Tolerance to NADH/NAD⁺ imbalance anticipates aging and anti-aging interventions

Abstract

12Redox couples coordinate cellular function, but the consequences of their imbalances 13 are unclear. This is somewhat associated with the limitations of their experimental 14 quantification. Here we circumvent these difficulties by presenting a new approach that 15 characterizes fitness-based tolerance profiles to redox couple imbalances using an in 16 silico representation of metabolism. Focusing on the NADH/NAD + redox couple in 17 yeast, we demonstrate that reductive disequilibria generate metabolic syndromes 18 comparable to those observed in cancer cells. The tolerance of yeast mutants to redox 19 disequilibrium can also explain 30% of the variability in their experimentally measured 20 chronological lifespan. Moreover, by predicting the significance of some metabolites to 21 help stand imbalances, we correctly identify nutrients underlying mechanisms of 22 pathology, lifespan-protecting molecules or caloric restriction mimetics. Tolerance to 23 redox imbalances becomes thus a valid framework to recognize fundamental 24 properties of the aging phenotype while providing a firm biological rationale to assess 25 anti-aging interventions. 26 27 Keywords 28 Aging, metabolism, in silico models, flux balance analysis, Warburg effect 29 30 33 Gutteridge, 2015). Among the most paradigmatic molecular agents underlying this 34 homeostasis emerge the ratios of redox couples, like those of the conjugate forms of 35 2 glutathione, NADPH and NADH. Both glutathione and NADPH act as essential 36 scavenging mechanisms of reactive oxygen species (ROS) in mitochondria, while 37 NADPH and NADH couple anabolic and catabolic pathways, respectively, with the 38 redox state of the cell. 39 40 Even so, new mechanisms linking NADPH/NADP + and NADH/NAD + pairs to redox 41 homeostasis continue to be recognized. For instance, the balance of NADPH/NADP + 42 partially explains the pro-survival consequences of AMP-activated protein kinase 43 (AMPK) (She et al., 2014) and also associates circadian timekeeping with redox state 44 (Rey et al., 2016). The NADH/NAD + ratio is currently thought to be involved in the 45 coordination of mitochondrial and nuclear function, the epigenetic regulation of DNA 46 repair and cellular identity, and the tuning of energy metabolism to environmental 47 variables (Cantó et al., 2015; Gomes et al., 2013). In non-pathological conditions, the 48 NADH/NAD + ratio fluctuates with environmental redox state, with hypoxic conditions 49 and higher oxygen availability correspondingly co-occurring with reductive and 50 oxidative deviations (Clanton, 2007; Graef et al., 1999). 51 52 But the growing interest in redox couple ratios mainly comes from their implications in 53 pathology. The appearance of ROS in both the reductive (hypoxic, NADH prone) and 54 the oxidative (hyperoxic, NAD + prone) senses has been related to divergences from an 55 optimal redox potential that ensures the best performance of the mitochondria (Aon et 56 al., 2010; Clanton, 2007). Regarding cancer, decreased NADH/NAD + may underlie 57 lethality ...

Neuroprotection in Glaucoma: NAD+/NADH Redox State as a Potential Biomarker and Therapeutic Target

“…argues that POAG lymphoblasts have a mitochondrial defect which is more modest than LHON lymphoblasts and not severe enough to alter the redox status of the lymphoblast cells [32]. However, several studies in human and animal models have shown that there is evidence that the NAD + /NADH redox state may be a useful biomarker for monitoring and management of several diseases [184][185][186][187][188][189][190][191]. Mitochondrial dysfunction in POAG has been reported by many studies in human lymphocyte, lymphoblast and fibroblast models (Table 1), raising the point that if NAD levels underlie such dysfunction, then one might expect to be able to measure such differences in these cells.…”