Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan

Abstract

Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.

Keywords: NAD+; NMN; SIRT1; age-related diseases; aging; flavonoids; geroprotectors; healthspan; longevity; nutraceuticals; resveratrol; senolytics; supplements.

Figure 1

The CD38/NAD+/SIRT1 Axis. NAD+ levels in the body can be influenced by the supplementation of precursors nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). NAD+ levels decrease with age and are further metabolized by the activation of SIRT1, PARP1, SARM1, and CD38. Restoring NAD+ levels allows for an increase in SIRT1 activity due to increased substrate availability, resulting in the inhibition of age-promoting pathways and activation of adaptive and protective transcription factors and processes. The central lineage may be described as the CD38/NAD+/SIRT1 axis, and targeting this access with nutraceutical interventions may prevent the age-related decline of NAD+ levels in the body. Black lines indicate conversion or activation. Red lines indicate inhibitors or destroyers of the indicated target.

Figure 2

Chemical structures of the aforementioned nutraceutical compounds are organized into their respective categories.

Figure 3

Hypothesized model of supplementing NAD+ precursors with other NAD+ enhancing geroprotectors. In addition to NAD+ precursors to raise NAD+ levels and enhance SIRT1 activity, stilbenes are able to support NAD+ levels and further activate SIRT1. Many flavonoids retain senolytic and CD38-inhibitory activity and can further innervate NAD+ stores. Curcumin and carotenoids retain similar properties in addition to SIRT1 activation. This interacting web of support may result in higher NAD+ stores than precursor-alone administration, producing longevity-promoting transcriptional benefits.