Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

Abstract

The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress) signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility) may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest that as oxidative stress determines functional longevity, a rather more descriptive term for the metabolic syndrome is the 'lifestyle-induced metabolic inflexibility and accelerated ageing syndrome'. Ultimately, thriftiness is good for us as long as we have hormetic stimuli; unfortunately, mankind is attempting to remove all hormetic (stressful) stimuli from his environment.

Figure 1

Insulin resistance protective cycle – the underlying principle for 'redox-thriftiness'.

Figure 2

The tipping point and the metabolic syndrome. Without hormesis, and in the presence of excess calories, VAT can build up, which is associated with excessive ectopic fat due to metabolic inflexibility. This is associated with rising oxidative stress and a shift from thrifty to inflammatory insulin resistance; this results in the metabolic syndrome and an accelerated ageing phenotype.

Figure 3

How polyphenols might work. Blocking or modulating growth and stress signalling reduces growth drive and redox stress, so reducing need for activation of 'growth' stress inhibitory pathways (e.g. JNK). Mildly inhibiting mitochondrial function may decrease ATP and increase ROS, which is a strong stimulus for mitochondrial biogenesis (it is a hormetic signal), resulting in an enhanced anti-inflammatory/ROS cellular phenotype (1). However, excessive inhibition of this pathway may induce apoptosis in some cell types (2). This paradigm might follow the general evolutionary function of these polyphenols in plants: improved resistance to stress and pathogens.

Figure 4

Depictions of metabolic flexibility. The metabolic flexibility 'bowl' and metabolic 'adaptability envelope'.

Figure 5

Oxidative stress increases insulin resistance. Oxidative stress increases insulin resistance, which is a feedback mechanism to reduce oxidative stress that is modulated by mitochondrial function.