Is Nicotinamide a SIRT Inhibitor or a SIRT Promoter?
As someone who cares about aging well, maintaining youthful NAD levels and sirtuin activation in your body is likely to be a consideration. Here's the science behind the link between nicotinamide (NAM) and the sirtuins.
Sirtuins are Longevity Genes
Sirtuins are a family of proteins also called your longevity genes that are activated by NAD+ within your cells. They are responsible for many of the beneficial effects resulting from high NAD+ levels. Sirtuins are so important they are found in every cell and have been conserved throughout evolution.
There is great interest in sirtuins due to their ability to reverse signs of ageing and prevent disease. DNA repair, stress resistance, enhancing immune function, improving mitochondrial function, neuroprotection, decreasing inflammation and enhancing metabolism are just a few of the benefits of sirtuin activation.
Nicotinamide is NOT a SIRT Inhibitor
Before we begin to unravel the relationship between nicotinamide and sirtuins, we must appreciate that NAM is the bodies preferred NAD+ precursor and has the highest bioavailability of all the precursors (NAM, NR and NMN). Furthermore, the majority of cellular NAD+ is made via the Salvage Pathway which converts NAM the waste product from NAD+ breakdown into fresh NAD+. This means that NAM doesn’t hang around for long inside healthy young cells as it is rapidly converted to NAD+, so in the body it is unlikely to inhibit sirtuins.
Studies suggesting NAM is a sirtuin inhibitor do not reflect human physiology
The studies which suggest that NAM is a sirtuin inhibitor are conducted in vitro meaning they are done on isolated cells within a test tube or petri dish. Therefore, they are not representative of what occurs inside the body. In our body cells do not act or function in isolation, they are connected via many networks and feedback pathways and constantly communicate with each other.
It is not uncommon for scientific studies to be conducted in vitro but it is well understood that any findings from such research may not be reproduced in vivo (when studying whole organisms). The majority of in vitro studies are a starting point and any conclusions are studied in animals or humans to ensure the data is robust.
Furthermore, these studies use exceptionally high concentrations of NAM that would never be reached under normal physiological conditions. Cells have many feedback pathways and sensors to maintain homeostasis, this ensures that conditions within the cell are kept at optimal levels. If NAM levels within the cell were getting abnormally high then the cell would methylate NAM, tagging it for removal from the cell.
The Salvage Pathway is the key to NAD production
As described earlier NAM is quickly used up in young cells via the salvage pathway. The problems occur when our cells get older and the salvage pathway begins to fail, due to decreased levels of the NAMPT enzyme. Ultimately causing levels of NAM to accumulate and potentially leading to its inhibitory effects on sirtuins.
All the data indicates that NAD+ is needed to activate sirtuins, the solution is therefore to repair the salvage pathway. By increasing levels of NAMPT and enabling the salvage pathway to recycle NAM into fresh NAD+ all these issues are overcome. The cell has high levels of NAD+, increased sirtuin activity and no methyl donor depletion.
The most common issues and misconceptions surrounding NAD+ supplements are all due to taking precursors (NR and NMN) alone. Simply filling the cells with more of the raw materials does not address the underlying issues which cause the age-related decline in NAD+. To restore youthful NAD+ levels you must target and fix the salvage pathway which is at the heart of NAD+ production. Once that has been repaired feeding the cells with NAM actually provides a long-term sustainable boost in NAD+ and enhances sirtuin activity.
To learn about other Myths and Misconceptions regarding NAD.
References
Bonkowski, M. S., & Sinclair, D. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nature reviews. Molecular cell biology, 17(11), 679–690.
Imai, S. I., & Guarente, L. (2016). It takes two to tango: NAD+ and sirtuins in aging/longevity control. npj Aging and Mechanisms of Disease, 2(1), 1-6.
Hwang, E. S., & Song, S. B. (2017). Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cellular and Molecular Life Sciences, 74(18), 3347-3362.