NAD+ Supplements
One of the main causes of aging and the physical and mental symptoms associated with it is a reduction in cellular NAD+. Restoring NAD+ levels in the body, therefore, has been associated with increased energy production, muscle function, cognitive activity and DNA damage repair.
The roles of calorie restriction and exercise in increasing the body’s NAD levels have been well established. However, it is possible to go further and restore the cell’s fundamental ability to make and recycle NAD.
Scientific research over the years has sought to identify ways in which the biological pathways can be influenced so that the cell makes more NAD and the symptoms associated with aging are reduced. This research has gone beyond the early approach of simply providing more precursor ingredients to the cell and now, recognising the complexity of the biology, aims to address the NAD production network as a whole.
NAD+ Supplementation: A Whole System Approach to
The body makes NAD+ within each individual cell and the biology associated with this is complex. NAD production involves multiple precursors, processes, enzymes and subnetworks. Over ten years of scientific research has established how the different processes interact with each other and, importantly, which parts of the network have the biggest impact on NAD+ production. This approach to the system as a whole, rather than targeting one element, is called network pharmacology.
A network pharmacology approach to NAD production has identified three priority goals to achieve with supplementation. These target areas address both the underlying problems that are causing a decline in NAD as well as the pathways that can restore the cell’s youthful ability to recycle NAD.
1. Increase NAD+ recycling via NAMPT
Whilst NAD can be made via three different pathways, it is the salvage pathway that recycles waste products from NAD to new NAD+ that has been identified as a priority. This is because the salvage pathway is the primary way in which youthful cells sustain high levels of NAD+. However, this recycling mechanism relies on the enzyme NAMPT and it is this NAMPT which declines with age. This loss in NAMPT results in the depletion of the salvage pathway.
Increasing NAMPT will help restore the cell’s youthful ability to recycle NAD.
2. Decrease methylation of Nicotinamide
In addition to restoring the salvage pathway, it is important to decrease the cell’s mechanism to excrete the ingredients that could, otherwise, be recycled back into NAD+. This mechanism involves a process called methylation whereby a methyl group is added to a compound so that the cell can discard it. In this context, it is a building block of NAD called nicotinamide that is methylated and excreted rather than being recycled back into NAD via the salvage pathway.
The methylation is driven by an enzyme called NNMT and this enzyme has been found to increase with age. This results in the cell favouring the methylation and excretion of nicotinamide rather than recycling it back into NAD+ within the cell.
Decreasing NNMT will reduce waste and increase recycled NAD.
3. Decrease consumption of NAD+ via CD38
One of the most significant consumers of NAD+ in the body is the inflammatory protein, CD38. In fact, it is believed that breakdown of NAD+ by CD38 is one of the major causes of NAD+ decline as we age. Furthermore, because CD38’s consumption of NAD+ occurs via a pathway unrelated to the salvage pathway, the NAD cannot be recycled.
Inhibiting CD38 even just a small amount can give a significant boost to cellular NAD+ levels.
Find out more about the whole system approach to boosting NAD.
NAD Precursors
As NAD precursors are simply raw ingredients for the cell to convert into NAD+, it is essential to first restore the cell’s ability to make and recycle NAD from the relevant precursors. Without addressing the root causes that lead to a reduction in NAD, there will be limitations in the body’s ability to utilise a precursor. In fact, this lack of utilisation of precursor ingredients may, itself, have the potential to dysregulate the system further.
Precursor supplements, such as NR or NMN, enter the cell and are made into NAD. This is then used up by the cell and broken down into nicotinamide. This is where problems may occur. Whilst the body has initially benefited from an increase in NAD+ from the precursor ingredient, the cell’s vital and youthful ability to recycle nicotinamide into NAD has not been restored. This means the cell has no choice but for nicotinamide to be methylated via NNMT and excreted to prevent it building up within the cell. This increases the amount of methylated nicotinamide in the body which can lead to methylation issues that often need to be counteracted with additional supplementation.
This is avoidable by addressing the fundamental problem; restoring the cell’s ability to utilise the precursors and recycle nicotinamide via the salvage pathway. Only then can precursors, such as nicotinamide, help to increase NAD in an efficient and sustainable way.