Systematic gene expression profile of hypothalamus in calorie-restricted mice implicates the involvement of mTOR signaling in neuroprotective activity

Wu, Pu; Jiang, Chunmiao; Shen, Qian; Hu, Yinghe

doi:10.1016/j.mad.2009.07.005

Cited by 32 publications

(23 citation statements)

References 50 publications

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“…Similarly, 30–40% CR starting at 3–4 months of age for ≥6 months (Sharma et al, 2012; Yang et al, 2014) did not alter the level of mTOR, S6K or TSC2 expression in the hippocampus, neocortex or cerebellum. But 30% CR for variable times (~4, 11, 18, or 23 months) starting at weaning reduced the expression of genes that participate in this cascade (such as S6K) in the hypothalamus of inbred mice (Wu et al, 2009). Given the similarity between two of these reports (Wu et al, 2009; Yang et al, 2014), the most likely explanation is that CR has differential impact depending on the age at diet onset or the brain region, as previously suggested (Zeier et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…But 30% CR for variable times (~4, 11, 18, or 23 months) starting at weaning reduced the expression of genes that participate in this cascade (such as S6K) in the hypothalamus of inbred mice (Wu et al, 2009). Given the similarity between two of these reports (Wu et al, 2009; Yang et al, 2014), the most likely explanation is that CR has differential impact depending on the age at diet onset or the brain region, as previously suggested (Zeier et al, 2011). Although CR and the ketogenic diet both inhibit the mTOR pathway (McDaniel et al, 2011), this is unlikely to be the only anti-epileptic mechanism of action of these treatments since they differ in important respects (Bough et al, 2000, 2003; Hartman et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway

Phillips-Farfán

Rubio

Ramírez

et al. 2015

Front. Cell. Neurosci.

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Caloric restriction (CR) has been shown to possess antiepileptic properties; however its mechanism of action is poorly understood. CR might inhibit the activity of the mammalian or mechanistic target of rapamycin (mTOR) signaling cascade, which seems to participate crucially in the generation of epilepsy. Thus, we investigated the effect of CR on the mTOR pathway and whether CR modified epilepsy generation due to electrical amygdala kindling. The former was studied by analyzing the phosphorylation of adenosine monophosphate-activated protein kinase, protein kinase B and the ribosomal protein S6. The mTOR cascade is regulated by energy and by insulin levels, both of which may be changed by CR; thus we investigated if CR altered the levels of energy substrates in the blood or the level of insulin in plasma. Finally, we studied if CR modified the expression of genes that encode proteins participating in the mTOR pathway. CR increased the after-discharge threshold and tended to reduce the after-discharge duration, indicating an anti-convulsive action. CR diminished the phosphorylation of protein kinase B and ribosomal protein S6, suggesting an inhibition of the mTOR cascade. However, CR did not change glucose, β-hydroxybutyrate or insulin levels; thus the effects of CR were independent from them. Interestingly, CR also did not modify the expression of any investigated gene. The results suggest that the anti-epileptic effect of CR may be partly due to inhibition of the mTOR pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway

Phillips-Farfán

Rubio

Ramírez

et al. 2015

Front. Cell. Neurosci.

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“…Fewer genes were regulated and minor effects were observed on age-related changes. A recent study has shown that more changes in the regulation of hypothalamic gene expression could be observed in mature (12 months) than in old calorie-restricted mice (24 months) [61]. Whether or not this is the case in the hypothalamus of aging rats submitted to LTMCR remains to be documented.…”

Section: Discussionmentioning

confidence: 99%

Aging and Diets Regulate the Rat Anterior Pituitary and Hypothalamic Transcriptome

Bédard

Bédard²,

Rocheleau³

et al. 2012

Neuroendocrinology

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Dietary interventions involving caloric restriction represent a powerful strategy to prevent or delay age-related deteriorations and diseases. Their beneficial effects have been observed in several tissues and species. This microarray study investigated the effects of aging, long-term moderate caloric restriction (LTMCR) and long-term dietary soy on the regulation of gene expression in the anterior pituitary and hypothalamus of 20-month-old Sprague-Dawley rats. In both tissues, aging regulated genes mainly involved in cell defense and repair mechanisms related to apoptosis, DNA repair, cellular stress, inflammatory and immune response. In the aging pituitary, the highest upregulated gene was the regenerating islet-derived 3β (5.77-fold), coding for a secretory protein involved in acute stress and inflammation. A protective effect of LTMCR on age-related change of gene expression was observed for 35 pituitary genes. In addition, beneficial effects of LTMCR in the pituitary were observed on new regulated genes mainly involved in cell death and cell stress response. In the hypothalamus, the effects of LTMCR on age-related changes were modest. Finally, changing the quality of dietary protein (20% casein for soy) had a low impact on the regulation of mRNA levels in both tissues. Genes associated with the somatotroph function were also differentially expressed in the aging pituitary. Interestingly, LTMCR prevented the effect of aging on insulin-like growth factor-binding protein-3 gene. Altogether, this study proposes novel pituitary and hypothalamic molecular targets and signaling pathways to help in understanding the mechanisms involved in aging processes and LTMCR.

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“…Inhibition of related pathways in worms, flies, and yeast has been shown to extend life span (62)(63)(64), and in mammals, mTOR has become increasingly understood as a central regulator of energy homeostasis and cellular metabolism (65). Given that CR has been shown to inhibit target of rapamycin signaling in multiple species including mice (62,66), mTOR has become a candidate mediator of at least some of CR's beneficial effects and agents that inhibit mTOR signaling are candidate CRM.…”

Section: Mtor Signaling Pathwaymentioning

confidence: 99%

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

Minor

Allard

Younts

et al. 2010

The Journals of Gerontology Series A: Biological Sciences and M

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The societal impact of obesity, diabetes, and other metabolic disorders continues to rise despite increasing evidence of their negative long-term consequences on health span, longevity, and aging. Unfortunately, dietary management and exercise frequently fail as remedies, underscoring the need for the development of alternative interventions to successfully treat metabolic disorders and enhance life span and health span. Using calorie restriction (CR)-which is well known to improve both health and longevity in controlled studies-as their benchmark, gerontologists are coming closer to identifying dietary and pharmacological therapies that may be applicable to aging humans. This review covers some of the more promising interventions targeted to affect pathways implicated in the aging process as well as variations on classical CR that may be better suited to human adaptation.

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Systematic gene expression profile of hypothalamus in calorie-restricted mice implicates the involvement of mTOR signaling in neuroprotective activity

Cited by 32 publications

References 50 publications

Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway

Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway

Aging and Diets Regulate the Rat Anterior Pituitary and Hypothalamic Transcriptome

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

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