Exploring the therapeutic space around NAD+

Abstract

NAD(+) is a central metabolite in the cell. Changes in NAD(+) abundance and the activity of NAD(+)-dependent enzymes, such as the sirtuins, are at the core of metabolic/mitochondrial diseases, such as obesity and diabetes, and of cancer and neurodegeneration. Here, we discuss how maintaining or raising NAD(+) levels can improve metabolism and prevent age-related functional decline and associated disease, and how basic scientific discoveries in the NAD(+) signaling pathway are being translated to the clinic.

Figure 1.

Diverse metabolic actions of NAD⁺. Schematic overview of how NAD⁺ and NADH are used as metabolic cofactors, either in more traditional oxidoreductase reactions (green NAD⁺) or in more recently discovered regulatory roles as a cosubstrate for the reactions catalyzed by sirtuins and PARPs (red NAD⁺). Note: reactions shown here are only a small representation of those that involve NAD⁺.

Figure 2.

Metabolic control by modulating NAD⁺ levels. (A) NAD⁺ levels dictate the activity of SIRT1 and SIRT3, which in turn regulate a variety of metabolic proteins. The protein targets shown here just represent a selection. (B) Mitochondrial function is regulated by sirtuin enzymes, notably SIRT1 and SIRT3, which are under the control of NAD⁺ levels. Modulating NAD⁺ levels results in improved mitochondrial function with clinically beneficial effects.