Reactive oxygen species, dietary restriction and neurotrophic factors in age-related loss of myenteric neurons.
We have studied the mechanisms underlying nonpathological age-related neuronal cell death. Fifty per cent of neurons in the rat enteric nervous system are lost between 12 and 18 months of age in ad libitum (AL) fed rats. Caloric restriction (CR) protects almost entirely against this neuron loss. Using the ROS-sensitive dyes, dihydrorhodamine (DHR) and 2-[6-(4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (HPF) in vitro, we show that the onset of cell death is linked with elevated intraneuronal levels of reactive oxygen species (ROS). Treatment with the neurotrophic factors NT3 and GDNF enhances neuronal antioxidant defence in CR rats at 12-15 months and 24 months but not in adult or aged AL-fed animals. To examine the link between elevated ROS and neuronal cell death, we assessed apoptotic cell death following in vitro treatment with the redox-cycling drug, menadione. Menadione fails to increase apoptosis in 6-month neurons. However, in 12-15mAL fed rats, when age-related cell death begins, menadione induces a 7- to 15-fold increase in the proportion of apoptotic neurons. CR protects age-matched neurons against ROS-induced apoptosis. Treatment with neurotrophic factors, in particular GDNF, rescues neurons from menadione-induced cell death, but only in 12-15mCR animals. We hypothesize that CR enhances antioxidant defence through neurotrophic factor signalling, thereby reducing age-related increases in neuronal ROS levels and in ROS-induced cell death.
Thrasivoulou
C
C
Department of Anatomy and Developmental Biology, University College London, Royal Free Campus, London NW3 2PF, UK.
Soubeyre
V
V
Ridha
H
H
Giuliani
D
D
Giaroni
C
C
Michael
G J
GJ
Saffrey
M J
MJ
Cowen
T
T
D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D064032:Calbindin 2; D064026:Calbindins; D031204:Caloric Restriction; D016923:Cell Death / Q000187:drug effects; D008297:Male; D009197:Myenteric Plexus / Q000166:cytology / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000494:pharmacology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism
D000975:Antioxidants; D064032:Calbindin 2; D064026:Calbindins; D009414:Nerve Growth Factors; D017382:Reactive Oxygen Species; D064030:S100 Calcium Binding Protein G