Effects of aging and calorie restriction of Fischer 344 rats on hepatocellular response to proliferative signals.
It is well established that the proliferative potential of the liver declines with aging. Epidermal growth factor (EGF)-stimulated DNA synthesis is reduced in hepatocytes from aged rats relative to young rats, and this reduction correlates with diminished activation of the extracellular signal-regulated kinase (ERK) pathway and lower phosphorylation of the EGF receptor on residue Y1173. Calorie restriction (CR) can increase rodent life span and retard many age-associated declines in physiologic function, but its influence on cell proliferation is unknown. Here, we investigated the effects of long-term CR on proliferation of hepatocytes derived from young and aged rats following in vitro stimulation with either low-dose hydrogen peroxide or EGF. CR reduced the proliferative response of hepatocytes derived from young hosts, but long-term CR was associated with enhanced proliferation in aged cells relative to that of ad libitum (AL)-fed animals. ERK activation mirrored the effects of CR on proliferation, in that young CR cells exhibited lower ERK activation than young AL cells, but old CR cells showed higher ERK activation than old AL cells. Finally, a decline in EGF receptor phosphorylation on Y1173, which normally occurs with aging, was absent in cells of old hosts maintained on long-term CR, supporting the view that alterations in this early signaling event underlie the age-related decline in proliferative potential in rat hepatocytes.
Ikeyama
Shizuo
S
Cell Stress and Aging Section, Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, MD 21224, USA. ikeyamash@grc.nia.nih.gov
Kokkonen
Gertrude
G
Martindale
Jennifer L
JL
Wang
Xian-Tao
XT
Gorospe
Myriam
M
Holbrook
Nikki J
NJ
D000375:Aging / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D018797:Cell Cycle Proteins; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D054638:Dual Specificity Phosphatase 1; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D016758:Genes, jun; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000235:genetics; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D011233:Precipitin Tests / Q000379:methods; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D013268:Stimulation, Chemical
D018797:Cell Cycle Proteins; D004040:Dietary Carbohydrates; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D004247:DNA; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases