Secrets of the lac Operon

Abstract

Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in ␤-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

“…A key element of this model is that the protective effects of dietary restriction do not require reduction in metabolic rate, that is, the mechanism is “ATP-neutral”. In fact, generation of ATP from glucose metabolism requires less oxygen per ATP molecule than generation of ATP from lipid metabolism, but also produces more oxidative stress [26, 27]. Therefore the protective effects of dietary restriction may actually require increased oxygen consumption, consistent with reported results [2, 3].…”

“…This hypothesis is supported by evidence that dietary restriction entails a metabolic switch away from glucose utilization and toward beta oxidation [26, 27]. Of particular importance, inhibition of Cbp prevents this switch and also prevents the protective effects of dietary restriction [6].…”

“…The precise mechanisms by which glucose metabolism is relatively more toxic than lipid, amino acid, or ketone metabolism are complex. However mechanisms mediating toxic effects of glucose metabolism probably entail increased production of oxidative stress (in part due to increased NADH), reduced ability to counter oxidative stress (in part due to reduced production of NADPH), reduced turnover of oxidized protein and lipids, a pattern originally observed in VMH but probably exhibited by most tissues [26, 27] (Figure 1). …”

“…However, BDNF and Sf-1 neurons in the VMN, which are stimulated by glucose and inhibition of which causes obesity [60] likely also play a role, plausibly in part by reciprocally activating POMC neurons, which in turn play a dominant role in regulating peripheral glucose homeostasis [61, 62] (Figure 2). A cumulative and persistent effect of glucose to activate these and POMC neurons, and possibly reduce Ppar-alpha and Cbp activity, may also drive increased glucose metabolism during aging, potentially accounting for weight loss, impaired counterregulation, and anorexia that occurs late in life [26]. …”

A novel kinase regulates dietary restriction‐mediated longevity in Caenorhabditis elegans

“…The electrons from NADH and FADH2 enter ETC at Complex I and Complex II, respectively. During beta-oxidation, relatively more Complex II is utilized to transfer electrons to ETC, compared to when glucose is the sole source of energy (Mobbs et al ., 2007). We reasoned that if we disrupt Complex II activity, mekk-3 knock-down may not be able to extend lifespan.…”