Gliotoxin reverses age-dependent nuclear morphology phenotypes, ameliorates motility, but fails to affect lifespan of adult Caenorhabditis elegans.
Specific mutations in human LMNA or loss of ZMPSTE26 activity cause abnormal processing of lamin A and early aging diseases, including Hutchinson Gilford progeria syndrome (HGPS). HGPS fibroblasts in culture undergo age-dependent progressive changes in nuclear architecture. Treating these cells with farnesyl transferase inhibitors (FTIs) reverse these nuclear phenotypes and also extend lifespan of mice HGPS models. Dermal cells derived from healthy old humans also accumulate the abnormally processed lamin A. However, the effect of FTIs on normal aging cells was not tested. Aging adult C. elegans cells show changes in nuclear architecture similar to HGPS fibroblasts and down regulating lamin expression in adult C. elegans reduces their lifespan. Here, we show that nuclei of adult C. elegans, in which lamin is down-regulated, have similar phenotypes to normal aging nuclei, but at an earlier age. We further show that treating adult C. elegans with the FTI gliotoxin reverses nuclear phenotypes and improves motility of aging worms. However, the average lifespan of the gliotoxin-treated animals was similar to that of untreated animals. These results suggest that lamins are involved in the process of normal aging in C. elegans.
Bar
Daniel Z
DZ
Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904 Israel.
Neufeld
Ester
E
Feinstein
Naomi
N
Gruenbaum
Yosef
Y
D000818:Animals; D017173:Caenorhabditis elegans; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure*; D016922:Cellular Senescence; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005912:Gliotoxin / Q000494:pharmacology*; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000502:physiology; D008136:Longevity / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D009068:Movement / Q000187:drug effects; D034881:Nuclear Lamina / Q000502:physiology; D010641:Phenotype
D034904:Lamin Type A; D005912:Gliotoxin; D051231:Farnesyltranstransferase