Abstract
Caloric restriction (CR) decelerates the aging process, extends lifespan and exerts neuroprotective effects in diverse species by so far unknown mechanisms. Based on known neuroprotective effects of fibroblastic growth factor 21 (Fgf21) we speculate that CR upregulates Fgf21, which phosphorylates neuronal AMP-activated protein kinase (AMPK), leading to a decrease of mammalian target of rapamycin (mTOR) signaling activity and an inhibition of tau-hyperphosphorylation. This in turn reduces the formation of neurofibrillary tangles, a neuropathological hallmark of Alzheimer's disease. ApoE-deficient mice (ApoE−/−), serving as a model of neurodegeneration, showed upon CR vs. ad libitum feeding increased Fgf21 levels in both, plasma and brain as well as higher phosphorylation of fibroblastic growth factor receptor 1c (Fgfr1c), extracellular signal-regulated kinases 1/2 (ERK1/2) and AMPK in brain, lower activity of mTOR and decreased Tau-phosphorylation. Finally, CR in ApoE−/− mice caused neuroprotection as indicated by a higher synaptic plasticity shown by immunohistochemical analysis with increased numbers of PSD95-positive neurons and a better cognitive performance as analyzed with Morris water maze test. These data provide substantial evidence that neuroprotection upon CR seems to be Fgf21-dependent. Further experiments are necessary to evaluate Fgf21 as a therapeutic tool to treat tauopathy for improvement of cognitive performance.
Highlights
In all species studied to date, restricted calorie intake by 20-50% while providing adequate micronutrient supply significantly extends mean and maximal lifespan [1, 2]
Based on known neuroprotective effects of fibroblastic growth factor 21 (Fgf21) we speculate that Caloric restriction (CR) upregulates Fgf21, which phosphorylates neuronal AMP-activated protein kinase (AMPK), leading to a decrease of mammalian target of rapamycin signaling activity and an inhibition of tau-hyperphosphorylation
CR-fed mice were smaller in body size than the ad libitum (AL)-fed mice (Fig. 1A)
Summary
In all species studied to date, restricted calorie intake by 20-50% while providing adequate micronutrient supply significantly extends mean and maximal lifespan [1, 2]. Age-related deficits in learning and motor coordination are ameliorated by caloric restriction (CR) in rodents [3, 4]. The fibroblastic growth factor 21 (Fgf21) was described as starvation hormone [10]. Fgf activity occurs when Fgf binds to fibroblast growth factors receptor (Fgfr) and β-klotho, a single transmembrane protein [12]. Fgfrs consist of seven major isoforms (1b, 1c, 2b, 2c, 3b, 3c and 4), whereby the isoform Fgfr1c is the primary receptor of Fgf in the mediation of its activity in in vivo studies [13]. When Fgf binds to its receptor, it leads to a rapid phosphorylation of downstream pathway components, including the MAPK cascade [14] and results via protein kinase A to activation of AMP-activated protein kinase (AMPK) [15]. Fgf is a direct target gene of the peroxisome proliferator-activated receptor-α (pparα) [16, 17], a regulator for CR-induced lipolysis
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