Godoy Juan A, Zolezzi Juan M, Braidy Nady, Inestrosa Nibaldo C
Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Alameda 340, Santiago, Chile.
Mol Neurobiol. 2014 Dec;50(3):744-56. doi: 10.1007/s12035-014-8645-5. Epub 2014 Feb 5.
Ageing is a stochastic process associated with a progressive decline in physiological functions which predispose to the pathogenesis of several neurodegenerative diseases. The intrinsic complexity of ageing remains a significant challenge to understand the cause of this natural phenomenon. At the molecular level, ageing is thought to be characterized by the accumulation of chronic oxidative damage to lipids, proteins and nucleic acids caused by free radicals. Increased oxidative stress and misfolded protein formations, combined with impaired compensatory mechanisms, may promote neurodegenerative disorders with age. Nutritional modulation through calorie restriction has been shown to be effective as an anti-ageing factor, promoting longevity and protecting against neurodegenerative pathology in yeast, nematodes and murine models. Calorie restriction increases the intracellular levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+)), a co-substrate for the sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1) activity and a cofactor for oxidative phosphorylation and ATP synthesis. Promotion of intracellular NAD(+) anabolism is speculated to induce neuroprotective effects against amyloid-β-peptide (Aβ) toxicity in some models for Alzheimer's disease (AD). The NAD(+)-dependent histone deacetylase, Sirt1, has been implicated in the ageing process. Sirt1 serves as a deacetylase for numerous proteins involved in several cellular pathways, including stress response and apoptosis, and plays a protective role in neurodegenerative disorders, such as AD.
衰老 是一个随机过程,与生理功能的逐渐衰退相关,而生理功能衰退易引发多种神经退行性疾病的发病机制。衰老的内在复杂性仍然是理解这一自然现象成因的重大挑战。在分子水平上,衰老被认为其特征在于自由基对脂质、蛋白质和核酸造成的慢性氧化损伤的积累。氧化应激增加和错误折叠的蛋白质形成,再加上补偿机制受损,可能会随着年龄的增长促进神经退行性疾病的发生。通过热量限制进行营养调节已被证明是一种有效的抗衰老因素,在酵母、线虫和小鼠模型中可促进长寿并预防神经退行性病变。热量限制会增加必需吡啶核苷酸烟酰胺腺嘌呤二核苷酸(NAD⁺)的细胞内水平,NAD⁺是沉默信息调节因子1(Sirt1,沉默交配型信息调节因子2同源物1)活性的共底物,也是氧化磷酸化和ATP合成的辅助因子。在一些阿尔茨海默病(AD)模型中,推测促进细胞内NAD⁺合成代谢可诱导对淀粉样β肽(Aβ)毒性的神经保护作用。依赖NAD⁺的组蛋白脱乙酰酶Sirt1与衰老过程有关。Sirt1作为多种参与细胞途径(包括应激反应和细胞凋亡)的蛋白质的脱乙酰酶,在神经退行性疾病(如AD)中发挥保护作用。
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