Abstract
Neurodegeneration of the central and enteric nervous systems is a common feature of aging and aging-related diseases, and is accelerated in individuals with metabolic dysfunction including obesity and diabetes. The molecular mechanisms of neurodegeneration in both the CNS and ENS are overlapping. Sirtuins are an important family of histone deacetylases that are important for genome stability, cellular response to stress, and nutrient and hormone sensing. They are activated by calorie restriction (CR) and by the coenzyme, nicotinamide adenine dinucleotide (NAD+). Sirtuins, specifically the nuclear SIRT1 and mitochondrial SIRT3, have been shown to have predominantly neuroprotective roles in the CNS while the cytoplasmic sirtuin, SIRT2 is largely associated with neurodegeneration. A systematic study of sirtuins in the ENS and their effect on enteric neuronal growth and survival has not been conducted. Recent studies, however, also link sirtuins with important hormones such as leptin, ghrelin, melatonin, and serotonin which influence many important processes including satiety, mood, circadian rhythm, and gut homeostasis. In this review, we address emerging roles of sirtuins in modulating the metabolic challenges from aging, obesity, and diabetes that lead to neurodegeneration in the ENS and CNS. We also highlight a novel role for sirtuins along the microbiota-gut-brain axis in modulating neurodegeneration.
Highlights
Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience
We address emerging roles of sirtuins in modulating the metabolic challenges from aging, obesity, and diabetes that lead to neurodegeneration in the enteric nervous system (ENS) and Central nervous system (CNS)
Neurodegeneration in the CNS is characterized by a progressive loss of distinct groups of neurons in specific regions of the brain, deposition of misfolded proteins in neurons, and alterations in astrocytes (Przedborski et al, 2003; Maragakis and Rothstein, 2006) which results in cognitive dysfunction, loss of synapses, impaired synaptic plasticity, disrupted neuronal signaling, and cell
Summary
Aging is a multifactorial process accompanied by many changes at the cellular, tissue, and organismal level over time and has shown to be a major risk factor for neurodegeneration of the CNS and the ENS (Wade and Cowen, 2004; Hou et al, 2019). In mouse Other studies in the ENS using mice models of high fat diet and obesity induced diabetic neuropathy reported a reduction in hormones such as ghrelin, cholecystokinin (CCK), and leptin levels; and inhibitory neurons expressing nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and galanin as well as their expression levels (Chandrasekharan and Srinivasan, 2007; Li et al, 2011; Voukali et al, 2011; Stenkamp-Strahm et al, 2015). The neuronal changes characterized by the loss of important neurotransmitters and hormones resulted in altered gastric emptying, diarrhea and constipation that is characteristic of enteric neurodegeneration (Stenkamp-Strahm et al, 2015) These alterations could be a compensatory mechanism to increase satiety and decrease food intake to balance weight gain in diet induced obese mice (Coll et al, 2007).
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