A multimodal Darwinian strategy for alleviating the atherosclerosis pandemic

Abstract

The conflict between our ‘primitive’ genes and ‘modern’ lifestyle probably lies at the root of several disorders that afflict modern man. Atherosclerosis, which is relatively unknown among contemporary hunter-gatherer populations, has reached pandemic proportions in recent times. Being an evolutionary problem with several inter-related pathologies, current therapeutic strategy for treating atherosclerosis has inherent limitations. Reviewing evolution-linked risk factors suggests that there are four aspects to the etiology of atherosclerosis namely, decreased intestinal parasitism, oversensitivity of evolutionarily redundant mast cells, chronic underactivation of AMPK (cellular energy sensor) and a deficiency of vitamin D. A combination of these four causes appear to have precipitated the atherosclerosis pandemic in modern times. Man and worms co-existed symbiotically in the past. Massive de-worming campaigns could have disrupted this symbiosis, increasing nutritional availability to man (pro-obesity) at the cost of decreased immunotolerance (pro-atherogenicity). A reduction in helminth-induced chronic T_H2 activation could also have enhanced T_H1 polarization, eventually disrupting the reciprocal regulation of T_H1/T_H2 balance and resulting in atherosclerosis. The riddance of helminth infestations may have rendered mast cells immunologically redundant, making them oversensitive to inflammatory stimuli, thereby playing a pro-atherogenic role. AMPK activation exerts pleiotropic anti-atherogenic effects, such as suppression of fatty acid, cholesterol, protein synthesis, reduction of vascular smooth muscle proliferation, etc. As energy deficit is the chief stimulus for AMPK activation, the over-nourished modern man appears to be suffering from chronic underactivation of AMPK, legitimising the unrivalled supremacy of metformin, the oldest prescribed antidiabetic drug. The fact that humans evolved in the sunny tropics suggests that humans are selected for high vitamin D levels. Vitamin D deficiency is now linked to several conditions including increased risk of CV disorders, diabetes, etc. The manifold decrease in vitamin D levels in modern man justifies a need for supplementation. We therefore hypothesize that a judicious combination of mast cell stabilization, AMPK activation, vitamin D supplementation, and moderation in hygiene practices could be an evolution-based multimodal strategy for both preventing and mitigating the pandemic of atherosclerosis.

Introduction

“Nothing in biology makes sense except in the light of evolution” – Theodosius Dobzhansky

Modern man, relentlessly plagued by an inescapable conflict between ‘primitive’ genes and modern lifestyle [1], is suffering from several disorders that were unknown when people had little to eat and were less obsessed about hygiene [2]. The etiology of atherosclerosis appears to be linked to human evolution [3]. A cursory glance tells us that risk factors for atherosclerosis are rare among contemporary hunter-gatherer populations [4], [5]. Though calcified arterial plaques have been found in mummies of hunter-gatherers [6], this may be attributed to conditions other than atherosclerosis, because of the preordained role of dyslipidemia in atherosclerosis [7]. Interestingly, even today, cardiovascular (CV) events are low in developing countries with poor nutrition, sanitation and massive worm infections [8]. Modern lifestyle plays an important role in the development of atherosclerosis [7]. The global epidemic of atherosclerosis is perhaps an outcome of an evolutionary conflict.

A comprehensive review by Weber et al. [9] in Nature Reviews Immunology elaborates the involvement of different leucocytes subtypes in atherosclerosis, including mast cells, T cells and vascular smooth muscle progenitor cells. Conventional therapy for atherosclerosis comprises a combination of lifestyle changes and drugs that individually target risk factors such as obesity, diabetes, hypertension, dyslipidemia, etc. Nevertheless, current drug therapy fails to target the root cause of atherosclerosis [10], because it addresses only the risk factors in a fragmented manner. We hypothesize an evolution-based multimodal therapeutic strategy to mitigate atherosclerosis, which comprehensively addresses multiple targets and offers a holistic solution compatible with modern lifestyle.