Stress Hormesis and Lifespan in C elegans

We showed that the lifespan of C. elegans decreases with increasing environmental oxygen concentration (39). On the other hand, low oxygen concentrations extend the lifespan (3), indicating that environmental oxygen concentration is one of lifespan determinants. Since ROS are thought to arise in organisms depending on the oxygen concentration (40), these findings suggest that ROS are involved in determination of lifespan. On the other hand, short-term exposure to hyperoxia slightly lengthened lifespan (6), short-term exposure to hyperbaric oxygen also increases lifespan (7). These effects are thought to be a form of hormesis for lifespan. In response to oxidative stress, the level of SOD activity and the expression of CuZnSOD, MnSOD, and catalase genes and oxidative stress resistance (6,8) increase in C. elegans. Pretreatment with hyperbaric oxygen or juglone (an intracellular generator of ROS) significantly increased subsequent resistance to the same or reciprocal stressors (7). The most widespread explanation is that an increased ability to remove ROS induced by oxidative stress could reduce normally occurred oxidative stress that may cause aging.

High doses of ionizing radiation reduce the lifespan of C. elegans, but low doses induce moderate lifespan extensions (4). We reproduced this result (S. Honda, Y. Honda, and S. Suzuki, unpublished observation) but Cypser and Johnson (7) found no lifespan extension by low-dose ionizing radiation as well as UV. These hormetic effects may be weak and occasional.

Heat treatment at sublethal temperatures induces increased resistance to subsequent lethal heat stress and modestly extends the lifespan of C. elegans (5). Heat shock induces a small heat shock protein (SHSP), HSP-16, in wildtype animals (41). Hsu et al. (42) also showed the increased expression of shsp genes, hsp-16.1, hsp-16.49, hsp-12.6, and sip-1 by heat shock. Yokoyana et al. (43) showed the induction of hsp70F and lifespan extension by heat shock. The overexpression of hsp70F, predominantly in the muscles, induces lifespan extension, and overexpression of the hsp16 gene induces thermal resistance and extended lifespan (44). These HSPs may play an important role as the molecular chaperon for preventing improper protein associations accumulated in the aging process.

Treatment of C. elegans worms with salen-manganese complexes, EUK-8 or EUK-134, synthetic SOD/catalase mimetics increased lifespan by 44% (45), but other investigators could not reproduce their results (46). The extension of lifespan by SOD/catalase mimetics may only occur under very particular culture conditions. SOD/catalase mimetics was reported to have cytoprotective activities in ischemic rat brain injury (47), and reverse age-related learning impairment and brain protein oxidation in mice (48).

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