Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice

Abstract

In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.is an inherited neurodegenerative disorder characterized by degeneration of neurons in the striatum and cerebral cortex resulting in abnormal involuntary movements (chorea), and psychiatric and cognitive abnormalities (1). The genetic defect involves expansion of CAG trinucleotide repeats in exon 1 of the HD gene resulting in polyglutamine expansions in the huntingtin protein (2-4). Neither the normal function of huntingtin nor the mechanism whereby polyglutamine expansions result in selective loss of striatal neurons is known, although impaired energy metabolism (5, 6), excitotoxicity (7), and oxidative stress (8) are implicated. It has been proposed that the mutant huntingtin causes neuronal dysfunction and death by altering the transcription of certain genes, including those encoding neurotransmitters and neurotrophic factors (9). Transgenic mice expressing polyglutamine expanded full-length or N-terminal fragments of huntingtin exhibit neurodegenerative changes in the striatum, progressive motor dysfunction, and premature death (10, 11). Oxidative stress and apoptosis are suggested in the pathogenic process because antioxidants (12) and caspase inhibitors (13) can slow disease progression in huntingtin mutant mice.Deficits in striatal and cortical glucose metabolism precede the appearance of symptoms in HD patients (14-16). Many HD patients and huntingtin mutant mice also exhibit hyperglycemia, apparently as the result of decreased insulin production and͞or sensitivity (17,18). A deficit in cellular energy metabolism may contribute to disease onset and progression because administration of creatine, an agent that reduces ATP depletion, delays the onset of symptoms and increases the survival times of huntingtin mutant mice (19). Another alteration in HD is decreased production of brain-derived neurotrophic factor (BDNF) (...

Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging

“…Nevertheless, the PMRS was capable of responding to an environmental condition (CR) that preserves brain function during aging. Previous studies have shown that neurons in the brains of rats and mice maintained on CR regimens are relatively resistant to oxidative and metabolic stress compared with control animals fed AL in models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and stroke (18,19,22,53). The mechanism by which CR protects neurons against oxidative injury is unknown.…”

“…CR has been shown to lower the rate of production of free radicals by mitochondria and to protect cells against oxidative stress (12)(13)(14)(15)(16)(17), a mechanism consistent with the free radical theory of aging. CR can attenuate age-related deficits in brain function and can protect neurons against dysfunction and death in animal models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and stroke (11,(18)(19)(20)(21)(22). The mechanisms by which CR protects brain cells during aging are unknown but may involve induction of the expression of neurotrophic factors (20,23), protein chaperones (22), and mitochondrial uncoupling proteins (24).…”

Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease

“…All mice were housed under standard conditions with free access to food and water for 24 h, and 12-h light/dark cycle. We used male N171-82Q HD mice for all our studies since we found that there is significant variability in all phenotypes between male and female N171-82Q mice (Duan et al 2003). N171-82Q male mice usually develop motor performance deficit after 19 weeks of age; the average life-span in these mice is about 22 weeks.…”

Impaired Adaptive Cellular Responses to Oxidative Stress and the Pathogenesis of Alzheimer's Disease

“…Activation of adaptive stress responses in animal models of neurodegenerative diseases have been able to provide benefits in cognition and motor function, and suggest that these molecular pathways maybe able to be activated through cognitive stimulation, exercise, and CR (41,42,67,76,108,125). One of the key factors that may help protect against the decline of cognitive function in aging and disease is BDNF.…”