A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
XPF-ERCC1 endonuclease is required for repair of helix-distorting DNA lesions and cytotoxic DNA interstrand crosslinks. Mild mutations in XPF cause the cancer-prone syndrome xeroderma pigmentosum. A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms. It is not known how unrepaired DNA damage accelerates ageing or its relevance to natural ageing. Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome. Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan. Similar changes are seen in wild-type mice in response to chronic genotoxic stress, caloric restriction, or with ageing. We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension. This highlights a causal contribution of DNA damage to ageing and demonstrates that ageing and end-of-life fitness are determined both by stochastic damage, which is the cause of functional decline, and genetics, which determines the rates of damage accumulation and decline.
Niedernhofer
Laura J
LJ
Center for Biomedical Genetics Medical Genetic Center Department of Cell Biology and Genetics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Garinis
George A
GA
Raams
Anja
A
Lalai
Astrid S
AS
Robinson
Andria Rasile
AR
Appeldoorn
Esther
E
Odijk
Hanny
H
Oostendorp
Roos
R
Ahmad
Anwaar
A
van Leeuwen
Wibeke
W
Theil
Arjan F
AF
Vermeulen
Wim
W
van der Horst
Gijsbertus T J
GT
Meinecke
Peter
P
Kleijer
Wim J
WJ
Vijg
Jan
J
Jaspers
Nicolaas G J
NG
Hoeijmakers
Jan H J
JH
D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D011371:Progeria / Q000235:genetics* / Q000503:physiopathology*; D052683:Somatotrophs / Q000378:metabolism*; D013577:Syndrome
D004268:DNA-Binding Proteins; C095888:xeroderma pigmentosum group F protein; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D004720:Endonucleases; C499360:Ercc1 protein, mouse