A case of evolutionary mismatch?

Background and objectives: Human susceptibility to chronic non-communicable disease may be explained, in part, by mismatches between our evolved biology and contemporary environmental conditions. Disease-induced fatigue may function to reduce physical activity during acute infection, thereby making more energy available to mount an effective immune response. However, fatigue in the context of chronic disease may be maladaptive because long-term reductions in physical activity increase risks of disease progression and the acquisition of additional morbidities. Here, we test whether cumulative chronic morbidity is associated with subjective fatigue. Methodology: We constructed a cumulative chronic morbidity score using self-reported diagnoses and algorithm-based assessments, and a subjective fatigue score based on four questionnaire items using cross-sectional survey data from the Study on global AGEing and adult health, which features large samples of adults from six countries (China, Ghana, India, Mexico, Russia and South Africa). Results: In a mixed-effects linear model with participants nested in countries (N1⁄4 32 455), greater cumulative chronic morbidity is associated with greater subjective fatigue (b1⁄4 0.34, SE1⁄4 0.005, P< 2e 16). This association replicates within each country and is robust to adjustment for key sociodemographic and physical covariates (sex, age, household wealth, physical function score, habitual physical activity, BMI and BMI). VC The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 156 ORIGINAL RESEARCH ARTICLE Evolution, Medicine, and Public Health [2022] pp. 156–169 https://doi.org/10.1093/emph/eoac011 Conclusions and implications: Fatigue is a common but perhaps maladaptive neuropsychological response to chronic morbidity. Disease-induced fatigue may mediate a self-perpetuating cycle, in which chronic morbidity reduces physical activity, and less physical activity increases cumulative chronic morbidity. Longitudinal research is needed to test whether chronic morbidity, fatigue and physical activity form a cyclical feedback loop. Lay Summary: Fatigue during acute illness may promote recovery, but persistent fatigue in the context of chronic disease may make matters worse. We present evidence from six countries that more chronic disease is associated with more fatigue. This fatigue may reduce physical activity, which increases risks of acquiring additional chronic health problems. K E Y W O R D S : chronic diseases; mental health; aging; epidemiology BACKGROUND AND OBJECTIVES Chronic non-communicable diseases (e.g. heart diseases, diabetes and cancer) now account for most of the global burden of death and disability [1, 2]. Epidemics of chronic disease tend to emerge in environments where extrinsic mortality rates are relatively low and obesity rates are relatively high [3]. These chronic non-communicable diseases were likely rare throughout the vast majority of our evolutionary history [4]. Obesity-related chronic disease risk factors are rare in contemporary hunter-gatherers and other minimally market-integrated subsistence societies [5, 6]. Infectious diseases, on the other hand, account for 20–85% of deaths in contemporary and ethnographically known hunter-gatherer groups [7–12]. The rise of agriculture (starting 10–15 000 BP) brought about new sources of infectious disease risk, with dense population centers and proximity to domesticated animals [13]. Despite periodic pandemics (e.g. COVID-19, influenza and HIV/AIDS), global infectious disease mortality rates have declined in the past 100–200 years [14] and rates of obesity have increased [15]. In many countries, obesity was once associated with high socioeconomic status but is now prevalent across social strata and disproportionately impacts those of low socioeconomic status [16, 17]. Reductions in global infectious disease mortality have been accompanied by an increase in life expectancy at birth, along with a dramatic increase chronic non-communicable disease [1–3]. Along with changes in diet and reductions in subsistence-related physical activity, longer average lifespans have led to a higher prevalence of aging-related chronic conditions (e.g. cardiometabolic diseases and cancers) [1–3]. Mortality from agingrelated diseases was relatively rare for most of human evolutionary history, in part because fewer individuals lived long enough to die of these aging-related diseases [3]. In contrast, infectious disease has been a persistent cause of morbidity and mortality across the lifespan for most of our evolutionary history [7–12]. Our somatic maintenance systems may therefore be poorly adapted to prevent the kinds of morbidity and mortality that are most common in aging populations that consume highly processed, calorie-dense diets and exhibit low levels of physical activity [4]. In populations that have experienced evolutionarily novel increases in the average life expectancy, there is considerable variability in healthy aging [18]. Some individuals experience multiple decades of disabilityfree life in older adulthood, while other individuals experience rapid decline in functional status with age. Research is needed to identify processes across the lifecourse that explain this variation in healthy aging. Given the rapid, recent rise of chronic non-communicable diseases as a major source of morbidity and mortality, our evolved brains and bodies may be poorly equipped to deal with these diseases [19]. Much of our susceptibility to chronic disease may be explained by mismatches between our evolved biology and contemporary environmental conditions [4]. For example, humans have a propensity to generate large fat reserves when it is nutritionally feasible [20]. In the environments typical of our evolutionary history, the capacity to form large fat deposits provided a mechanism to maintain a stable energy supply for funding the high metabolic costs of maintaining our large brains, supporting multiple dependent offspring, foraging and lactating during extended periods of negative energy balance [21, 22]. In contemporary environments characterized by calorie-dense foods and sedentary lifestyles, our propensity for adiposity makes us vulnerable to obesity. Along the same lines, human immune systems seem to be mismatched with contemporary environments that are low in microbial diversity and feature low rates of exposure to infectious pathogens that were common for most of our evolutionary history (e.g. parasitic worms) [23, 24]. This lack of exposure to our long-time microbial and macroparasitic co-evolutionary companions influences the development of our immune systems, making us vulnerable to allergies, autoimmune diseases and inflammation-related disorders [24, 25]. In this article, we consider another feature of our evolved biology that appears to be mismatched with contemporary environments—disease-induced fatigue. Multiple lines of evidence suggest that disease-induced fatigue evolved to promote host survival during acute infection. But like chronic inflammation, fatigue may be counterproductive when it is deployed chronically in response to chronic noncommunicable diseases. Chronic disease and fatigue: a case of evolutionary mismatch? Schrock et al. | 157