carlos Izpisua Belmonte
A
ging is a complex process. Progressive molecular changes lead to a decline in the ability of living beings to maintain homeostasis and overcome cellular stress, protein damage, and disease (1). At the organismal level, stem cells play a fundamental role in maintaining tissue integrity, and their functional and proliferative exhaustion is a major cause of aging (2). Hematopoietic stem cells, which reside in the bone marrow and give rise to all blood cell types, are a favored model for studying stem cell aging.
“…decline of stem cell function with age due to intrinsic factors…and extrinsic factors…could potentially be reverted…” However, the exact molecular mechanisms underlying their aging remain unknown. Sirtuins, a family of nutrient-sensing proteins (SIRT1 to SIRT7) that regulate gene expression and protein function in mammalian cells, orchestrate multiple pathways that are associated with age-related processes and longevity. On page 1374 of this issue, Mohrin et al. (3) connect SIRT7 to a metabolic checkpoint that controls aging in hematopoietic stem cells. SIRT7 is a nicotinamide adenine dinucleotide (NAD)–dependent deacetylase that senses the nutrient status of a cell and adjusts cell function accordingly. Thus, under nutrient deprivation, SIRT7 alters transcription to reduce cell metabolism and decrease cell growth, thereby promoting cell survival. By analyzing all proteins that 20 MARCH 2015 • VOL 347 ISSUE 6228
Published by AAAS
1319
Downloaded from www.sciencemag.org on March 19, 2015
The Great Barrier Reef is the largest coral system in the world. In response to multiple threats, fishing has been prohibited since 2004 over 33% of the Great Barrier Reef Marine Park, and efforts have begun to reduce runoff of nutrients, pesticides, herbicides, and sediments from land. However, these interventions may be too little, too late. Approximately half of the coral cover has been lost in recent decades (13), and the outlook is “poor, and declining,” with climate change, coastal development, and dredging as major future threats (14). The World Heritage Committee has warned that in the absence of a solid long-term plan, it would consider listing the reef as “in danger” in 2015 (15). The Amazon rainforest is one of the world’s great biological treasures and a vital component of Earth’s climate system. Yet this ecosystem is under increasing pressure from climate change as well as local stressors such as logging and forest fire (9). Brazil has shown leadership by slowing down Amazon deforestation by 70% (16) and by creating the largest protected area (PA) network in the world. Yet these successes are now being partially undermined by major infrastructure and natural resource extraction projects and by shifts in legislation (17).
potentially interact with SIRT7 ing pathways exert in multiple Young adult Older adult (the SIRT7 “interactome”), cells, tissues, and organs, ultihematopoietic hematopoietic Mohrin et al. identified nuclear mately controlling an organstem cells stem cells respiratory factor 1 (NRF1) as a ism’s health and longevity. new SIRT7 partner. The interacHuman aging research sugtion between SIRT7 and NRF1 gests that aging is a malleable High Low suppressed the transcription of process that can be altered by genes encoding constituents of manipulating conserved bioSIRT7 the mitochondrial translational logical pathways. In addition SIRT7 NRF1 expression machinery. This suppression to the hematopoietic system, led to a reduction in mitochonage-associated changes in stem drial biogenesis and decreased cells have been reported in cellular respiration (oxidative other mammalian adult stem metabolism). Consistent with cell compartments, including the metabolic sensing nature muscle, bone, forebrain, and Mitochondria Decreases Increases of sirtuins, SIRT7 expression germ line (9, 10). Thus, decline biogenesis and increased in cultured mamof stem cell function with age energy metabolism malian cells upon nutrient due to intrinsic factors (such deprivation. Thus, by cooperatas SIRT7) and extrinsic factors ing with NRF1, SIRT7 hampers (such as chronic inflammation mitochondrial activity, alters and circulatory factors) could Quiescence Cell cycle state Proliferation metabolism, and enhances cell potentially be reverted, indicatsurvival by promoting resising that rejuvenation strategies tance to nutritional