SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

Herskovits, A. Zara; Hunter, Timothy N.; Maxwell, Nicholas; Pereira, Katherine; Whittaker, Charles A.; Valdez, Gregorio; Guarente, Leonard

doi:10.1111/acel.12839

Cited by 35 publications

(20 citation statements)

References 50 publications

(62 reference statements)

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“…Interestingly, intraperitoneal injection (but not oral administration) of resveratrol, a potential SIRT1 activator, led to a significant improvement in both symptoms and survival in the SOD1 G93A mouse model of ALS [ 50 ]. This is consistent with recent findings where overexpression of SIRT1 in MN of SOD1 G93A mice delays the onset of the disease and increases survival [ 51 ]. Moreover, SIRT1 may have wide-reaching implications on mitochondrial biogenesis via the deacetylation of PGC-1α [ 52 ].…”

Section: Mitochondria and The Mechanism Of Motor Neuron Deathsupporting

confidence: 93%

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

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Section: Mitochondria and The Mechanism Of Motor Neuron Deathsupporting

confidence: 93%

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

et al. 2020

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“…Finally, some contraindications and even discourse in the literature could be attributed to changes in the activation of the anti-aging gene. Recent studies [68,69] have identified molecular underpinnings consistent with a substantial portion of this study's results. For example, SIRT1 is an NAD+-dependent deacetylase that functions in a variety of cells and tissues to mitigate age-associated diseases [68].…”

Section: "Controversial" Interventions That May Be Related To Decreassupporting

confidence: 83%

“…For example, SIRT1 is an NAD+-dependent deacetylase that functions in a variety of cells and tissues to mitigate age-associated diseases [68]. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor neurons during aging and ALS [68].…”

Section: "Controversial" Interventions That May Be Related To Decreasmentioning

confidence: 99%

Associations of Patient Mood, Modulators of Quality of Life, and Pharmaceuticals with Amyotrophic Lateral Sclerosis Survival Duration

Bond

Bowen

Mertens

et al. 2020

Behavioral Sciences

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Associations of modulators of quality of life (QoL) and survival duration are assessed in the fatal motor neuron disease, Amyotrophic Lateral Sclerosis. Major categories include clinical impression of mood (CIM); physical health; patient social support; and usage of interventions, pharmaceuticals, and supplements. Associations were assessed at p < 0.05 and p < 0.001 significance thresholds using applicable methods (Chi-square, t-test, ANOVA, logistical regression, random forests, Fisher’s exact test) within a retrospective cohort of 1585 patients. Factors significantly correlated with positive (happy or normal) mood included family support and usage of bi-level positive airway pressure (Bi-PAP) and/or cough assist. Decline in physical factors like presence of dysphagia, drooling, general pain, and decrease in ALSFRS-R total score or forced vital capacity (FVC) significantly correlated with negative (depressed or anxious) mood (p < 0.05). Use of antidepressants or pain medications had no association with ALS patient mood (p > 0.05), but were significantly associated with increased survival (p < 0.05). Positive patient mood, Bi-PAP, cough assist, percutaneous endoscopic gastrostomy (PEG), and accompaniment to clinic visits associated with increased survival duration (p < 0.001). Of the 47 most prevalent pharmaceutical and supplement categories, 17 associated with significant survival duration increases ranging +4.5 to +16.5 months. Tricyclic antidepressants, non-opioids, muscle relaxants, and vitamin E had the highest associative increases in survival duration (p < 0.05). Random forests, which examined complex interactions, identified the following pharmaceuticals and supplements as most predictive to survival duration: Vitamin A, multivitamin, PEG supplements, alternative herbs, antihistamines, muscle relaxants, stimulant laxatives, and antispastics. Statins, metformin, and thiazide diuretics had insignificant associations with decreased survival.

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“…557 Besides, overexpression of SIRT1 in motor neurons slows down the progression of ALS in severely phenotypic SOD1G93A (with high copy numbers) mice, partly by activating the HSF1/HSP70i molecular chaperone system. 558,559 However, SIRT1 and SIRT2 are generally reduced in ALS primary motor cortex while they are upregulated in the spinal cord in human post-mortem tissues. In contrast to the neuroprotection role of SIRT1, SIRT2 upregulation is toxic to neuronal cells.…”

Section: -Hk 3-hydroxykynureninementioning

confidence: 99%

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie

Zhang

Gao

et al. 2020

Sig Transduct Target Ther

409

281

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Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

Cited by 35 publications

References 50 publications

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Associations of Patient Mood, Modulators of Quality of Life, and Pharmaceuticals with Amyotrophic Lateral Sclerosis Survival Duration

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

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