Reactive Oxygen Species and Aging in Caenorhabditis elegans: Causal or Casual Relationship?

The free radical theory of aging proposes a causal relationship between reactive oxygen species (ROS) and aging. While it is clear that oxidative damage increases with age, its role in the aging process is uncertain. Testing the free radical theory of aging requires experimentally manipulating ROS production or detoxification and examining the resulting effects on lifespan. In this review, we examine the relationship between ROS and aging in the genetic model organism Caenorhabditis elegans, summarizing experiments using long-lived mutants, mutants with altered mitochondrial function, mutants with decreased antioxidant defenses, worms treated with antioxidant compounds, and worms exposed to different environmental conditions. While there is frequently a negative correlation between oxidative damage and lifespan, there are many examples in which they are uncoupled. Neither is resistance to oxidative stress sufficient for a long life nor are all long-lived mutants more resistant to oxidative stress. Similarly, sensitivity to oxidative stress does not necessarily shorten lifespan and is in fact compatible with long life. Overall, the data in C. elegans indicate that oxidative damage can be dissociated from aging in experimental situations. Antioxid. Redox Signal. 13, 1911–1953.

1. Introduction

2. Reactive Oxygen Species

   1. Generation of ROS

   2. Detoxification of ROS

   3. Molecular damage caused by ROS

3. Caenorhabditis elegans

   1. C. elegans as a model organism

   2. Studying aging in C. elegans

   3. Assessing the role of ROS in determining C. elegans lifespan

   4. Hormesis

4. Long-Lived Mutants Show Increased Resistance to Oxidative Stress

   1. age-1–phosphoinositol 3-kinase

   2. daf-2–insulin/IGF-1 receptor

   3. eat-2–dietary restriction

   4. Dauer larvae

   5. Summary

5. Screening for Mutants with Altered Sensitivity to Oxidative Stress

   1. Genetic mutants with altered sensitivity to paraquat

   2. Genetic mutants with increased sensitivity to juglone

   3. Genetic mutants with increased sensitivity to hyperoxia and paraquat

   4. RNA interference screen for increased resistance to paraquat

   5. Summary

6. Mitochondrial Mutants Have Divergent Effects on Lifespan

   1. clk-1-hydroxylase involved in synthesis of ubiquinone

   2. isp-1-Rieske iron sulfur protein subunit of complex III

   3. nuo-6–NADH ubiquinone oxidoreductase subunit 6 (complex I)

   4. lrs-2–mitochondrial leucyl-tRNA synthetase

   5. mev-1–succinate dehydrogenase subunit C (complex II)

   6. gas-1 and nduf-2.2–iron sulfur protein subunit of complex I

   7. nuo-1–NADH ubiquinone oxidoreductase subunit 1 (complex I)

   8. sdhb-1–succinate dehydrogenase subunit b (complex II)

   9. phb-1- and phb-2-prohibitins

   10. frh-1-frataxin

   11. Uncoupling increases lifespan

   12. Mutations affecting mitochondrial function increase lifespan without decreasing ROS

   13. Summary

7. Endogenous Antioxidant Defenses

   1. Superoxide dismutase: sod-1, sod-2, sod-3, sod-4, and sod-5

   2. Catalase: ctl-1, ctl-2, and ctl-3

   3. Peroxiredoxin: prdx-2, prdx-3, and prdx-6

   4. Thioredoxin (trx-1 and trx-2) and thioredoxin reductase (trxr-1 and trxr-2)

   5. Glutaredoxin: glrx-5, glrx-10, glrx-21, and glrx-22

   6. Glutathione S-transferase: gst

   7. Nicotinamide nucleotide transhydrogenase: nnt-1

   8. Glyoxylase

   9. Summary

8. Effect of Exogenous Antioxidants on Lifespan

   1. SOD/catalase mimetics: Euk-8 and Euk-134

   2. Platinum nanoparticles

   3. N-acetyl cysteine

   4. Blueberry extract

   5. Coenzyme Q

   6. Ginkgo biloba extract: EGb761

   7. Epigallocatechin gallate

   8. α-lipoic acid

   9. Vitamin C and vitamin E

   10. Herbal medicines

   11. Predictive ability of in vitro antioxidant capacity on in vivo antioxidant capacity and lifespan

   12. Summary

9. Environmental Effects on ROS and Lifespan

   1. Temperature

   2. Oxygen concentration

   3. Axenic medium

   4. Summary

10. Functional Roles for ROS

    1. A role for ROS in combating pathogens

    2. A role for ROS in intracellular signaling

11. Executive Summary and Conclusions

12. Future Directions

    1. Develop new tools for measuring ROS

    2. Consideration of the role of ROS in signaling

    3. Reactive nitrogen species

    4. Combinatorial mechanisms of aging

    5. Cell specificity

    6. Measurement of oxidative damage

    7. Repair of oxidative damage