stress. may one day slow or even turn Is the connection between back the aging clock. SIRT7 and metabolism related Research based on heteroUnbiased Diferentiation Myeloid based to the mitochondrial unfolded chronic parabiosis (in which capacity protein response? Nutritional two living organisms are joined stress can perturb mitochontogether surgically and share a drial proteostasis, which leads SIRT7 metabolic checkpoint regulates hematopoietic stem cell aging. circulatory system) has demonto the accumulation of unfolded In young adult hematopoietic stem cells, SIRT7-NRF1 interaction suppresses strated that stem cell rejuvenaproteins in the mitochondria. mitochondrial biogenesis and respiration. In hematopoietic stem cells from an older tion in different compartments This situation activates the miadult, SIRT7 expression is reduced, leading to increased mitochondrial biogenesis is feasible through systemic tochondrial unfolded protein and mitochondrial protein stress. Consequently, old hematopoietic stem cells exit environment rejuvenation (9, response pathway to alleviate quiescence, increase proliferation, and are prone to a myeloid-biased differentiation. 11, 12). Strikingly, Mohrin et al. mitochondrial stress through demonstrate that by targeting repression of protein synthesis, degradarelevance of SIRT7 in hematopoietic stem cell-intrinsic deregulated programs—such tion of unfolded proteins, and increased cell aging. Accordingly, SIRT7 expression as the protective metabolic checkpoint esproduction of molecular chaperones for was reduced in aged hematopoietic stem tablished by SIRT7—it is possible to reverse the refolding of unfolded proteins. Thus, cells, and restoration of SIRT7 expression aging in hematopoietic stem cells. This apby halting production of the mitochondrial was sufficient to revert these cells to a proach has recently proved successful with protein synthesis machinery, the interyounger state with improved reconstitumuscle stem cells from old mice, where action between SIRT7 and NRF1 reduces tion capacity upon transplantation and an inhibition of age-associated pathways remitochondrial protein folding stress. unbiased differentiation. Thus, the authors stored muscle regeneration potential to a How is SIRT7 connected to stem cell connect reduced amounts of SIRT7 with younger state (13). Mohrin et al. seem to aging? Metabolic reprogramming plays high mitochondrial activity (and metabobring us a step closer to achieving a healthy fundamental roles during organismal delism) and low stress resistance in aged helongevity. ■ velopment, cellular reprogramming, and matopoietic stems cells. REFERENCES cellular differentiation (4). In a quiescent In line with the findings of Mohrin et al., 1. C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, G. state, hematopoietic stem cells have a high other sirtuins, such as the nuclear SIRT1 Kroemer, Cell 153, 1194 (2013). rate of glycolysis and low mitochondrial and mitochondrial SIRT3, are essential for 2. J. Oh, Y. D. Lee, A. J. Wagers, Nat. Med. 20, 870 (2014). activity, accompanied by a high expresmaintaining the regenerative capacity of 3. M. Mohrin et al., Science 347, 1374 (2015). sion of SIRT7. SIRT7-deficient hematopoihematopoietic stem cells (5, 6). By contrast, 4. J. Zhang, E. Nuebel, G. Q. Daley, C. M. Koehler, M. A. Teitell, etic stem cells (from young adult mice) in other tissues, sirtuins positively reguCell Stem Cell 11, 589 (2012). showed increased mitochondrial content late mitochondrial function. For instance, 5. P. Rimmelé et al., Stem Cell Rep. 3, 44 (2014). and reduced resistance to stress, as well SIRT7-deficient mice display mitochondrial 6. K. Brown et al., Cell Rep. 3, 319 (2013). 7. D. Ryu et al., Cell Metab. 20, 856 (2014). as features of aging, such as increased dysfunction across all tissues due to desta8. J. T. Rodgers et al., Nature 434, 113 (2005). programmed cell death (apoptosis) during bilization of a transcription factor complex 9. I. M. Conboy et al., Nature 433, 760 (2005). bone marrow transplantation and myeloid[guanine adenosine (GA)–binding protein 10. A. V. Molofsky et al., Nature 443, 448 (2006). biased differentiation. These observations α (GABPα) and β (GABPβ)] (7), whereas 11. L. Katsimpardi et al., Science 344, 630 (2014). 12. M. Sinha et al., Science 344, 649 (2014). led Mohrin et al. to explore the functional SIRT1 induces mitochondrial biogenesis in 13. P. Sousa-Victor et al., Nature 506, 316 (2014). hepatocytes (8). The findings of Mohrin et al. in hematopoietic stem cells reveal the Gene Expression Laboratory, Salk Institute for Biological 10.1126/science.aaa9608 heterogeneous effects that regulatory agStudies, La Jolla, CA 92037, USA. E-mail: [email protected] 1320
