Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets

Abstract

Aim/hypothesis Pancreatic beta cell function has been shown to decline with age in man. Depletion of mitochondrial DNA (mtDNA) copy number is associated with impaired insulin secretion in pancreatic beta cell lines, and decreased mtDNA copy number has been observed with age in skeletal muscle in man. We investigated whether mtDNA copy number decreases with age in human pancreatic beta cells, which might in turn contribute to the age-related decline in insulin secretory capacity. Methods We quantified mtDNA copy number in isolated human islet preparations from 15 pancreas donors aged between 17 and 75 years. Islets (n=20) were individually hand-picked and pooled from each donor isolate for the quantification of mtDNA copy number and deleted mtDNA (%), which were determined using real-time PCR methods. Results There was a significant negative correlation between mtDNA copy number and islet donor age (r=-0.53, p=0.044). mtDNA copy number was significantly decreased in islet preparations from donors aged ≥50 years (n=8) compared with those aged <50 years (n=7) (median [interquartile range]: 418 [236-503] vs 596 mtDNA copy number/diploid genome; p=0.032). None of the islet preparations harboured high levels of deleted mtDNA affecting the major arc. Conclusion/interpretation Given the correlation between mtDNA content and respiratory chain activity, the agerelated decrease in mtDNA copy number that we observed in human pancreatic islet preparations may contribute to the age-dependent decline in pancreatic beta cell insulin secretory capacity.

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

“…In accordance with our results, mtDNA copy number was recently reported to be lower in parents than in their children (Chu et al 2012). In addition, an age-related decline in mtDNA copy number has also been observed in the human pancreatic islet among pancreatic islet donors (Cree et al 2008) and in human muscletissue from muscle biopsy donors(Short KR 2005; Welle S et al 2003), as well as in liver and muscle cells from rats and several tissues from a short-lived fish(Barazzoni et al 2000; Hartmann et al 2011). Thus, the general age-related decline in mtDNA copy number in the later part of the life spanis probably not unique for human blood cells, suggesting that a uniform mtDNA copy number decline with age may take place across tissues and even species in the late life.…”

Age-Related Impairment of Pancreatic Beta-Cell Function: Pathophysiological and Cellular Mechanisms

“…This age-related impairment of beta-cell secretory capabilities has been variously attributed to several factors, including: (i) mitochondrial dysfunction (34, 67–69); (ii) reduced GLUT2 levels (54, 70); (iii) accumulation of advanced glycation end products (AGEs) (71, 72); (iv) telomerase deficiency and reduced telomere length (73, 74): (v) reduced expression of β 2 -adrenergic receptors (75); (vi) impaired Ca ++ handling (76, 77); (vii) reduced response to GLP-1 stimulation (62, 65, 78–83); (vii) increased autophagy (84); (viii) reduced expression of beta-cell-specific genes and transcription factors such as PDX-1 (54). …”

Hypoxia induces PGC-1α expression and mitochondrial biogenesis in the myocardium of TOF patients

“…The relative mtDNA copy number was determined by real-time quantitative PCR as described previously [49,50]. Genomic DNA was extracted from human samples or cardiac myocytes using the QIAamp DNA isolation kit (Qiagen, Hilden, Germany).…”