Commentary
Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories

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Abstract

Harman’s free radical theory of aging posits that oxidized macromolecules accumulate with age to decrease function and shorten life-span. However, nutritional and genetic interventions to boost anti-oxidants have generally failed to increase life-span. Furthermore, the free radical theory fails to explain why exercise causes higher levels of oxyradical damage, but generally promotes healthy aging. The separate anti-aging paradigms of genetic or caloric reductions in the insulin signaling pathway is thought to slow the rate of living to reduce metabolism, but recent evidence from Westbrook and Bartke suggests metabolism actually increases in long-lived mice. To unify these disparate theories and data, here, we propose the epigenetic oxidative redox shift (EORS) theory of aging. According to EORS, sedentary behavior associated with age triggers an oxidized redox shift and impaired mitochondrial function. In order to maintain resting energy levels, aerobic glycolysis is upregulated by redox-sensitive transcription factors. As emphasized by DeGrey, the need to supply NAD+ for glucose oxidation and maintain redox balance with impaired mitochondrial NADH oxidoreductase requires the upregulation of other oxidoreductases. In contrast to the 2% inefficiency of mitochondrial reduction of oxygen to the oxyradical, these other oxidoreductases enable glycolytic energy production with a deleterious 100% efficiency in generating oxyradicals. To avoid this catastrophic cycle, lactate dehydrogenase is upregulated at the expense of lactic acid acidosis. This metabolic shift is epigenetically enforced, as is insulin resistance to reduce mitochondrial turnover. The low mitochondrial capacity for efficient production of energy reinforces a downward spiral of more sedentary behavior leading to accelerated aging, increased organ failure with stress, impaired immune and vascular functions and brain aging. Several steps in the pathway are amenable to reversal for exit from the vicious cycle of EORS. Examples from our work in the aging rodent brain as well as other aging models are provided.

Introduction

The free radical theory of aging of Harman proposes that oxidized macromolecules accumulate with age to decrease cell function and shorten life-span (Harman, 1968). However, nutritional and genetic interventions to boost anti-oxidants have generally failed to increase life-span. The overall result of 19 clinical trials finds supplementation with the lipid-soluble anti-oxidant vitamin E failed to reduce mortality (Miller et al., 2005). The water soluble anti-oxidant vitamin C is also generally ineffective in reducing all-cause mortality (Bjelakovic et al., 2007). An even more important test of the free radical theory of aging involves genetic overexpression of anti-oxidant enzymes. To date, increases in SOD, or catalase or a combination, while lowering oxidized macromolecules, fail to increase life-span in mice (Perez et al., 2009). Only overexpression of the peroxide and redox-active thioredoxin 1 (Mitsui et al., 2002) and mitochondrial targeted catalase (Schriner et al., 2005) have been shown to increase mouse life-span. In their review of aging theories, Jang and Van Remmen conclude that these and other studies “challenge” the mitochondrial and free radical theories of aging (Jang and Van Remmen, 2009) while Howes enumerates a list of failures of the free radical theory (Howes, 2006). A more complex regulation is suggested by experiments in Caenorhabditis elegans, in which careful titration with RNAi against mitochondrial function revealed a middle dose that promoted life-span extension that was not correlated with oxidative stress (Rea et al., 2007). In addition, the free radical theory fails to explain why higher levels of oxyradical damage occur with exercise (Powers and Jackson, 2008), which generally promotes healthy human aging (Nakamura et al., 1996) and extends life-span in mice (Navarro et al., 2004) and extends survival in rats (Holloszy et al., 1985). Table 1 summarizes this dilemma.

The separate anti-aging paradigm of genetic or caloric reductions in the insulin signaling pathway is thought to slow the rate of living to reduce metabolism and oxyradical production (Weindruch et al., 2001, Carter et al., 2002, Heilbronn et al., 2006, Al-Regaiey et al., 2007). The decrease in animal size from genetic or caloric interventions and lower oxyradical damage could reflect a slower rate of living (Pearl, 1928). However, recent evidence from Westbrook and Bartke suggests metabolism as VO2 and heat/gm body mass actually increases in genetically long-lived mice with decreased insulin signaling (Westbrook et al., 2009). This unexpected finding conflicts with a slower rate of living theory in terms of lower lifetime oxygen input to generate lower oxyradicals. Further, although the resting metabolic rate seems to decrease with age in humans, a study of 28 long-lived people (>95 years old) indicated an actual increase in metabolic rate compared to 27 aged subjects (66–94 years old) (Rizzo et al., 2005). And yeast grown in low glucose to increase life-span actually respires at higher rates with less ROS than normal glucose (Barros et al., 2004). Numerous caloric or dietary restriction studies in rodents that result in increased longevity are also associated with lower activities of the insulin signaling pathway that regulates much of glucose energy intake (Masternak et al., 2005). However, the lower levels of ROS observed from this intervention are not easily explained if the rate of metabolism is not decreased, but increased (Westbrook et al., 2009) (Table 1).