sciencemag.org SCIENCE
20 MARCH 2015 • VOL 347 ISSUE 6228
Published by AAAS
ILLUSTRATION: C. BICKEL/SCIENCE
INSIGHTS | P E R S P E C T I V E S
Holding your breath for longevity Alejandro Ocampo and Juan Carlos Izpisua Belmonte Science 347, 1319 (2015); DOI: 10.1126/science.aaa9608
This copy is for your personal, non-commercial use only.
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The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 19, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6228/1319.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6228/1319.full.html#related This article cites 13 articles, 3 of which can be accessed free: http://www.sciencemag.org/content/347/6228/1319.full.html#ref-list-1 This article appears in the following subject collections: Cell Biology http://www.sciencemag.org/cgi/collection/cell_biol
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
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have for enhancing climate resilience of ecosystems places direct responsibility on governments to ensure implementation. However, investment will only happen if costs of refraining from activities that undermine resilience are distributed in ways that lead to effective action. Realizing such incentive schedules may be challenging. However, there are three specific reasons that building a safe operating space for ecosystems by controlling local stressors is more conducive to immediate action than global control of greenhouse gases. From global to local commons. Potential incentives for local protection are much stronger than those to supply the global public good of abating greenhouse gas emissions (18), for the same reason that countries tend to favor adaptation over mitigation. Mitigation requires global collective action and is vulnerable to free riding, whereas adaptation can be done unilaterally, with benefits accruing almost exclusively to the country doing the adaptation. However, iconic ecosystems also provide a global public good. This is why they are on the World Heritage list in the first place. In some cases, the local interventions can result in substantial global mitigation. For instance, slowing down Amazon deforestation made Brazil a global leader in climate change mitigation (16).
From high to low uncertainty. Perceived uncertainty has often paralyzed policy (19), and experimental evidence suggests that uncertainty about climate change tipping points undermines efforts to avoid crossing a dangerous threshold (20). There is less uncertainty on the ecosystem level than on the global level when it comes to effects of management options. From negative to positive framing. Gloom-and-doom perceptions may backfire to block action. Terms such as “extreme events” and “catastrophic transitions” may express the urgency of the matter. However, social experiments reveal that accounts of disastrous future effects of climate change can invoke cognitive dissonance that causes many people to disbelieve climate change altogether. This response disappears if a feasible approach to take action and abate the problems is presented simultaneously (21). A positive, action-oriented framing of a safe operating space for the world’s iconic ecosystems may help stimulate societal consensus that climate change is real and should be addressed. ■ REFERENCES AND NOTES
1. M. Scheffer, S. Carpenter, J. A. Foley, C. Folke, B. Walker, Nature 413, 591 (2001) 2. J. Rockström et al., Ecol. Soc. 14, 32 (2009). 3. R. P. Kelly et al., Science 332, 1036 (2011). 4. M. Holmgren, M. Hirota, E. H. Van Nes, M. Scheffer, Nat. Clim. Change 3, 755 (2013). 5. B. Moss et al., Inland Waters 1, 101 (2011). 6. S. Kosten et al., Glob. Change Biol. 18, 118 (2012). 7. T. P. Hughes et al., Science 301, 929 (2003). 8. T. P. Hughes et al., Curr. Biol. 17, 360 (2007). 9. Y. Malhi et al., Science 319, 169 (2008). 10. K. J. Feeley, S. Joseph Wright, M. N. Nur Supardi, A. R. Kassim, S. J. Davies, Ecol. Lett. 10, 461 (2007). 11. P. M. Brando et al., Proc. Natl. Acad. Sci. U.S.A. 111, 6347 (2014). 