目次

Editorials

IPCC(気候変動に関する政府間パネル)の第5次評価報告書の最新発表は、世界の置かれた状況と今後の課題を明確に示している。

Brace for impacts p.7

The latest instalment of the Fifth Assessment Report from the Intergovernmental Panel on Climate Change lays out the state of the world — and the challenges ahead.

doi: 10.1038/508007a

自然を詳しく観察し、記録する博物学専攻の研究者が減っているが、博物学は最先端の生物学にとって重要な基盤である。

Natural decline p.7

Few biology degrees still feature natural history. Is the naturalist a species in crisis?

doi: 10.1038/508007b

神経科学分野のビッグサイエンスの成果が上がっているが、その究極のゴールを思い出すことも大切だ。

Brain waves p.8

Above the ‘big neuroscience’ commotion, literature plays its part.

doi: 10.1038/508008a

News

ロシアによるクリミア編入により、ウクライナの科学が混乱状態に。

Ukraine’s science in turmoil p.15

Crimean institutions put their future in Russia’s hands as Ukraine attempts research reforms.

doi: 10.1038/508015a

疾患がますます厳密に定義されるようになってきており、オーファン・ドラッグに指定される薬剤が増加。

Regulators adopt more orphan drugs p.16

Agencies face rising applications for rare-disease therapies resulting from increasingly precise disease definitions.

doi: 10.1038/508016a

ヨーロッパの火星探査計画エクソマーズが着陸地点を絞り込み、4か所が候補に。

ExoMars scientists narrow down landing sites p.19

Facing engineering constraints, researchers propose four destinations for European rover.

doi: 10.1038/508019a

エルニーニョ現象の兆しが現れているが、データ不足が予測の精度向上の妨げに。

El Niño tests forecasters p.20

As hints emerge of a major weather event this year, poor data could thwart attempts to improve predictions.

doi: 10.1038/508020a

全エピゲノム関連研究(EWAS)によって、疾患の解明に役立つ手がかりが得られると、期待が。

Epigenomics starts to make its mark p.22

Analysis of chemical patterns on DNA shows promise for explaining disease, but few results have yet been replicated.

doi: 10.1038/508022a

News Features

がんの治療:内なる殺人者

Cancer treatment: The killer within p.24

免疫系はがんに対する強力な武器になる可能性があるが、免疫系ががんをどのように制御するかはいまだに解決されていない。

doi: 10.1038/508024a

宇宙論:南極の星

Cosmology: Polar star p.28

南極での数年にわたる観測によって、宇宙が誕生時に膨張したことを示す有力な証拠が得られた。

doi: 10.1038/508028a

News & Views

がん:脳での防御を無効にする

Cancer: Disabling defences in the brain p.46

酵素のプラスミンには脳に転移したがん細胞を防御する働きがあり、腫瘍細胞のタンパク質であるセルピンはプラスミン産生を阻害することが突き止められた。この結果は脳への転移形成機構の主な特色を明らかにしている。

doi: 10.1038/508046a

免疫:ビタミンAは免疫にも重要

Immunology: A is for immunity p.47

妊娠中のマウスでビタミンAが不足すると、生まれた仔のリンパ節が小型になり成体になってからの免疫応答が損なわれることが分かった。この知見は、ビタミンAが他の多くの重要な機能に加えて、免疫の発生にも関与していることを示している。

doi: 10.1038/nature13216

太陽系:新しき星の環 

Solar System: Ring in the new p.48

太陽系中で環系を誇示している天体は、もはや惑星だけではなくなった。ケンタウルス族の天体の1つの周りに2つの高密度の環が観測されたのである。この天体は比較的小型で氷でできており、太陽系の遠い場所から侵入してきたものだ。

doi: 10.1038/nature13218

血管生物学:絞扼される脳血管

Vascular biology: Brain vessels squeezed to death p.50

脳の毛細血管を取り囲む収縮性の細胞は、健全なニューロンへの血液供給を制御していて、こうした細胞が死ぬと血管が絞扼されて脳の損傷が悪化することが分かった。

doi: 10.1038/nature13217

惑星科学:地球の年齢を知るための精密時計

Planetary science: A chronometer for Earth's age p.51

地球の成長のシミュレーションによって、月の形成時期とその時期以降に地球に集積した質量の間の相関が明らかになった。この関係から、地球の年齢を測定する方法が得られる。

