title: Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver.
abstract: Telomeres, a validated biomarker of aging, comprise multiple nucleotide repeats capping chromosomes that shorten with each cell cycle until a critical length is achieved, precipitating cell senescence. Only two previous studies focused on the effect of aging in "normal" liver tissue, but these studies were compromised by small sample size, limited age range, tissue derived from individuals with an increased risk of senescence, and the use of liver homogenates. We developed a robust large-volume, four-color quantitative fluorescent in situ hybridization technique to measure telomere length in large numbers of hepatocytes, Kupffer cells, hepatic stellate cells, CD4-positive and CD8-positive lymphocytes, and cholangiocytes. Following validation against the gold standard (Southern blotting), the technique was applied to normal archived paraffin-embedded liver tissue obtained following reperfusion of implanted donor liver. We studied 73 highly selected donors aged 5-79 years with a short medical illness preceding death and no history of liver disease, reperfusion injury, or steatosis and normal graft function 1-year posttransplantation. Cholangiocytes had significantly longer telomeres compared with all other intrahepatic lineages over a wide age range (P < 0.05). Age-related telomere attrition was restricted to sinusoidal cells (i.e., Kupffer cells [P = 0.0054] and stellate cells [P = 0.0001]). Cholangiocytes and hepatocytes showed no age-related telomere shortening.
  
  
  CONCLUSIONS
  In normal liver and over a broad age range, cholangiocytes have longer telomeres than all other intrahepatic lineages. Age-related telomere length decline is restricted to Kupffer cells and stellate cells.
authors.affiliation: Division of Gastroenterology & Hepatology, University Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Suman
authors.initials: S
authors.lastname: Verma
authors.forename: Phaedra
authors.initials: P
authors.lastname: Tachtatzis
authors.forename: Sue
authors.initials: S
authors.lastname: Penrhyn-Lowe
authors.forename: Cinzia
authors.initials: C
authors.lastname: Scarpini
authors.forename: Diana
authors.initials: D
authors.lastname: Jurk
authors.forename: Thomas
authors.initials: T
authors.lastname: Von Zglinicki
authors.forename: Nick
authors.initials: N
authors.lastname: Coleman
authors.forename: Graeme J M
authors.initials: GJ
authors.lastname: Alexander
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D001652:Bile Ducts / Q000166:cytology* / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007728:Kupffer Cells / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D015203:Reproducibility of Results; D018570:Risk Assessment; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D016615:Telomere / Q000235:genetics* / Q000502:physiology; D059506:Telomere Shortening / Q000235:genetics; D055815:Young Adult