12. C. Guardiola-Albert, C. R. Jackson, Wetlands 31, 907 (2011). 13. D. R. Bellwood, T. P. Hughes, C. Folke, M. Nyström, Nature 429, 827 (2004). 14. A Great Barrier Reef Marine Park, Great Barrier Reef Outlook Report 2014: In Brief (Great Barrier Reef Marine Park Authority, Townsville, Queensland, 2014). 15. D. Normile, L. Dayton, Science 346, 683 (2014). 16. D. Nepstad et al., Science 344, 1118 (2014) 17. J. Ferreira et al., Science 346, 706 (2014). 18. E. Ostrom, J. Burger, C. B. Field, R. B. Norgaard, D. Policansky, Science 284, 278 (1999). 19. N. Oreskes, E. M. Conway, Merchants of Doubt: How a Handful of Scientists Obscured the Truth on Issues from Tobacco Smoke to Global Warming (Bloomsbury Press, New York, 2010). 20. S. Barrett, A. Dannenberg, Nat. Clim. Change 4, 36 (2014). 21. M. Feinberg, R. Willer, Psychol. Sci. 22, 34 (2011). ACKNOWLEDGMENTS
M.S. is supported by a European Research Council advanced grant and Spinoza award. C.F. is supported by the Stellenbosch Institute for Advanced Study. S.R.C.’s research is supported by NSF. A.J.G. was supported by a WIMEK research fellowship and S.K. by Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Veni grant 86312012. M.S., C.F., and S.R.C. are also at the South American Institute for Resilience and Sustainability Studies. This work was carried out under the program of the Netherlands Earth System Science Centre (NESSC). 10.1126/science.aaa3769
SCIENCE sciencemag.org
STEM CELLS
Holding your breath for longevity A nutrient-sensing protein is important for the health of hematopoietic stem cells during aging By Alejandro Ocampo and Juan Carlos Izpisua Belmonte
A
ging is a complex process. Progressive molecular changes lead to a decline in the ability of living beings to maintain homeostasis and overcome cellular stress, protein damage, and disease (1). At the organismal level, stem cells play a fundamental role in maintaining tissue integrity, and their functional and proliferative exhaustion is a major cause of aging (2). Hematopoietic stem cells, which reside in the bone marrow and give rise to all blood cell types, are a favored model for studying stem cell aging.
“…decline of stem cell function with age due to intrinsic factors…and extrinsic factors…could potentially be reverted…” However, the exact molecular mechanisms underlying their aging remain unknown. Sirtuins, a family of nutrient-sensing proteins (SIRT1 to SIRT7) that regulate gene expression and protein function in mammalian cells, orchestrate multiple pathways that are associated with age-related processes and longevity. On page 1374 of this issue, Mohrin et al. (3) connect SIRT7 to a metabolic checkpoint that controls aging in hematopoietic stem cells. SIRT7 is a nicotinamide adenine dinucleotide (NAD)–dependent deacetylase that senses the nutrient status of a cell and adjusts cell function accordingly. Thus, under nutrient deprivation, SIRT7 alters transcription to reduce cell metabolism and decrease cell growth, thereby promoting cell survival. By analyzing all proteins that 20 MARCH 2015 • VOL 347 ISSUE 6228
Published by AAAS
1319
Downloaded from www.sciencemag.org on March 19, 2015
The Great Barrier Reef is the largest coral system in the world. In response to multiple threats, fishing has been prohibited since 2004 over 33% of the Great Barrier Reef Marine Park, and efforts have begun to reduce runoff of nutrients, pesticides, herbicides, and sediments from land. However, these interventions may be too little, too late. Approximately half of the coral cover has been lost in recent decades (13), and the outlook is “poor, and declining,” with climate change, coastal development, and dredging as major future threats (14). The World Heritage Committee has warned that in the absence of a solid long-term plan, it would consider listing the reef as “in danger” in 2015 (15). The Amazon rainforest is one of the world’s great biological treasures and a vital component of Earth’s climate system. Yet this ecosystem is under increasing pressure from climate change as well as local stressors such as logging and forest fire (9). Brazil has shown leadership by slowing down Amazon deforestation by 70% (16) and by creating the largest protected area (PA) network in the world. Yet these successes are now being partially undermined by major infrastructure and natural resource extraction projects and by shifts in legislation (17).
