Sci. Aging Knowl. Environ., 19 June 2002
Vol. 2002, Issue 24, p. pe10
[DOI: 10.1126/sageke.2002.24.pe10]


Oxygen? No Thanks, I'm on a Diet

Valter D. Longo

The author is in the Andrus Gerontology Center, Division of Biogerontology, and Department of Biological Sciences at the University of Southern California, Los Angeles, CA 90089-0191, USA. E-mail: vlongo{at};2002/24/pe10

Key Words: hypoxia • daf-2SCH9Caenorhabditis elegans • stress resistance • longevity

Depending on environmental conditions, the nematode worm Caenorhabditis elegans can take one of two developmental paths: It can progress from the larva stage to fertile adulthood, or the larva can become arrested in a form known as the dauer (see "Hard Times Teach Life-Extending Lessons"). In response to starvation, worms that have not yet reached sexual maturity can enter this alternative dauer larva stage, which is characterized by resistance to environmental stresses and low metabolism. Mutations that reduce the function of daf-2 [daf-2(rf)], which encodes the worm homolog of the human insulin/insulin-like growth factor-1 (IGF-1) receptor, cause constitutive formation of dauer larvae whether or not sufficient food is available. However, daf-2(rf) mutations are best known for doubling the life-span of the adult worm and increasing resistance to oxidative and thermal stress (1). Reduction-of-function mutations in the yeast glucose signaling pathway, which is analogous to the worm insulin/IGF-1-like signaling pathway, also regulate life-span, stress resistance, and metabolic rates (2). Similar pathways activated by insulin/IGF-1 regulate longevity in flies and possibly in mammals (see "Growing Old Together") (1-3). Although the discovery of conserved pathways that regulate longevity is playing an unprecedented role in unraveling the fundamental mechanisms of aging, it is not clear whether this knowledge can be translated into therapies that prevent or treat common diseases of the aged.

The recent study by Scott et al., which was published in Science Express on 13 June 2002, takes a step in this direction. The authors provide evidence that suggests that Methuselah worms and worms living under starvation conditions might eventually teach us how to protect mammalian cells against the damage and death caused by lack of oxygen (hypoxia). By screening for C. elegans mutants that survive in a very-low-oxygen environment, Scott et al. identified a number of daf-2(rf) mutants that are resistant to hypoxia (Hyp). This DAF-2-dependent sensitivity to hypoxia appears to be mediated by the serine/threonine kinase AKT-1 and blocked by the forkhead transcription factor DAF-16 (see daf-16), which also regulates stress resistance and longevity (see Tatar Perspective and "Stay Mellow, Stay Young"). However, the authors also studied a number of previously discovered daf-2 alleles and identified eight long-lived and seven thermotolerant daf-2 mutants that are weakly resistant or nonresistant to hypoxia. Therefore, the mechanisms that control the Hyp phenotype might diverge from those that regulate stress resistance and longevity. Taken together, these results suggest that the degree of inactivation of the DAF-2/AKT-1 pathway and the consequent activation of DAF-16 might result in distinct gene expression patterns that favor either longevity and thermotolerance or survival in a nearly anaerobic environment, or both.

Previous studies have shown that life-span extension in daf-2 mutants (for example, the e1370 rf mutant) is abolished by restoring the activity of the daf-2 pathway in neurons, but not in muscle or intestine, suggesting that senescence in organs outside the nervous system might be regulated by neuroendocrine signaling (4). By contrast, Scott and colleagues show that resistance to hypoxia is reversed by restoring DAF-2 signaling in either neurons or muscle, indicating that the DAF-16 pathway can increase protection against certain forms of cell damage independently of the nervous system. This cell-autonomous role of DAF-2 in the regulation of resistance to hypoxia is reminiscent of that of the yeast Ras2p and Sch9p pathways in the regulation of oxidative and thermal stress (see Kaeberlein Perspective). The increase in stress resistance observed in long-lived yeast ras2{Delta} and sch9{Delta} mutants is mediated in part by the transcription factors Msn2p / Msn4p and Gis1p, which bind to stress response elements in the promoters of genes that encode mitochondrial superoxide dismutase 2 (SOD2), catalase, and heat shock proteins (5). Although it is still unclear how events that take place downstream of DAF-16 lead to a delay in aging in the worm, both mitochondrial SOD and catalase have been implicated in the effect of daf-2(rf) on life-span extension (Fig. 1) (6, 7).

