Scientists have identified a previously unknown route for cellular fuel delivery.
The finding could shed light on the process of aging and the chronic diseases that often accompany it.
With age, cells gradually lose their ability to take in and process fuel. A cell that can’t fill its fuel tank, so to speak, can’t perform its proper functions. Researchers are interested in finding ways to boost the energy supply of aging cells in an effort to stave off the detrimental effects of the inevitable passage of time.
A key element of any cell’s fuel supply chain is a molecule called nicotinamide adenine dinucleotide (NAD). Past work has shown that NAD levels in tissues throughout the body decrease with age. One way cells manufacture NAD begins with a precursor molecule called nicotinamide mononucleotide (NMN), which is naturally in foods such as edamame, broccoli, cabbage, cucumber, and avocado. But how NMN gets into cells for processing into NAD has long been a mystery.
In the new study, scientists identified a protein responsible for transporting NMN directly into cells, where they can use it for cellular fuel production. Not only does this protein move NMN into cells, it does so rapidly.
‘The mystery transporter’
The researchers long suspected there was a direct route for NMN to get into cells, simply because they had measured the speed with which NMN made the journey from the gut into the bloodstream and then into tissues throughout the body. In mice, that journey happens in a matter of minutes. The researchers felt there wasn’t time for complex biochemical reactions that might convert NMN into another form that cells could take up.
“To achieve such fast uptake of NMN into the tissues, we speculated that there must be a specific NMN transporter that moves NMN directly into cells, even though no one had ever seen such a thing,” says Shin-ichiro Imai, a professor of developmental biology at Washington University School of Medicine in St. Louis.
The researchers conducted multiple experiments in cells and mice, identifying and then verifying that a protein called Slc12a8 is in fact the mystery transporter. The researchers also showed that Slc12a8 requires the presence of sodium ions to transport NMN into cells.
In addition, the scientists showed, intriguingly, that cells dial up the expression of the Slc12a8 gene when NAD levels fall. When first author Alessia Grozio, a staff scientist in developmental biology, deliberately lowered NAD levels inside cells and then gave NMN to compensate, the resulting NAD the cell manufactured overshot the amount she was expecting to see.
This suggested that cells don’t just passively accept loss of NAD; they work to maintain their fuel supply by increasing amounts of the NMN transporter, thereby increasing their capacity to bring the raw materials required to make NAD into the cell. So aging cells can, to a degree, compensate for a depleted fuel supply. When NAD inside the cell drops, cells make more NMN transporters, increasing the amount of NMN they can bring inside.
Imai and Grozio point to the importance of the interaction of NMN and its transporter. It may not be enough, for example, to give NMN if the transporter is not working well. They see a role for both supplementing NMN and enhancing the function of Slc12a8—the NMN transporter—in therapies that might help maintain cellular energy levels with age.
Indeed, past work in Imai’s lab has shown that giving NMN to older mice has beneficial effects on metabolism throughout the body, including positive effects in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight, and activity levels. They also found that the benefits of supplementing NMN only applied to older mice. Young, healthy mice likely have no trouble manufacturing sufficient NAD.
“What may be important in a future strategy is the combination of giving NMN along with stimulating the transport of NMN into cells,” Imai says. “With aging, we see a bottleneck in NAD production. The body loses its ability to manufacture NAD over time. At the same time, it seems to begin burning more NAD, likely due to chronic inflammation. If we can give NMN and aid its transport into cells, that may be a way to bypass the bottleneck.”
With this in mind, Imai’s lab already has identified small molecules that enhance the function of the NMN transporter. Working with Washington University’s Office of Technology Management, a company in Japan called Teijin Limited that is working on new therapies targeting the chronic diseases of aging has licensed this technology. There also is an ongoing clinical trial investigating the effects of NMN on older adults. Washington University and Teijin also have a sponsored research agreement related to this work.
The study appears in the journal Nature Metabolism.
The Diabetes Research Center; the Nutrition Obesity Research Center; and the Hope Center for Neurological Disorders, all at Washington University School of Medicine, supported the research. The National Center for Research Resources of the National Institutes of Health; a Tanaka Scholarship from Tsunemaru and Megumi Tanaka; the UK Research Council and Biotechnology and Biological Science Research Council; and the National Institute on Aging of the NIH further supported the research.