potentially interact with SIRT7 ing pathways exert in multiple Young adult Older adult (the SIRT7 “interactome”), cells, tissues, and organs, ultihematopoietic hematopoietic Mohrin et al. identified nuclear mately controlling an organstem cells stem cells respiratory factor 1 (NRF1) as a ism’s health and longevity. new SIRT7 partner. The interacHuman aging research sugtion between SIRT7 and NRF1 gests that aging is a malleable High Low suppressed the transcription of process that can be altered by genes encoding constituents of manipulating conserved bioSIRT7 the mitochondrial translational logical pathways. In addition SIRT7 NRF1 expression machinery. This suppression to the hematopoietic system, led to a reduction in mitochonage-associated changes in stem drial biogenesis and decreased cells have been reported in cellular respiration (oxidative other mammalian adult stem metabolism). Consistent with cell compartments, including the metabolic sensing nature muscle, bone, forebrain, and Mitochondria Decreases Increases of sirtuins, SIRT7 expression germ line (9, 10). Thus, decline biogenesis and increased in cultured mamof stem cell function with age energy metabolism malian cells upon nutrient due to intrinsic factors (such deprivation. Thus, by cooperatas SIRT7) and extrinsic factors ing with NRF1, SIRT7 hampers (such as chronic inflammation mitochondrial activity, alters and circulatory factors) could Quiescence Cell cycle state Proliferation metabolism, and enhances cell potentially be reverted, indicatsurvival by promoting resising that rejuvenation strategies tance to nutritional stress. may one day slow or even turn Is the connection between back the aging clock. SIRT7 and metabolism related Research based on heteroUnbiased Diferentiation Myeloid based to the mitochondrial unfolded chronic parabiosis (in which capacity protein response? Nutritional two living organisms are joined stress can perturb mitochontogether surgically and share a drial proteostasis, which leads SIRT7 metabolic checkpoint regulates hematopoietic stem cell aging. circulatory system) has demonto the accumulation of unfolded In young adult hematopoietic stem cells, SIRT7-NRF1 interaction suppresses strated that stem cell rejuvenaproteins in the mitochondria. mitochondrial biogenesis and respiration. In hematopoietic stem cells from an older tion in different compartments This situation activates the miadult, SIRT7 expression is reduced, leading to increased mitochondrial biogenesis is feasible through systemic tochondrial unfolded protein and mitochondrial protein stress. Consequently, old hematopoietic stem cells exit environment rejuvenation (9, response pathway to alleviate quiescence, increase proliferation, and are prone to a myeloid-biased differentiation. 11, 12). Strikingly, Mohrin et al. mitochondrial stress through demonstrate that by targeting repression of protein synthesis, degradarelevance of SIRT7 in hematopoietic stem cell-intrinsic deregulated programs—such tion of unfolded proteins, and increased cell aging. Accordingly, SIRT7 expression as the protective metabolic checkpoint esproduction of molecular chaperones for was reduced in aged hematopoietic stem tablished by SIRT7—it is possible to reverse the refolding of unfolded proteins. Thus, cells, and restoration of SIRT7 expression aging in hematopoietic stem cells. This apby halting production of the mitochondrial was sufficient to revert these cells to a proach has recently proved successful with protein synthesis machinery, the interyounger state with improved reconstitumuscle stem cells from old mice, where