doi: 10.1038/508051a

がん:クローン同士の協力

Cancer: Clonal cooperation p.52

ヒト腫瘍中の細胞には遺伝学的不均一性が広く見られるが、これは最適なクローンが優勢になるのを何が妨げているのかという疑問につながる。異なるクローン間での相互依存性が実証されたことは、この謎の答えを見つける手がかりとなりそうだ。

doi: 10.1038/508052a

Articles

血管生物学:毛細血管の周皮細胞は健康時および病態時の脳血流量を調節する

Capillary pericytes regulate cerebral blood flow in health and disease p.55

Neuronal activity relaxes pericytes, leading to capillary dilation and increased blood flow, before arterioles dilate, suggesting that pericytes initiate blood-oxygen-level-dependent (BOLD) functional imaging signals; pericytes constrict and die in rigor in ischaemia, which will cause a long-lasting blood flow decrease after stroke, and damage the blood–brain barrier.

doi: 10.1038/nature13165

構造生物学:分子レベルで詳細に明らかにされたTc毒素の作用機構

Mechanism of Tc toxin action revealed in molecular detail p.61

High-resolution structures of the Photorhabdus luminescent TcA toxin subunit and the entire Tc toxin complex reveal important new insights into Tc complex structure and function.

doi: 10.1038/nature13015

分子生物学:ポリ(A)尾部のプロファイリングで明らかになった胚期の翻訳制御の切り替え

Poly(A)-tail profiling reveals an embryonic switch in translational control p.66

A new high-throughput sequencing method to determine mRNA poly(A)-tail length enabled studies of individual RNAs across species and developmental stages to investigate the role of poly(A) length in translational regulation; the relationship between poly(A) length and translational efficiency shown in early embryo systems does not occur later in development, a finding that explains different regulatory consequences of microRNAs acting at different developmental times.

doi: 10.1038/nature13007

Letters

宇宙:ケンタウルス族の小惑星カリクロ(小惑星番号 10199)の周囲に発見された環系

A ring system detected around the Centaur (10199) Chariklo p.72

Hitherto, rings have been found exclusively around the four giant planets in the Solar System. Rings are natural laboratories in which to study dynamical processes analogous to those that take place during the formation of planetary systems and galaxies. Their presence also tells us about the origin and evolution of the body they encircle. Here we report observations of a multichord stellar occultation that revealed the presence of a ring system around (10199) Chariklo, which is a Centaur—that is, one of a class of small objects orbiting primarily between Jupiter and Neptune—with an equivalent radius of 124  9 kilometres (ref. 2). There are two dense rings, with respective widths of about 7 and 3 kilometres, optical depths of 0.4 and 0.06, and orbital radii of 391 and 405 kilometres. The present orientation of the ring is consistent with an edge-on geometry in 2008, which provides a simple explanation for the dimming of the Chariklo system between 1997 and 2008, and for the gradual disappearance of ice and other absorption features in its spectrum over the same period. This implies that the rings are partly composed of water ice. They may be the remnants of a debris disk, possibly confined by embedded, kilometre-sized satellites.

doi: 10.1038/nature13155

分子物理学:ヘリウムバッファーガスによるクーロン結晶化分子イオンの高効率回転冷却

Efficient rotational cooling of Coulomb-crystallized molecular ions by a helium buffer gas p.76

The preparation of cold molecules is of great importance in many contexts, such as fundamental physics investigations, high-resolution spectroscopy of complex molecules, cold chemistry and astrochemistry. One versatile and widely applied method to cool molecules is helium buffer-gas cooling in either a supersonic beam expansion or a cryogenic trap environment. Another more recent method applicable to trapped molecular ions relies on sympathetic translational cooling, through collisional interactions with co-trapped, laser-cooled atomic ions, into spatially ordered structures called Coulomb crystals, combined with laser-controlled internal-state preparation. Here we present experimental results on helium buffer-gas cooling of the rotational degrees of freedom of MgH+ molecular ions, which have been trapped and sympathetically cooled in a cryogenic linear radio-frequency quadrupole trap. With helium collision rates of only about ten per second—that is, four to five orders of magnitude lower than in typical buffer-gas cooling settings—we have cooled a single molecular ion to a rotational temperature of  kelvin, the lowest such temperature so far measured. In addition, by varying the shape of, or the number of atomic and molecular ions in, larger Coulomb crystals, or both, we have tuned the effective rotational temperature from about 7 kelvin to about 60 kelvin by changing the translational micromotion energy of the ions. The extremely low helium collision rate may allow for sympathetic sideband cooling of single molecular ions, and eventually make quantum-logic spectroscopy of buffer-gas-cooled molecular ions feasible. Furthermore, application of the present cooling scheme to complex molecular ions should enable single- or few-state manipulations of individual molecules of biological interest.