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Fig. 1. Regulation of stress resistance and oxygen consumption in response to starvation: a conserved molecular strategy to extend longevity. In both worms and yeast, mutations [daf-2(rf) and sch9{Delta}, respectively] or starvation conditions (i) cause the down-regulation of pathways activated by an insulin/IGF-1-like growth factor or glucose, (ii) increase stress resistance, (iii) decrease oxygen consumption, and (iv) extend longevity. In worms, daf-2(rf) mutations or starvation increase resistance to hypoxia. In yeast, hypoxia is not toxic because the cells can survive anaerobically by generating energy through glucose fermentation. Although a decrease in metabolic rates is associated with longevity extension in several yeast and worm mutants, stress resistance and life-span in these organisms are also increased by mutations that don't reduce metabolic rates. Therefore, the role of the oxygen consumption rate on longevity and stress resistance is unclear.

To interpret the effect of daf-2(rf) mutations on the resistance to hypoxia, we must consider the role of DAF-2 in the regulation of metabolic rates and starvation resistance. Like some microorganisms, worms in the wild are thought to undergo cycles of long periods of starvation, followed by brief periods during which nutrients become available. In both yeast and worms, the depletion of external nutrients is accompanied by an intracellular/organismal storage of nutrients in the form of glycogen or fat, and entry into alternative metabolic phases. Depending on nutrient availability, yeast spend the majority of their chronological life-span in a dormant spore state, a low-metabolism stationary phase, or a high-metabolism postdiauxic phase. Similarly, food supply determines whether worms grow and become metabolically active adults or exit development at the L2 larva stage to enter the low-respiration dauer larva stage. Therefore, a dauer must be able to survive by using very low amounts of oxygen. In fact, Scott et al. show that dauers are resistant to hypoxia. The ability to decrease metabolic rates and use low amounts of oxygen might result in (i) the preservation of stored nutrients, (ii) the ability to survive under conditions of overcrowding, and (iii) the prevention of oxidative damage, all of which provide a survival advantage (Fig. 1). The life-span extension caused by exposure of worms to 1% oxygen is consistent with a role for the down-regulation of oxygen consumption in the reduction of oxidative damage and aging (see "The Two Faces of Oxygen") (8). Alternatively, low oxygen conditions might extend longevity by inducing the expression of dauer-associated genes. Most likely, longevity extension under 1% oxygen is the result of a combination of both decreased oxidative damage and the induction of a semi-dauer stage. Microorganisms and certain small animals generate overcrowded colonies to create a shield against environmental oxygen and other forms of stress. For example, yeast mutants that lack the cytosolic antioxidant enzyme Sod1p (sod1{Delta}) survive much longer as a compact colony at the bottom of small tubes than as a population dispersed in a shaking flask, where the organisms are exposed to 20% O2 (9). If starved dauers survive by using very low amounts of oxygen and saving energy, then it is not surprising that dauer constitutive mutations in the DAF-2 pathway decrease oxygen consumption and increase resistance to hypoxia. More surprising is the low correlation between hypoxia and resistance to heat observed by Scott et al. It is possible that certain daf-2 alleles reduce DAF-2 signaling but also increase the frailty of the animal. This might occur because the reduction of DAF-2 signaling also negatively affects growth and might therefore generate a weaker animal. In fact, flies with mutations in the InR signaling pathway, which is analogous to the worm daf-2 pathway, are long-lived, but they fail to grow to normal size, are infertile, and are not resistant to oxidative or thermal stress, although they have nearly twice as much superoxide dismutase activity as do wild-type flies (10, 11) (see Tatar Science article and Clancy Science article). Thus, it is possible that certain daf-2 alleles induce the expression of stress resistance genes, but, at the same time, cause frailty that counterbalances the increased protection during exposure to acute stress. Worms that express daf-2(rf) alleles might be sensitive to heat but able to take advantage of the lower respiratory rates to survive under low oxygen.

The identification of one of the pathways that regulates resistance to hypoxia in worms provides important clues for the development of treatments for hypoxic injury associated with diseases. In humans, ischemia/hypoxia is associated with heart diseases and stroke and can cause extensive death of many cell types, including neurons and muscle cells. It will be important to identify mammalian pathways analogous to the worm DAF-2 and yeast Sch9p pathways and to determine their role in resistance to hypoxia. A recent study in rats (12) shows that caloric restriction protects retinal ganglion cells from death after ischemia/re-perfusion. This observation raises the possibility that starvation-induced responses analogous to those caused by daf-2(rf) in worms might protect mammalian cells against hypoxia. A major challenge will be to learn how to induce resistance to ischemia/hypoxia without causing major side effects. For this purpose, it will be particularly important to exploit the billions of years of R&D conducted by natural selection in order to learn how evolution has yielded systems that prevent the damage caused by low or high oxygen concentrations without affecting fitness. If this system is conserved in yeast, worms, and flies, it's probably hiding somewhere in mammals. We just have to find it.

June 19, 2002
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