action between SIRT7 and NRF1 reduces tion capacity upon transplantation and an inhibition of age-associated pathways remitochondrial protein folding stress. unbiased differentiation. Thus, the authors stored muscle regeneration potential to a How is SIRT7 connected to stem cell connect reduced amounts of SIRT7 with younger state (13). Mohrin et al. seem to aging? Metabolic reprogramming plays high mitochondrial activity (and metabobring us a step closer to achieving a healthy fundamental roles during organismal delism) and low stress resistance in aged helongevity. ■ velopment, cellular reprogramming, and matopoietic stems cells. REFERENCES cellular differentiation (4). In a quiescent In line with the findings of Mohrin et al., 1. C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, G. state, hematopoietic stem cells have a high other sirtuins, such as the nuclear SIRT1 Kroemer, Cell 153, 1194 (2013). rate of glycolysis and low mitochondrial and mitochondrial SIRT3, are essential for 2. J. Oh, Y. D. Lee, A. J. Wagers, Nat. Med. 20, 870 (2014). activity, accompanied by a high expresmaintaining the regenerative capacity of 3. M. Mohrin et al., Science 347, 1374 (2015). sion of SIRT7. SIRT7-deficient hematopoihematopoietic stem cells (5, 6). By contrast, 4. J. Zhang, E. Nuebel, G. Q. Daley, C. M. Koehler, M. A. Teitell, etic stem cells (from young adult mice) in other tissues, sirtuins positively reguCell Stem Cell 11, 589 (2012). showed increased mitochondrial content late mitochondrial function. For instance, 5. P. Rimmelé et al., Stem Cell Rep. 3, 44 (2014). and reduced resistance to stress, as well SIRT7-deficient mice display mitochondrial 6. K. Brown et al., Cell Rep. 3, 319 (2013). 7. D. Ryu et al., Cell Metab. 20, 856 (2014). as features of aging, such as increased dysfunction across all tissues due to desta8. J. T. Rodgers et al., Nature 434, 113 (2005). programmed cell death (apoptosis) during bilization of a transcription factor complex 9. I. M. Conboy et al., Nature 433, 760 (2005). bone marrow transplantation and myeloid[guanine adenosine (GA)–binding protein 10. A. V. Molofsky et al., Nature 443, 448 (2006). biased differentiation. These observations α (GABPα) and β (GABPβ)] (7), whereas 11. L. Katsimpardi et al., Science 344, 630 (2014). 12. M. Sinha et al., Science 344, 649 (2014). led Mohrin et al. to explore the functional SIRT1 induces mitochondrial biogenesis in 13. P. Sousa-Victor et al., Nature 506, 316 (2014). hepatocytes (8). The findings of Mohrin et al. in hematopoietic stem cells reveal the Gene Expression Laboratory, Salk Institute for Biological 10.1126/science.aaa9608 heterogeneous effects that regulatory agStudies, La Jolla, CA 92037, USA. E-mail: [email protected] 1320
sciencemag.org SCIENCE
20 MARCH 2015 • VOL 347 ISSUE 6228
Published by AAAS
ILLUSTRATION: C. BICKEL/SCIENCE
INSIGHTS | P E R S P E C T I V E S
Holding your breath for longevity Alejandro Ocampo and Juan Carlos Izpisua Belmonte Science 347, 1319 (2015); DOI: 10.1126/science.aaa9608
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 19, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6228/1319.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6228/1319.full.html#related This article cites 13 articles, 3 of which can be accessed free: http://www.sciencemag.org/content/347/6228/1319.full.html#ref-list-1 This article appears in the following subject collections: Cell Biology http://www.sciencemag.org/cgi/collection/cell_biol
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on March 19, 2015
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