Inadequate mito-biogenesis in primary dermal fibroblasts from old humans is associated with impairment of PGC1A-independent stimulation.
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 PPARγ-coactivator 1α (PGC1A) and decreased levels of NAD(+)-dependent deacetylase sirtuin 1. 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.
Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University, Med. Faculty, Düsseldorf, Germany.
Faiza
F
Kalfalah
Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University, Med. Faculty, Düsseldorf, Germany.
Stefan
S
Sobek
Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University, Med. Faculty, Düsseldorf, Germany.
Beatrice
B
Bornholz
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
Christine
C
Götz-Rösch
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
Julia
J
Tigges
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
Ellen
E
Fritsche
Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
Jean
J
Krutmann
Genomics & Transcriptomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich Heine University, Düsseldorf, Germany.
Karl
K
Köhrer
Genomics & Transcriptomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich Heine University, Düsseldorf, Germany.
René
R
Deenen
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany; Freiburg Institute for Advanced Studies - FRIAS, Albert-Ludwigs-University, Freiburg, Germany.
Sebastian
S
Ohse
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Freiburg Institute for Advanced Studies - FRIAS, Albert-Ludwigs-University, Freiburg, Germany.
Melanie
M
Boerries
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany; German Cancer Consortium (DKTK), Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Freiburg Institute for Advanced Studies - FRIAS, Albert-Ludwigs-University, Freiburg, Germany.
Hauke
H
Busch
Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich Heine University, Med. Faculty, Düsseldorf, Germany. Electronic address: boege@med.uni-duesseldorf.de.
Fritz
F
Boege
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063269:Mitochondrial Turnover / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D015595:Skin Aging / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C031143:AICA ribonucleotide
AMP-dependent protein kinase subunits α1 and α2; Ageing; Dermal fibroblasts; Mitochondrial gene expression; NAD(+)-dependent deacetylase sirtuin 1; PPARγ-coactivator 1α