Journal
EXPERIMENTAL GERONTOLOGY
Volume 56, Issue -, Pages 59-68Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2014.03.017
Keywords
Dermal fibroblasts; Ageing; Mitochondrial gene expression; AMP-dependent protein kinase subunits alpha 1 and alpha 2; PPAR gamma-coactivator 1 alpha; NAD(+)-dependent deacetylase sirtuin 1
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFB 728, GK 1033]
- Excellence Initiative of the German Federal and State Governments [FRIAS LifeNet]
- German Ministry of Research and Education [Network Gerontosys, Stromal Ageing]
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Extrinsic skin ageing converges on the dermis, a post-mitotic tissue compartment consisting of extracellular matrix and long-lived fibroblasts prone to damage accumulation and maladaptation. Aged human fibroblasts exhibit mitochondrial and nuclear dysfunctions, which may be a cause or consequence of ageing. We report on a systematic study of human dermal fibroblasts retrieved from female donors aged 20-67 years and analysed ex vivo at low population doubling precluding replicative senescence. According to gene set enrichment analysis of genome wide array data, the most prominent age-associated change of the transcriptome was decreased expression of mitochondrial genes. Consistent with that, mitochondrial content and cell proliferation declined with donor age. This was associated with upregulation of AMP-dependent protein kinase (AMPK), increased mRNA levels of PPAR gamma-coactivator 1 alpha (PGC1A) and decreased levels of NAD(+)-dependent deacetylase sirtuin I. In the old cells the PGC1A-mediated mito-biogenetic response to direct AMPK-stimulation by AICAR was undiminished, while the PGC1A-independent mito-biogenetic response to starvation was attenuated and accompanied by increased ROS-production. In summary, these observations suggest an age-associated decline in PGC1A-independent mito-biogenesis, which is insufficiently compensated by upregulation of the AMPK/PGC1A-axis leading under baseline conditions to decreased mitochondrial content and reductive overload of residual respiratory capacity. (C) 2014 Elsevier Inc All rights reserved.
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