doi: 10.1038/nature12996

光物性:無反跳γ線光子の波形のコヒーレント制御

Coherent control of the waveforms of recoilless γ-ray photons p.80

The concepts and ideas of coherent, nonlinear and quantum optics have been extended to photon energies in the range of 10–100 kiloelectronvolts, corresponding to soft γ-ray radiation (the term used when the radiation is produced in nuclear transitions) or, equivalently, hard X-ray radiation (the term used when the radiation is produced by electron motion). The recent experimental achievements in this energy range include the demonstration of parametric down-conversion in the Langevin regime, electromagnetically induced transparency in a cavity, the collective Lamb shift, vacuum-assisted generation of atomic coherences and single-photon revival in nuclear absorbing multilayer structures. Also, realization of single-photon coherent storage and stimulated Raman adiabatic passage were recently proposed in this regime. More related work is discussed in a recent review. However, the number of tools for the coherent manipulation of interactions between γ-ray photons and nuclear ensembles remains limited. Here we suggest and implement an efficient method to control the waveforms of γ-ray photons coherently. In particular, we demonstrate the conversion of individual recoilless γ-ray photons into a coherent, ultrashort pulse train and into a double pulse. Our method is based on the resonant interaction of γ-ray photons with an ensemble of nuclei with a resonant transition frequency that is periodically modulated in time. The frequency modulation, which is achieved by a uniform vibration of the resonant absorber, owing to the Doppler effect, renders resonant absorption and dispersion both time dependent, allowing us to shape the waveforms of the incident γ-ray photons. We expect that this technique will lead to advances in the emerging fields of coherent and quantum γ-ray photon optics, providing a basis for the realization of γ-ray-photon/nuclear-ensemble interfaces and quantum interference effects at nuclear γ-ray transitions.

doi: 10.1038/nature13018

地球物理学:月を形成した衝突に対する時計としての地球マントルの高親鉄性元素

Highly siderophile elements in Earth’s mantle as a clock for the Moon-forming impact p.84

A large number of N-body simulations of the giant-impact phase of planet formation, combined with the measured concentrations of highly siderophile elements in Earth’s mantle, reveal that the Moon must have formed at least 40 million years after the condensation of the first solids of the Solar System.

doi: 10.1038/nature13172

神経科学:海馬のCA2領域は社会性記憶に不可欠である

The hippocampal CA2 region is essential for social memory p.88

The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when. Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus to CA3 and then to CA1, the main hippocampal output. Genetic lesions of EC (ref. 3) and hippocampal dentate gyrus (ref. 4), CA3 (ref. 5) and CA1 (ref. 6) regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output. Here we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioural role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory—the ability of an animal to remember a conspecific—with no change in sociability or several other hippocampus-dependent behaviours, including spatial and contextual memory. These behavioural and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.

doi: 10.1038/nature13028

細胞:ヒト繊維芽細胞から作製した肝細胞によるマウス肝臓の再生

Mouse liver repopulation with hepatocytes generated from human fibroblasts p.93

Human induced pluripotent stem cells (iPSCs) have the capability of revolutionizing research and therapy of liver diseases by providing a source of hepatocytes for autologous cell therapy and disease modelling. However, despite progress in advancing the differentiation of iPSCs into hepatocytes (iPSC-Heps) in vitro, cells that replicate the ability of human primary adult hepatocytes (aHeps) to proliferate extensively in vivo have not been reported. This deficiency has hampered efforts to recreate human liver diseases in mice, and has cast doubt on the potential of iPSC-Heps for liver cell therapy. The reason is that extensive post-transplant expansion is needed to establish and sustain a therapeutically effective liver cell mass in patients, a lesson learned from clinical trials of aHep transplantation. Here, as a solution to this problem, we report the generation of human fibroblast-derived hepatocytes that can repopulate mouse livers. Unlike current protocols for deriving hepatocytes from human fibroblasts, ours did not generate iPSCs but cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) could be efficiently differentiated. For this purpose we identified small molecules that aided endoderm and hepatocyte differentiation without compromising proliferation. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of aHeps. Unfractionated iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state. Our results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.

