Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H ₂ O ₂ and superoxide dismutase activity

Abstract

The free radical theory of aging posits oxidative damage to macromolecules as a primary determinant of lifespan. Recent studies challenge this theory by demonstrating that in some cases, longevity is enhanced by inactivation of oxidative stress defenses or is correlated with increased, rather than decreased reactive oxygen species and oxidative damage. Here we show that, in Saccharomyces cerevisiae, caloric restriction or inactivation of catalases extends chronological lifespan by inducing elevated levels of the reactive oxygen species hydrogen peroxide, which activate superoxide dismutases that inhibit the accumulation of superoxide anions. Increased hydrogen peroxide in catalase-deficient cells extends chronological lifespan despite parallel increases in oxidative damage. These findings establish a role for hormesis effects of hydrogen peroxide in promoting longevity that have broad implications for understanding aging and age-related diseases.aging | hydrogen peroxide | hormesis | antioxidant enzymes | oxidative damage T he longstanding free radical theory has guided investigations into the causes and consequences of aging for more than 50 y (1). However, the results of a number of recent studies have failed to provide support for the free radical theory or suggest that this theory is at best incomplete (2). Studies of naked mole rats, for example, demonstrated that this extremely long-lived rodent exhibits high levels of oxidative damage compared with mice or rats, whose lifespans are ≈1/10 that of naked mole rats (3). In addition, caloric restriction (CR), which extends the lifespans of a variety of eukaryotic organisms, promotes longevity in Caenorhabditis elegans by a mechanism that involves increased oxidative stress (4). In fact, in contrast to the destructive effects of reactive oxygen species (ROS), recent evidence indicates that in mammals, hydrogen peroxide (H 2 O 2 ) and other forms of ROS function as essential secondary messengers in the regulation of a variety of physiological processes (reviewed in ref. 5). For example, H 2 O 2 activates prosurvival signaling pathways mediated by p53, NF-κB, AP-1, and other molecules (6). Furthermore, increases in the intracellular steady-state production of H 2 O 2 by SOD2 overexpression can block the activation of cellular processes required for programmed cell death (7). However, a causal relationship between CR and effects on oxidative stress has been difficult to establish.To better understand how CR impacts oxidative stress and longevity in the model organism Saccharomyces cerevisiae, in this study we examined intracellular levels of H 2 O 2 and superoxide anions (O 2 − ), which are two forms of ROS implicated in aging in all eukaryotes, under CR and other conditions. Our findings indicate that CR or inactivation of catalases extends chronological lifespan (CLS) by inducing elevated levels of H 2 O 2 , which activate superoxide dismutases that inhibit the accumulation of O 2 − . These findings establish a role for hormesis effects of H 2 O 2 in promoting l...

Taking a “good” look at free radicals in the aging process

“…These findings suggest that increased mitochondrial superoxide generation acts as a signal in young mutant animals to trigger changes of gene expression that prevent or attenuate the effects of subsequent aging. These findings were consistent with, and significantly extended, earlier studies in yeast [45] and in worms [46] that had suggested that an increase in ROS from mitochondria might be important in triggering the lifespan extension produced by glucose restriction.…”

Artemisinin mimics calorie restriction to extend yeast lifespan via a dual-phase mode: a conclusion drawn from global transcriptome profiling

“…A recent study has also shown CR elevates H 2 O 2 levels in an early stationary phase, and induces SOD activity to help extending CLS [20,47]. Our results showing H 2 O 2 can mimic CR to extend yeast CLS provides supports to such putative mechanisms.…”

“…While ME occurs only in the early CR phase (short-term or acute CR), PME maintains in the late CR phase (life-long or chronic CR). Because CR can trigger hydrogen peroxide (H 2 O 2 ) burst and induce superoxide dismutase (SOD) overexpression [20], and NO can reversibly bind to the heme moiety of COX [21], we assume CR-triggered NO may interact with COX to result in H 2 O 2 generation and SOD induction through mitochondrial uncoupling, thereby scavenging reactive oxygen species (ROS), attenuating oxidative stress, guiding metabolic conversion, and eventually extending lifespan.…”

Model-based identification of drug targets that revert disrupted metabolism and its application to ageing

“…Notably, these genes could not be predicted by neither gene expression analysis alone nor by the commonly used prediction methods. Providing mechanistic explanations to their workings, we further show that in accordance with the model's predictions, the knockout of the two lifespan-extending genes results in a significant elevation in ROS levels, potentially suggesting a hormetic mechanism, as previously shown by Masquita et al 48 for H 2 O 2 . Of note, knockout of ADH2 was previously found to extend yeast CLS by driving metabolism away from acetic-acid production 49 , similar to the mechanism suggested by our flux analysis (Fig.…”