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

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.

Fig 1

Biological redox energy scale. The highly reduced energy levels of NADPH, GSH and NADH are used to power catabolism with molecular oxygen as the terminal electron acceptor. The step-wise electron transport in mitochondria is used to generate ATP, a lower denomination of energy currency.

Fig. 2

Three alternative mechanisms for energy production that maintain NAD⁺ levels for glycolysis and redox balance. 1) NADH is consumed by complex one of the electron transport chain with low levels of oxyradical production. In aerobic glycolysis, 2) lactate dehydrogenase reduces pyruvate to lactic acid and 3) the plasma membrane NAD(P)H oxidoreductase (NOX) stoichiometricly produces one oxygen radical anion for every NADH reoxidized, relying on antioxidant defenses.

Fig. 3

Oxidative shift in NADH/NAD redox levels with age in old rat brains and in neurons isolated from them. Adapted from (Parihar et al., 2008).

Figure 4

Insulin and IGF1 signaling pathway to promote glucose uptake by GluT3 in neurons (shown) or GlutT4 in muscle (not shown). Note redox-sensitive cysteines (yellow dots) in the insulin and IGF1 receptors, in protein tyrosine phosphatase (PTP1b) and in Keap1. In insulin resistance, constitutive phosphorylation (red dots) activates the NOX enzyme which generates higher levels of oxyradicals (3) and NADH is recycled by lactate dehydrogenase (LDH, broken red line). See text for more details.

Fig. 5

Use it or lose it, the downward spiral of aging enforced by an epigenetic oxidized redox shift (EORS).