Chronic inflammatory systemic diseases: An evolutionary trade-off between acutely beneficial but chronically harmful programs

Abstract

It has been recognized that during chronic inflammatory systemic diseases (CIDs) maladaptations of the immune, nervous, endocrine and reproductive system occur. Maladaptation leads to disease sequelae in CIDs. The ultimate reason of disease sequelae in CIDs remained unclear because clinicians do not consider bodily energy trade-offs and evolutionary medicine. We review the evolution of physiological supersystems, fitness consequences of genes involved in CIDs during different life-history stages, environmental factors of CIDs, energy trade-offs during inflammatory episodes and the non-specificity of CIDs. Incorporating bodily energy regulation into evolutionary medicine builds a framework to better understand pathophysiology of CIDs by considering that genes and networks used are positively selected if they serve acute, highly energy-consuming inflammation. It is predicted that genes that protect energy stores are positively selected (as immune memory). This could explain why energy-demanding inflammatory episodes like infectious diseases must be terminated within 3-8 weeks to be adaptive, and otherwise become maladaptive. Considering energy regulation as an evolved adaptive trait explains why many known sequelae of different CIDs must be uniform. These are, e.g. sickness behavior/fatigue/depressive symptoms, sleep disturbance, anorexia, malnutrition, muscle wasting-cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, alterations of steroid hormone axes, disturbances of the hypothalamic-pituitary-gonadal (HPG) axis, hypertension, bone loss and hypercoagulability. Considering evolved energy trade-offs helps us to understand how an energy imbalance can lead to the disease sequelae of CIDs. In the future, clinicians must translate this knowledge into early diagnosis and symptomatic treatment in CIDs.

Keywords: disease sequelae; energy regulation; inflammatory systemic disease; neuroendocrine immunology.

Figure 1.

Incidence rate of rheumatoid arthritis (RA). The black line indicates the normal situation with a menopause starting at 45 years of age. The red line demonstrates a fictitious situation with accelerated menopause years before

Figure 2.

There is a critical difference between typical inflammation and chronic inflammatory systemic diseases, which separates the asymptomatic phase from the symptomatic phase of a chronic inflammatory systemic disease, the asymptomatic-symptomatic-threshold (a-s-threshold). Importantly from an evolutionary point of view, reproduction is only impeded during the symptomatic, but not during the asymptomatic phase. Genes enabling an adaptive inflammatory response, allowing the organism to overcome an infection, will thus increase survival probability and the potential for future reproduction and as such evolutionary fitness in young age. After initiation of chronic systemic inflammation, however, reproduction is inhibited, and this for prolonged periods, often for years and until death, causing fitness costs. However, as these costs typically occur only at the end of the reproductive life-history stage or in post-reproductive age, these fitness costs are lower than the fitness benefits in early life leading to an overall increase in Darwinian fitness