NMN Supports Intestinal Function in Aging Pig Cells and Mice
Our gut regenerates itself nearly every day to keep our metabolism sharp. But as we age, this process slows, and the billions, if not trillions, of microbes that live in our gut become unbalanced. That's why many grocery items, from yogurt to cereal to kombucha, and supplements have been developed as probiotics—foods or supplements that contain live microorganisms intended to maintain or improve the "good" bacteria in the body. But is there a way to directly support the health of the aging gut?
Chinese researchers show that NMN supplementation can support intestinal structural and functional health in aging cells and tissues. The research team from the Jiangxi Academy of Sciences thinks that the underlying mechanism is likely that NMN supplementation boosts the NAD+ pool in the intestine and activates the signaling pathways related to antioxidant, anti-inflammatory, and barrier functions that support healthy intestinal aging in mice. In cultures of senescent cells, which mimic the aging hallmark of attested cell growth and replication, NMN supported protective effects on oxidative stress and barrier dysfunction.
“To the best of our knowledge, this study is the first to report the effects of NMN supplementation on intestinal function in aging models, and we hope the findings could help future endeavors to develop agents to retard intestinal aging and explain the underlying regulatory mechanism,” wrote the authors.
Improving Intestinal Integrity
The intestine is a physical and chemical barrier that extensively interacts with outer stimuli, including various metabolites, signals from immune cells, and commensal microorganisms. The intestine also takes up nutrients throughout the lifetime. As the intestine ages, the ability of this interface to sift through nutrients, block out pathogens, and keep the microbiome balanced begins to deteriorate. Increasing evidence has shown the mutual effect between aging and gut microbiota. While some studies have shown the effects of NMN on gut microbiota in adult mice, the present study found that NMN supplementation for four months had little effect on aging mice's gut microbial diversity and composition.
To investigate the regulatory effect of NMN on the age-related intestinal tissue structure, lead author Meng Ru and colleagues analyzed crucial gut structures—the duodenum, jejunum, and ileum of the small intestine, and the colon (large intestine)—of aging mice in the control and NMN-intervention groups. The Chinese research team found that NMN administration has a noticeable effect on the jejunum and colon rather than the duodenum and ileum, such as decreased pockets of intestinal stem cells (crypt) and length of the grooves critical for intestinal function (villi) in aged mice. Intestinal villi have vital roles in nutritional absorption. NMN administration enhanced the jejunal villus length, implying that NMN may play a role in preventing the intestinal villus structural and functional decline and thus improving nutritional absorption. Aging can cause a decrease in stemness and proliferation of intestinal stem cells (ISCs) and an increase in apoptosis. But, in this study, NMN may not directly impact the ISCs.
NAD+ levels are a critical hallmark for physiological aging. Raised NAD+ content was observed in the jejunum after long-term administration of NMN. The duodenum, jejunum, and ileum are the primary tissues for digestion and absorption, while the colon is responsible for the absorption of water and electrolytes. Previous research pinned down a specific NMN transporter encoding gene (Slc12a8) that shows higher gene activity levels in the jejunum and ileum rather than in the colon. Ru and colleagues speculate that the high levels of Slc12a8 facilitate the jejunum's higher absorption of NMN molecules, increasing the jejunal NAD+ level.
Bolstering Barrier Function
Ru and colleagues then dove deeper into understanding how NMN supports intestinal integrity during aging. Since NMN is an NAD+ precursor, they took a look at certain enzymes involved with cell health, aging, and survival that depend on NAD+ to function, such as the sirtuin family of enzymes. The Chinese researchers found that aging mice treated with NMN showed significantly increased gene activation of two sirtuins: SIRT3 and SIRT6. SIRT3 is involved in fighting off oxidative stress by bolstering the antioxidant response. SIRT6 is involved in inflammation, genome stability, and metabolic balance, and stimulation of this gene has been reported to extend lifespan in mice.
In addition, NMN enhanced the activity of genes related to intestinal barrier function and antioxidant defense, notably Nrf2. SIRT6 was uncovered as an Nrf2 coactivator to regulate oxidative stress in stem cells. Nrf2-based signaling also further improves the levels of tight junction proteins necessary for the intestine to work as a barrier to only allow the absorption of specific molecules, such as water and nutrients.
An earlier study has reported that SIRT3 can preserve SIRT6 levels through declined oxidative stress, while SIRT6 maintains the SIRT3 level via upregulating Nrf2-dependent SIRT3 gene activity. Thus, Ru and colleagues think that the underlying mechanism might be that NMN boosts the NAD+ pool and activates SIRT3/6. These changes enhance gene activity concerning the antioxidant and epithelial barrier function, which retards the aging caused by excessive production of oxidative stress and improves the intestinal barrier function.
To further verify the role of NMN in relieving the age-related intestinal barrier function and its underlying molecular mechanism, Ru and colleagues used pig intestinal cells to evaluate the effect of NMN on the cellular antioxidant capacity and epithelial barrier function. Treating the cultured pig intestinal cells with a senescence-inducing molecule called D-gal led to increases in two key drivers of cell aging: oxidative stress and activity of inflammatory genes. However, both oxidative stress and the activation of these inflammatory genes in D-gal-treated intestinal pig cells were reduced by NMN treatment.
This research connects the dots between the effects of NMN on the jejunum in aging mice with the ability of NMN to attenuate aging-associated intestinal oxidative stress and barrier dysfunction by modulating the SIRT6/3-Nrf2-based antioxidant signaling pathway. To date, there is not much known about the effect of NMN on the gut in humans. While there is data that corroborates the high levels of the NMN transporter Slc12a8 in the gut of humans, future research will need to tease out whether the ability of NMN to support healthy gut aging carries over to humans.
Luo C, Ding W, Yang C, Zhang W, Liu X, Deng H. Nicotinamide Mononucleotide Administration Restores Redox Homeostasis via the Sirt3-Nrf2 Axis and Protects Aged Mice from Oxidative Stress-Induced Liver Injury. J Proteome Res. 2022;10.1021/acs.jproteome.2c00167. doi:10.1021/acs.jproteome.2c00167