Key Points:
- Aging interventions containing NAD+ precursors have evolved from counteracting the age-related reductions in cellular NAD+ to additionally targeting other pathways influencing aging.
- With its product, Restorin, Seragon has included advanced NAD+ precursor technology and added components targeting multiple hallmarks of aging, like the age-related accumulation of dysfunctional cells.
Aging interventions based on increasing the cellular molecule nicotinamide adenine dinucleotide (NAD+), essential for life-sustaining reactions, have evolved substantially over the years. For starters, researchers’ understanding of NAD+ began with recognizing its crucial role in metabolism and that its cellular levels decline with age across multiple species, including humans. NAD+ research has subsequently evolved to recognizing NAD+ as a regulator of aging and age-related diseases, a notion that has nearly reached consensus across the field of aging studies.
Early studies related to NAD+ focused on single-target approaches to restore cellular NAD+ levels, such as supplementing with NAD+ precursors like nicotinamide mononucleotide (NMN). Inconsistencies in data from human trials have subsequently led to a shift towards systems-based approaches that target multiple interconnected pathways in NAD+ metabolism and aging. This newer approach aims to address the complexity of factors contributing to aging, potentially leading to more effective NAD+ pathway-based aging interventions.
Key Stages in the Evolution of NAD+ Precursor Interventions
Early Research Focused on NAD+ Levels
Initial NAD+ research as it pertains to aging primarily focused on the role of cellular NAD+ as a critical molecule in cellular metabolism and its decline with age. The overarching idea from this research was that increasing NAD+ levels through supplementation with NAD+ precursors could improve cellular function, counteract age-related diseases, and possibly extend lifespan.
Unraveling Knowledge of NAD+ Metabolism
As research progressed, it became clear that multiple factors influence NAD+ levels. Studies investigated the different pathways for NAD+ synthesis and degradation, as well as the role of various enzymes and transporters in NAD+ homeostasis. Notably, cellular enzymes like CD38 and PARP, with roles in immunity and DNA repair, respectively, were identified as key consumers of cellular NAD+ that become more active with age.
Exploring NAD+ Precursors’ Effects On Age-Related Processes
Researchers moved on to investigating how NAD+ metabolism is linked to various hallmarks of aging, such as DNA damage and dysfunction of the cell’s powerhouse (the mitochondria). This research led to a more comprehensive understanding that NAD precursors like NMN play a role in preventing or mitigating these age-related changes. Along those lines, researchers found that treating mice with NMN alleviated age-related conditions like metabolic, cardiovascular, and neurological diseases.
NAD+ Precursor Clinical Studies
Following promising preclinical findings, researchers began exploring the efficacy of the NAD+ precursors NMN and nicotinamide riboside (NR) in humans. Their human trials focused on areas like mitochondrial health, muscle function, and metabolism.
So far, human trial research has yielded mixed results, with some studies associating taking NAD+ precursors with improvements in sleep and insulin sensitivity. Other human trials have not given positive results. Thus, more research is necessary to fully understand NAD+ precursors’ effects on age-related physiological decline as well as optimal dosing.
New Product Incorporating NAD+ Precursors Adds Components that Target Multiple Hallmarks of Aging
Intriguingly, Seragon Pharmaceuticals released a new product called Restorin in 2023. Roughly based on the drug SRN-901, which extended the lifespan of aged mice by an eye-popping 1/3, Restorin incorporates NAD+ precursors with other components that target multiple hallmarks of aging. In this way, Seragon has taken a new step to address age-related declining cellular NAD+ and other processes of aging.
Seragon researchers have combined their expertise in aging intervention technologies with licensed patents from top-notch institutions like Harvard University, the Mayo Clinic, and Scripps Research. This has resulted in the incorporation of proprietary NAD+ precursors combined with controlled release technology—called SERC—to optimize cellular NAD+ levels.
Other Restorin Components Targeting Different Hallmarks of Aging
To optimize Seragon’s approach to increasing cellular NAD+ with Restorin, the research team at Seragon has included some other components. Notably, Restorin contains inhibitors of mTOR—a protein that plays a critical role in cell growth and metabolism. Some aging researchers believe that mTOR skews toward overactivation with age, which is associated with an age-related decline in muscle function and muscle loss. Hence, Seragon has included mTOR inhibitors in Restorin to target muscle function optimization during aging.
Restorin also contains autophagy activators. Autophagy is the mechanism whereby cells remove waste and recycle dysfunctional proteins. Malfunctioning autophagy is one of the identified hallmarks of aging, and Seragon has targeted this hallmark with its inclusion of autophagy activators.
Relatedly, Restorin also contains mitophagy activators. Mitophagy is the process by which cells remove and recycle damaged or unnecessary cell powerhouses—known as mitochondria—to improve mitochondrial function. Mitochondrial dysfunction is another hallmark of aging, and Seragon has targeted this hallmark with mitophagy activators.
Restorin also contains components called senolytics that eliminate dysfunctional cells that accumulate in tissues with age. Aside from their capabilities to remove these dysfunctional cells, many senolytics also confer anti-inflammatory and antioxidant effects. Since the buildup of dysfunctional cells with age and inflammation constitute yet more hallmarks of aging, Seragon has incorporated senolytics into Restorin to target these hallmarks.
The Evolution of Products Containing NAD+ Precursors May Entail Adding Components Targeting Additional Hallmarks of Aging
From the evolution of NAD+ precursor technology to combining advanced NAD+ precursors with components that target other hallmarks of aging, Restorin represents the next step in aging interventions with NAD+ precursors. With that in mind, its components, like mTOR inhibitors and senolytics, have been shown to extend lifespan in rodents. Still, human trials will be necessary to confirm that Restorin alleviates signs of aging as well as age-related diseases in people.
All the same, its proprietary components target multiple hallmarks of aging, such as inflammation, mitochondrial dysfunction, and impaired autophagy, all aimed at promoting longevity. As such, it appears that Seragon has propelled aging intervention technology with NAD+ precursors by adding components that target additional hallmarks of aging.
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