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In vitro proinflammatory gene expression predicts in vivo telomere shortening: A preliminary study.

Department of Biochemistry and Biophysics, University of California, 600 16thStreet, San Francisco, CA 94158, United States. Electronic address: jue.lin@ucsf.edu. Department of Biochemistry and Biophysics, University of California, 600 16thStreet, San Francisco, CA 94158, United States. Electronic address: jiesun316@gmail.com. Department of Biochemistry and Biophysics, University of California, 600 16thStreet, San Francisco, CA 94158, United States. Electronic address: stephaniewang93@gmail.com. Division of Experimental Medicine, University of California San Francisco, Building 100, 1001 Potrero Ave, San Francisco, CA, 94110, United States. Electronic address: Jeffrey.Milush@ucsf.edu. Division of Experimental Medicine, University of California San Francisco, Building 100, 1001 Potrero Ave, San Francisco, CA, 94110, United States. Electronic address: Chris.Baker@ucsf.edu. Department of Psychiatry, University of California, 3333 California St, Suite 465, San Francisco, CA 94143, United States. Electronic address: Michael.Coccia@ucsf.edu. Department of Pathology and Lab Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, 90095, United States. Electronic address: reffros@mednet.ucla.edu. School of Kinesiology, University of British Columbia, 6081 University Blvd, Vancouver, BC, V6T 1Z1, Canada. Electronic address: eli.puterman@ubc.ca. Department of Biochemistry and Biophysics, University of California, 600 16thStreet, San Francisco, CA 94158, United States. Electronic address: Elizabeth.Blackburn@ucsf.edu. Department of Psychiatry, University of California, 3333 California St, Suite 465, San Francisco, CA 94143, United States. Electronic address: Aric.Prather@ucsf.edu. Department of Psychiatry, University of California, 3333 California St, Suite 465, San Francisco, CA 94143, United States. Electronic address: Elissa.Epel@ucsf.edu.

Psychoneuroendocrinology. 2018;:179-187
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Abstract

The chronic psychological stress of caregiving leads to higher risks for many diseases. One of the mechanisms through which caregiving is associated with disease risk is chronic inflammation. Chronic inflammation may accelerate cellular aging via telomere dysfunction and cell senescence, although this has not been examined in human cells from healthy people. We examined peripheral blood mononuclear cells (PBMCs) from 20 healthy mothers of children with autism (caregivers) and 19 mothers of neurotypical children (controls) in an in vitro culture system where PBMCs were stimulated with phytohaemagglutinin (PHA). We measured RNA expression levels of a panel of immune function genes before and after PHA stimulation, as well as telomere length from PBMCs collected from the participants at baseline and 15 months later. Caregivers and controls had similar gene expression profiles in unstimulated PBMCs, but after PHA stimulation, caregivers had increased RNA levels of the master inflammatory regulator NF-κB and its proinflammatory cytokine targets IL-1β, IL-6 and its receptor IL-6R as well as inflammatory chemokines IL-8, CXCL1 and CXCL2. Gene expression analysis suggested caregivers have increased Treg and Th17 T cell differentiation. Additionally, key signaling molecules involved in the upregulation of COX-2, a critical enzyme in the synthesis of the inflammatory mediator prostaglandin, were elevated. When both groups were examined together, higher expression levels of proinflammatory genes were associated with shorter telomere length in PBMCs from blood drawn 15 months later, independent of baseline telomere length. Taken together, these results suggest that chronic stress is associated with an exaggerated inflammatory response in PBMCs, which in turn is associated with shorter telomere length measured from PBMCs collected 15 months later. To our knowledge, this is the first human study that shows increased proinflammatory expression predicts future telomere shortening.