title: Elevated p16ink4a Expression in Human Labial Salivary Glands as a Potential Correlate of Cognitive Aging in Late Midlife.
abstract: BACKGROUND
  The cell-cycle inhibitor and tumor suppressor cyclin dependent kinase inhibitor, p16ink4a, is one of the two gene products of the ink4a/ARF (cdkn2a) locus on chromosome 9q21. Up-regulation of p16ink4a has been linked to cellular senescence, and findings from studies on different mammalian tissues suggest that p16ink4a may be a biomarker of organismal versus chronological age.
  
  
  OBJECTIVE
  The aim of this study was to examine the immunolocalization pattern of p16ink4a 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 p16ink4a. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of LSGs.
  
  
  RESULTS
  p16ink4a immunoreactivity was observed in LSG ductal, myoepithelial, and stromal cells, but not in acinar cells. The mean relative expression of p16ink4a 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 p16ink4a expression and the participant's standardized regression residuals from early adulthood to late midlife cognitive performance scores.
  
  
  CONCLUSIONS
  p16ink4a 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.
authors.affiliation: Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christiane Elisabeth
authors.initials: CE
authors.lastname: Sørensen
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katerina
authors.initials: K
authors.lastname: Tritsaris
authors.affiliation: Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Reibel
authors.affiliation: Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, and Department of Clinical Neurophysiology, Rigshospitalet-Glostrup, Glostrup, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauritzen
authors.affiliation: Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Danish Aging Research Center, Universities of Aarhus, Southern Denmark and Copenhagen, Odense, Denmark.
authors.forename: Erik Lykke
authors.initials: EL
authors.lastname: Mortensen
authors.affiliation: Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Danish Aging Research Center, Universities of Aarhus, Southern Denmark and Copenhagen, Odense, Denmark.|Research Center for Prevention and Health, Rigshospitalet-Glostrup, Glostrup, Denmark.
authors.forename: Merete
authors.initials: M
authors.lastname: Osler
authors.affiliation: Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne Marie Lynge
authors.initials: AM
authors.lastname: Pedersen
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D000066492:Cognitive Aging / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D003718:Denmark; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012469:Salivary Glands / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16