Weakened Cholinergic Blockade of Inflammation Associates with Diabetes-Related Depression

Abstract

Emerging evidence demonstrates association of depression with both immune malfunctioning and worsened course of diverse aging-related diseases, but there is no explanation for the pathway(s) controlling this dual association. Here, we report that in post-reproductive and evolutionarily -blind" years, depression may weaken pathogen-host defense, compatible with the antagonistic pleiotropy hypothesis. In 15,532 healthy volunteers, depression scores associated with both inflammatory parameters and with increased circulation cholinesterase activities, implicating debilitated cholinergic blockade of inflammation as an underlying mechanism; furthermore, depression, inflammation and cholinesterase activities all increased with aging. In the entire cohort, combined increases in inflammation and the diabetic biomarker hemoglobin A1c associated with elevated depression. Moreover, metabolic syndrome patients with higher risk of diabetes showed increased cholinesterase levels and pulse values, and diabetic patients presented simultaneous increases in depression, inflammation and circulation cholinesterase activities, suggesting that cholinergic impairment precedes depression. Our findings indicate that dysfunctioning cholinergic regulation weakens the otherwise protective link between depression and pathogen-host defense, with global implications for aging-related diseases.

Figure 1.

Hierarchical plot of predictors of residual depression. Circles are color-coded by the calculated effect on residual depression (increase or decrease; scale). Of 20 physiological, psychological and medical parameters entered into the model, chronic pain, smoking, sport activity, inflammation parameters, and BMI all emerged as significant predictors. Note that chronic pain increases the residual depression (top row), whereas in pain-free volunteers, smoking increases the residual depression (second row), and over 1.94 exercise hours per week (third row, middle panel) elevated depression scores.

Figure 2.

Depression, inflammation and cholinergic activities increase with age. Depression scores (sum of 9 items of the “Patient Health Questionnaire– (PHQ)), Inflammation (as reflected by the erythrocyte sedimentation rate, ESR, mm/h) and cholinergic enzymatic activities (Cholinergic status, CS, the total capacity for acetylcholine hydrolysis, nmol substrate hydrolyzed/min per ml (19)) all increase with age in both genders. (Statistics: ANOVA of 4 age groups).

Figure 3.

Longer life expectancy in countries with lower historical pathogen load. (A) Mean mortality rate under 5 years (per 1,000 live births) and (B) life expectancy (data from http://data.worldbank.org/) were plotted against historical pathogen load values based on the presence of nine diseases (leishmanias, schistosomes, trypanosomes, leprosy, malaria, typhus, filariae, dengue and tuberculosis) taken from Murray and Schaller score (13). (C) Countries were divided to three equal parts reflecting escalating values of historical pathogen load. This analysis revealed that the higher the pathogen-load the lower total life expectancy (p < 0.001). (D) To avoid irrelevant death causes (for example, war or famine) we further focused this analysis of life expectancy on countries with mean life expectancy above 70 (p < 0.001). (E) The historical pathogen load and mean mortality under 5 years (per 1,000 live births) scores (p < 0.001).

Figure 4.

Co-increased depression and inflammation in apparently healthy and diabetic participants. (A) Inflammation associates with depression scores in healthy volunteers. Shown are serum C-reactive protein levels in mg/L as a function of total PHQ score. (B) Cholinergic status increase with the number of metabolic syndrome components. (C) Depression in diabetic patients is higher than in controls. (D) Cholinergic status in diabetic patients is larger than in controls. (E) The vicious cycle of cholinergic blockade of inflammation and depression. With aging, increasing cholinesterase (ChE) activities reduce acetylcholine (ACh) levels, interfering with the blockade of inflammation by ACh and potentiating depression that may reciprocally increase ChE activities.

Figure 5.

Triple association of hemoglobin A1c, inflammation and depression scores. Association of Hemoglobin A1c, white blood cells counts (WBCC) and depression score (PHQ). Each score presents the differences between the observed and expected value for individuals with the same age, gender and BMI. Depression scores (color code) were Square-root transformed. Note the increasing tendency for depression (blue) in those participants with higher values of both hemoglobin A1c and WBCC.