Volume 2 Issue 11, November 2020

The restoration of the progressive decline in nicotinamide adenine dinucleotide (NAD⁺) levels mitigates certain age-associated dysfunctions. A fundamental question is how the NAD⁺-consuming enzyme CD38 decreases NAD⁺ levels during ageing. Two new studies by Chini et al. and Covarrubias et al. in this issue of Nature Metabolism show that CD38 expression in macrophages induced by senescence-associated inflammation accounts for the age-related decline in NAD⁺ levels.

A new global measure of cell-to-cell transcriptional variability from single-cell RNA-sequencing data has been developed by Levy et al., on the basis of the transcriptional interrelations between genes. The new variable, termed global coordination level, decreases with age in different organisms and cell types and correlates with high mutational load in cells.

Cellular metabolism has emerged as a major biological node governing cellular behaviour. In their review, Boon et al. explore the mechanisms that maintain nuclear metabolic compartmentalization and the regulation of epigenetics, cell fate and cell physiology by nuclear metabolism.

When placed in an activity-based anorexia paradigm, mice with altered AgRP circuit function recapitulate characteristics of anorexia nervosa, including a reduction in food intake, compulsive exercise and death.

Oncogenic cell growth and proliferation rely on aberrant activation of metabolic pathways, such as glucose fermentation, resulting in elevated cytosolic pH. Koch et al. implicate increased cytosolic pH as a driver for cell proliferation through the transcriptional activation of cyclin D1.

Mitochondrial metabolism is critical for cardiac function and growth. Fernandez-Caggiano et al. show that maintenance of mitochondrial pyruvate transporter expression is a critical mediator of cardiac hypertrophy and heart failure.

Impaired myocardial metabolic flexibility is associated with cardiac dysfunction in diabetes and heart failure. McCommis et al. reveal a critical role for mitochondrial pyruvate use in cardiac function, and use dietary interventions to enhance cardiac fat metabolism in dilated cardiomyopathy.

Metabolic substrate partitioning underlies myocardial homeostatic capacity and adaptation to stress. Zhang et al. show that decreasing mitochondrial pyruvate carrier expression redirects glycolytic intermediates and leads to heart failure, which is prevented or reversed with a high-fat or ketogenic diet.

Senescent cells in fat and liver are shown to attract M1-like macrophages with increased expression of the NAD-consuming enzyme CD38, leading to their local accumulation and providing a mechanism for the age-associated decline in tissue NAD⁺ levels.

Chini et al. demonstrate that CD38⁺ expression in immune cells increases during aging, owing to the senescence-associated secretory phenotype of senescent cells, and the ecto-enzymatic activity of CD38⁺ affects intracellular NAD⁺ levels in vivo by hydrolyzing the NAD⁺ intermediate nicotinamide mononucleotide extracellularly.

Levy et al. report a method to measure transcriptional coordination between cells in single-cell RNA sequencing data and demonstrate that transcriptional dysregulation between cells is a general phenomenon in ageing and is associated with genetic damage.

Metformin holds the potential to extend healthy lifespan in aged, insulin-resistant individuals. Using C. elegans, Espada et al. uncover a deleterious metabolic response to metformin treatment in aged worms with unaltered insulin signalling.

PDGFRβ⁺ perivascular mesenchymal cells are shown to regulate chronic adipose-tissue inflammation in obesity through downregulation of ZFP423, a transcriptional corepressor of NF-κB.

The nuclear factor kappa B subunit c-Rel acts as a master regulator of metabolism and signalling in epithelial cells and macrophages that drives inflammation and fibrogenesis in various models of fibrosis.