doi: 10.1038/nature13020

がん:急性リンパ芽球性白血病における第21染色体の体質性再編成と体細胞性再編成

Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia p.98

Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

doi: 10.1038/nature13115

がん:XBP1はHIF1α経路の制御によってトリプルネガティブ乳がんを促進する

XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway p.103

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)—a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)—is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44highCD24low population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.

doi: 10.1038/nature13119

がん:グルコース制限とビグアナイドに対するがん細胞の感受性を決定する代謝因子

Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides p.108

As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.

doi: 10.1038/nature13110

がん:Wntが駆動する乳がんにおける腫瘍細胞の不均一性は協調的なサブクローンにより維持される

Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers p.113

Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones. As carcinogenesis involves a breakdown in the cell–cell cooperation that normally maintains epithelial tissue architecture, individual subclones within a malignant microenvironment are commonly depicted as self-interested competitors. Alternatively, breast cancer subclones might interact cooperatively to gain a selective growth advantage in some cases. Although interclonal cooperation has been shown to drive tumorigenesis in fruitfly models, definitive evidence for functional cooperation between epithelial tumour cell subclones in mammals is lacking. Here we use mouse models of breast cancer to show that interclonal cooperation can be essential for tumour maintenance. Aberrant expression of the secreted signalling molecule Wnt1 generates mixed-lineage mammary tumours composed of basal and luminal tumour cell subtypes, which purportedly derive from a bipotent malignant progenitor cell residing atop a tumour cell hierarchy. Using somatic Hras mutations as clonal markers, we show that some Wnt tumours indeed conform to a hierarchical configuration, but that others unexpectedly harbour genetically distinct basal Hras mutant and luminal Hras wild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on luminally produced Wnt1. When biclonal tumours were challenged with Wnt withdrawal to simulate targeted therapy, analysis of tumour regression and relapse revealed that basal subclones recruit heterologous Wnt-producing cells to restore tumour growth. Alternatively, in the absence of a substitute Wnt source, the original subclones often evolve to rescue Wnt pathway activation and drive relapse, either by restoring cooperation or by switching to a defector strategy. Uncovering similar modes of interclonal cooperation in human cancers may inform efforts aimed at eradicating tumour cell communities.

doi: 10.1038/nature13187

がん:黒色腫でのBRAF(V600E)抑制に対する可逆性および適応性の耐性

Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma p.118

Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a ‘drug holiday’ and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.

doi: 10.1038/nature13121

免疫:母体のレチノイドは3型自然リンパ球を制御して仔の免疫を設定する

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity p.123

The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.

doi: 10.1038/nature13158

生理学:線虫の寿命は成体早期におけるミトフラッシュの頻度によって予測される

Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans p.128

It has been theorized for decades that mitochondria act as the biological clock of ageing, but the evidence is incomplete. Here we show a strong coupling between mitochondrial function and ageing by in vivo visualization of the mitochondrial flash (mitoflash), a frequency-coded optical readout reflecting free-radical production and energy metabolism at the single-mitochondrion level. Mitoflash activity in Caenorhabditis elegans pharyngeal muscles peaked on adult day 3 during active reproduction and on day 9 when animals started to die off. A plethora of genetic mutations and environmental factors inversely modified the lifespan and the day-3 mitoflash frequency. Even within an isogenic population, the day-3 mitoflash frequency was negatively correlated with the lifespan of individual animals. Furthermore, enhanced activity of the glyoxylate cycle contributed to the decreased day-3 mitoflash frequency and the longevity of daf-2 mutant animals. These results demonstrate that the day-3 mitoflash frequency is a powerful predictor of C. elegans lifespan across genetic, environmental and stochastic factors. They also support the notion that the rate of ageing, although adjustable in later life, has been set to a considerable degree before reproduction ceases.

doi: 10.1038/nature13012

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