Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide). These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.

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Reactive and potentially toxic cofactors such as copper ions are imported into eukaryotic cells and incorporated into target proteins by unknown mechanisms. Atx1, a prototypical copper chaperone protein from yeast, has now been shown to act as a soluble cytoplasmic copper(I) receptor that can adopt either a two- or three-coordinate metal center in the active site. Atx1 also associated directly with the Atx1-like cytosolic domains of Ccc2, a vesicular protein defined in genetic studies as a member of the copper-trafficking pathway. The unusual structure and dynamics of Atx1 suggest a copper exchange function for this protein and related domains in the Menkes and Wilson disease proteins.

Comorbidities are associated with the severity of coronavirus disease 2019 . This meta-analysis aimed to explore the risk of severe COVID-19 in patients with pre-existing chronic obstructive pulmonary disease (COPD) and ongoing smoking history. A comprehensive systematic literature search was carried out to find studies published from December 2019 to 22 March 2020 from five databases. The languages of literature included English and Chinese. The point prevalence of severe COVID-19 in patients with pre-existing COPD and those with ongoing smoking was evaluated with this meta-analysis. Overall 11 case series, published either in Chinese or English language with a total of 2002 cases, were included in this study. The pooled OR of COPD and the development of severe COVID-19 was 4.38 (fixed-effects model; 95% CI: 2.34-8.20), while the OR of ongoing smoking was 1.98 (fixed-effects model; 95% CI: 1.29-3.05). There was no publication bias as examined by the funnel plot and Egger's test (P = not significant).The heterogeneity of included studies was moderate for both COPD and ongoing smoking history on the severity of COVID-19. COPD and ongoing smoking history attribute to the worse progression and outcome of COVID-19.COPD, COVID-2019, smoking 2.34-8.20), heterogeneity among the different studies being moderate (I 2 = 41%; P = .08). Sensitivity analysis showed that the results were not affected by any individual study. Publication bias, as accessed by funnel plot ( Figure 2B) and Egger's test, showed no publication bias in this analysis (P for Egger's test was 0.5492). | Pre-existing COPD and mortalityOnly two of the included studies reported the association between death and pre-existing COPD. 11,12 Death was reported in 6 of 10 (60%) of patients with COPD and 80 of 233 (34.3%) of non-COPD patients. The pooled OR of COPD for death was 1.93 (95%CI: 0.59-7.43); however, the heterogeneity in this analysis (I 2 = 61%; P = .11) was quite high. | Smoking history and the severity of COVID-19Seven studies reported the relationship between active smoking and the severity of 8,[11][12][13]16,17 The exact duration of smoking was not reported in most studies. The pooled OR is summarized in Figure 2C, which shows that smoking increases the risk of severe COVID-19 (fixed-effects model; OR = 1.98; 95% CI: 1.29-3.05) by around twofolds. The heterogeneity among the different studies was moderate (I 2 = 44%; P = .10). Sensitivity analysis by excluding each study one by one showed that the study from Guan 6 was a major source of heterogeneity. After excluding this F I G U R E 3 Subgroup analysis for the impact of COPD and smoking histology on the severity of COVID-19. CI, confidence interval; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; ICU, intesive care unit; OR, odds ratio ZHAO ET AL.| 5 overall sample size could be a possible explanation. When the study with the largest sample size was excluded from sensitivity analysis, the effect of smoking on the severity of COVID-19 was no longer significant. An...

Calorie restriction (CR) extends life span in a wide variety of species. Previously, we showed that calorie restriction increases the replicative life span in yeast by activating Sir2, a highly conserved NAD-dependent deacetylase. Here we test whether CR activates Sir2 by increasing the NAD/NADH ratio or by regulating the level of nicotinamide, a known inhibitor of Sir2. We show that CR decreases NADH levels, and that NADH is a competitive inhibitor of Sir2. A genetic intervention that specifically decreases NADH levels increases life span, validating the model that NADH regulates yeast longevity in response to CR. Received October 27, 2003; revised version accepted November 26, 2003. Calorie restriction (CR) extends life span in a wide spectrum of organisms and for decades was the only regimen known to promote longevity in mammals (Weindruch and Walford 1998;Roth et al. 2001). CR has also been shown to delay the onset or reduce the incidence of many age-related diseases including cancer and diabetes (Weindruch and Walford 1998;Roth et al. 2001). Although it has been suggested that CR may work by reducing the levels of reactive oxygen species through a slowing in metabolism (Weindruch and Walford 1998), the mechanism by which CR extends life span is still uncertain. To study the mechanism by which CR extends life span, we established a model of CR in the budding yeast Saccharomyces cerevisiae. In this system, life span can be extended by limiting glucose content in the media from 2% to 0.5% or by reducing the activity of the glucose-sensing cAMP-dependent kinase (PKA; Lin et al. 2000).The benefit of CR requires NAD (nicotinamide adenine dinucleotide, oxidized form) and Sir2 , a key regulator of life span in both yeast and animals (Kaeberlein et al. 1999;Tissenbaum and Guarente 2001). Sir2 is an NAD-dependent histone deacetylase and is required for chromatin silencing and life-span extension (Imai et al. 2000;Landry et al. 2000;Smith et al. 2000). The requirement of NAD for Sir2 deacetylase activity suggested CR may activate Sir2 by increasing the available pool of NAD for Sir2 (Guarente 2000).Our previous studies suggested that there was a second mechanism to activate Sir2 and extend the life span in yeast-osmotic stress . This stress mechanism was genetically distinguishable from CR. Mutations knocking out electron transport prevented CR from extending life span, but had no effect on the longevity conferred by osmotic stress Lin et al. 2002). This requirement for electron transport during CR is because of a shunting of carbon metabolism from fermentation to the mitochondrial TCA cycle. The concomitant increase in respiration is necessary and sufficient for the activation of Sir2-mediated silencing and extension in life span . The fact that respiration produces NAD from NADH (Bakker et al. 2001), reinforces the idea that changes in the NAD/NADH ratio regulate Sir2 during CR.A recent report, however, challenged this model by claiming that both stress and CR activated Sir2 by a different mechanism, namely, by ...