Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling

Abstract

Children reared in unfavorable socioeconomic circumstances show increased susceptibility to the chronic diseases of aging when they reach the fifth and sixth decades of life. One mechanistic hypothesis for this phenomenon suggests that social adversity in early life programs biological systems in a manner that persists across decades and thereby accentuates vulnerability to disease. Here we examine the basic tenets of this hypothesis by performing genome-wide transcriptional profiling in healthy adults who were either low or high in socioeconomic status (SES) in early life. Among subjects with low early-life SES, there was significant up-regulation of genes bearing response elements for the CREB/ATF family of transcription factors that conveys adrenergic signals to leukocytes, and significant down-regulation of genes with response elements for the glucocorticoid receptor, which regulates the secretion of cortisol and transduces its antiinflammatory actions in the immune system. Subjects from low-SES backgrounds also showed increased output of cortisol in daily life, heightened expression of transcripts bearing response elements for NF-kappaB, and greater stimulated production of the proinflammatory cytokine interleukin 6. These disparities were independent of subjects' current SES, lifestyle practices, and perceived stress. Collectively, these data suggest that low early-life SES programs a defensive phenotype characterized by resistance to glucocorticoid signaling, which in turn facilitates exaggerated adrenocortical and inflammatory responses. Although these response patterns could serve adaptive functions during acute threats to well-being, over the long term they might exact an allostatic toll on the body that ultimately contributes to the chronic diseases of aging.

Fig. 1.

Transcriptional activity of CREB, GR, and NF-κB signaling pathways. TELiS bioinformatics analysis compared the prevalence of response elements in the promoters of differentially expressed genes. Data represent the ratio (±SE) of response element prevalence in promoters of genes up-regulated in subjects with low early-life SES relative to genes up-regulated in subjects with high early-life SES.

Fig. 2.

IL6 production by early-life SES. PBMCs were cultured for 24 h with ligands against TLRs. After supernatants were harvested, the proinflammatory cytokine IL6 was measured by ELISA. Low early-life SES was associated with increased production of IL6 in cultures stimulated with (A) the TLR3 ligand poly(I:C) (P = 0.03) and (B) the TLR5 ligand flagellin (P = 0.05).

Fig. 3.

Diurnal cortisol output by early-life SES. Subjects collected saliva 6 times daily for 3 days, and cortisol was measured by immunoassay. Low early-life SES was associated with a relative increase in overall cortisol output across the monitoring period (P = 0.04). There were no SES differences in magnitude of the waking response or the shape of the diurnal rhythm across the day (P > 0.77).