bims-mignad 2025-07-06 papers

Issue of 2025–07–06
five papers selected by
Melisa Emel Ermert, Amsterdam UMC

Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00298-0. [Epub ahead of print]37(7): 1457-1459

The NARly side of whole-body NAD homeostasis.

Nicotinic acid riboside (NAR), one of two nucleoside precursors of nicotinamide adenine dinucleotide (NAD) coenzymes, is revealed to function in systemic NAD homeostasis. By knocking out Nmnat1 in liver, investigators discovered a liver-to-kidney NAR transit pathway and learned that kidney can be a donor in addition to a receiver of NAD precursors.

DOI: https://doi.org/10.1016/j.cmet.2025.06.003

Nihon Yakurigaku Zasshi. 2025 ;160(4): 268-273

[NAD+ metabolism as a target for anti-aging].

Hitoshi Uchida, Takashi Nakagawa.

Aging is a physiological process caused by various genetic and environmental factors. Recently, it has been proposed that the disturbance of the nutritional-metabolic sensing pathway is one of the aging characteristics. In particular, nicotinamide adenine dinucleotide (NAD+) plays an important role in this pathway and is considered the regulator of aging. NAD+ regulates an energy metabolism as a co-factor and is also involved in various biological processes including transcription, stress responses, DNA repair, inflammatory responses as well as post-transcriptional modifications, as a substrate for sirtuins, poly ADP-ribose polymerase (PARP), and CD38. With age, DNA damage and chronic inflammation increase in organs, resulting in overconsumption of NAD+ via PARP and CD38. The reduced NAD+ levels decrease the activity of sirtuins and PARPs and impair energy metabolism, ultimately leading to aging and aging-related diseases. However, the precise metabolism of NAD+ in vivo and the mechanism of how NAD+ regulates aging remain elusive. Moreover, the clinical application of NAD+ supplementation therapy is still under development. In this review, we overview the NAD+ metabolism and its relation to aging. In addition, we describe the current issue and perspective of NAD+ supplementation therapy to promote a healthy lifespan.

DOI: https://doi.org/10.1254/fpj.24072

npj metabolic health and disease... 2025 Jun 18. 3(1): 26

The role of NAD+ metabolism and its modulation of mitochondria in aging and disease.

Khalishah Yusri, Sandra Jose, Karen S Vermeulen, Trina Chia Min Tan, Vincenzo Sorrentino.

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme involved in a plethora of physiological reactions, with a key relevance in supporting mitochondrial function. Due to its critical role in these cellular processes, declining levels of NAD+ are associated with general aging and chronic disorders, including cognitive decline, sarcopenia, and metabolic diseases. These conditions are also typified by loss of mitochondrial health through dysfunction of homeostatic components such as mitophagy, unfolded protein response, and the antioxidant system. Therefore, raising cellular NAD+ through vitamin B3 family precursors or via drug-based interventions has become a broadly used strategy to restore mitochondrial and organismal homeostasis, with NAD+ precursors becoming a popular supplementation approach. As increasing components of the NAD+ biology are unraveled, this comprehensive review summarizes the advances in mechanisms of NAD+ metabolism and its modulation via compound-based strategies. Furthermore, it highlights the role of NAD+ in mitochondrial homeostasis in aging and disease conditions, the latest results of NAD+-boosting therapeutics in clinical trials, and areas of further translational development.

DOI: https://doi.org/10.1038/s44324-025-00067-0

Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456

Muscle needs NAD, but how much?

David W Frederick, Joseph P McGaunn, Joseph A Baur.

Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.

DOI: https://doi.org/10.1016/j.cmet.2025.06.001

Redox Biol. 2025 Jun 27. pii: S2213-2317(25)00253-8. [Epub ahead of print]85 103740

Acute stimulation of glucose metabolism by H2O2 sustains the NADPH steady-state under oxidative stress.

C Aburto, I Ruminot, A San Martín.

Oxidative stress reprograms metabolic flux from glycolysis to the pentose phosphate pathway. Recently, it has been proposed that NADPH acts as a key molecule in pentose phosphate pathway regulation by exerting negative feedback through tonic inhibition of glucose-6-phosphate dehydrogenase. Interestingly, recent studies show that NADPH levels remain stable during acute exposure to hydrogen peroxide in the presence of glucose, ruling out NADPH-dependent feedback inhibition. We hypothesize that hydrogen peroxide triggers a feedforward activation mechanism, increasing NADPH production even before any detectable NADPH depletion. To probe this hypothesis, we used a panel of genetically encoded fluorescent indicators to monitor glucose, NADPH, fructose 1,6-bisphosphate and pyruvate in single cells with high temporal resolution. Our results reveal that hydrogen peroxide rapidly activates glucose transport and consumption rates, enabling cells to preserve NADPH steady-state levels during early oxidative stress. Notably, this response precedes NADPH depletion, implying an anticipatory phenomenon that boosts NADPH production prior to its consumption. Furthermore, hydrogen peroxide induced an acute perturbation of fructose 1,6-bisphosphate steady-state and an increase of pyruvate accumulation. The pharmacological inhibition of the PPP's gateway enzymes, glucose-6-phosphate dehydrogenase and transketolase, abolished the hydrogen peroxide-dependent alterations in fructose 1,6-bisphosphate steady-state levels and pyruvate accumulation, respectively. These findings suggest that a substantial fraction of glucose-derived carbon flux is diverted to the pentose phosphate pathway under oxidative stress, underscoring the importance of feedforward control in maintaining redox balance.

Keywords: Feedforward and metabolism; Glycolysis; Hydrogen peroxide; NADPH; Pentose phosphate pathway

DOI: https://doi.org/10.1016/j.redox.2025.103740