Section snippets

The epigenetic oxidative redox shift (EORS) theory of aging

I propose that a metabolically initiated redox shift is upstream of the commonly observed increase in ROS damage to macromolecules. This shift with age occurs in the oxidized direction of the relative levels of important reductants and oxidants. It manifests as an extracellular decrease in the ratio of cysteine/cystine and an intracellular decrease in the ratio of GSH/GSSG and NAD(P)H/NAD(P). The oxidized redox shift is initiated by low demand for bursts of energy produced by mitochondria. The

Why redox state is more important than ROS

In order to begin to resolve these paradoxes, I propose that an oxidized redox state is upstream of the commonly observed ROS damage. Certainly, ROS damage is affected by the balance of oxyradical generation and anti-oxidant defenses. Numerous sources of oxyradical generation have been documented (Cohen, 1994), but less appreciation exists for the essential role that ROS or redox signaling plays in metabolism (Droge, 2002, Finkel, 2003). The common impression that the mitochondrial electron

Evidence for an oxidizing shift in redox state with age

Dean Jones at Emory University was the first to show that human plasma GSH/GSSG is controlled at a relatively constant redox state of −137 mV in 740 healthy adults through age 50 (Jones, 2006). However, an oxidative shift of about 7 mV/decade occurs over the next two decades, followed by a further decline to −110 mV in the 70- to 85-year-old group. In a longitudinal study, patients with age-related macular degeneration were observed at age 72 to decline from −121 mV to −118 mV over a 4-year period,

Dependence of metabolism on redox state and age

The obligate requirement for the oxidizing power of NAD+ to produce two ATP/glucose during glycolysis must be accompanied by a corresponding regeneration of NADH to NAD+ (Fig. 2). Since cellular energy is largely used to maintain ionic homeostasis, the large demands for ATP are most easily met by mitochondrial consumption of NADH at complex I (NADH oxidoreductase) generating up to 36 more ATP/glucose while regenerating NAD+ oxidizing power. However, in periods of high energy demand, oxygen

Redox dependence of insulin signaling

The well-known insulin signaling system leads to insertion of GluT4 glucose transporters into the plasma membrane to stimulate glucose uptake outside the brain (Fig. 4). In the brain, a different glucose transporter with a higher affinity for glucose, GluT3, ensures essential glucose uptake into the brain even during fasting. Surprisingly, the brain is also sensitive to endogenous insulin signaling through a similar pathway (Uemura and Greenlee, 2006). Further downstream in insulin signaling,

Caloric restriction

Mostly studied in mice and rats, caloric restriction with full vitamin and mineral supplementation prolongs life-span, reduces ROS damage, reduces inflammation, increases insulin sensitivity and decreases the incidence of cancer, even in human studies (Heilbronn et al., 2006, Fontana and Klein, 2007). Two landmark studies in mice showed strong evidence for increased mitochondrial function with caloric restriction in muscle (Desai et al., 1996) and fat tissue (Higami et al., 2004), which were

Epigenetic control imposed by a metabolic shift toward an oxidized redox state

Epigenetic controls are the histone acetylations, methylations, phosphorylations and sumolations and cytosine methylations that control gene expression (Fraga et al., 2005, Feinberg, 2008, Sedivy et al., 2008). In general, histone acetylation facilitates the removal of transcription-blocking histone tails from DNA. Methylation of CpG islands, often in the upstream regulatory sequences of a gene, blocks the binding of RNA polymerase. Both processes control differentiation and contribute to

How aging could induce an oxidized metabolic redox shift that drives epigenetic changes, insulin resistance and ROS damage in a downward spiral

Aging is often associated with a sedentary life style (Fig. 5). If there are no demands for the extra energy that can be produced by aerobic oxidative phosphorylation, then cells and organs may down-regulate the electron transport chain components and survive adequately on glycolysis (Fig. 2). Increased consumption of sugar in beverages (Sanchez-Lozada et al., 2008, Johnson et al., 2009) may also enforce reliance on glycolysis. An oxidative shift is proposed to ensure ample supplies of the

Acknowledgments

I thank Dean Jones for inspiring discussions on redox energetics. This work was supported in part by the NIA RO1 AG13435, AG032431 and the Kenneth Stark Endowed Chair in Alzheimer Research.

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