Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife

Christiane Elisabeth Sørensen, Katerina Tritsaris, Jesper Reibel, Martin Lauritzen, Erik Lykke Mortensen, M. Osler, Anne Marie Lynge Pedersen

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Background The cell-cycle inhibitor and tumor suppressor cyclin dependent kinase inhibitor, p16(ink4a), is one of the two gene products of the ink4a/ARF (cdkn2a) locus on chromosome 9q21. Upregulation of p16(ink4a) has been linked to cellular senescence, and findings from studies on different mammalian tissues suggest that p16(ink4a) may be a biomarker of organismal versus chronological age. Objective The aim of this study was to examine the immunolocalization pattern of p16(ink4a) in human labial salivary gland (LSG) tissue, and to analyze whether its expression level in LSGs is a peripheral correlate of cognitive decline in late midlife. Methods The present study was a part of a study of causes and predictors of cognitive decline in middle-aged men in a Danish birth cohort. It is based on data from 181 male participants from the Danish Metropolit birth cohort, born in 1953, who were examined for age-associated alterations in cognition, dental health, and morphological and autonomic innervation characteristics of the LSGs. The participants were allocated to two groups based on the relative change in cognitive performance from young adulthood to late midlife. LSG biopsies were analyzed by qRT-PCR for the expression level of p16(ink4a). Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of LSGs. Results p16(ink4a) immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells. The mean relative expression of p16(ink4a) in LSGs was higher in the group of participants with decline in cognitive performance. A logistic regression analysis revealed that the relative p16 expression was predictive of the participant's group assignment. A negative correlation was found between relative p16(ink4a) expression and the participant's standardized regression residuals from early adulthood to late midlife cognitive performance scores. Conclusions p16(ink4a) expression in human LSGs may constitute a potential peripheral correlate of cognitive decline. Human labial salivary glands seem suitable for studies on organismal as opposed to chronological age.
Original languageEnglish
Article number e0152612
Issue number3
Number of pages11
Publication statusPublished - 2016

Bibliographical note

ISI Document Delivery No.: DH9LB Times Cited: 0 Cited Reference Count: 37 Sorensen, Christiane Elisabeth Tritsaris, Katerina Reibel, Jesper Lauritzen, Martin Mortensen, Erik Lykke Osler, Merete Pedersen, Anne Marie Lynge Soerensen, Christiane/0000-0001-6814-1166; Osler, Merete/0000-0002-6921-220X Nordea Foundation; Danish Dental Association Research Foundation (KOF/FORSKU); Velux Foundation The Nordea Foundation funded this study. CES received funding for the study from the Danish Dental Association Research Foundation (KOF/FORSKU). The Velux Foundation funded the Copenhagen Aging and Midlife Biobank project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 0 Public library science San francisco


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