U.S. researchers 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.
Previous study shows that the levels of a molecule called nicotinamide adenine dinucleotide (NAD) in tissues throughout the body decrease with age, and NAD manufacture in cells begins with a precursor molecule called nicotinamide mononucleotide (NMN).
By experimenting in cells and mice, the researchers have identified and verified that a protein called Slc12a8 is in fact the mystery transporter, and Slc12a8 requires the presence of sodium ions to transport NMN into cells, showed the study published Monday in the inaugural issue of the journal Nature Metabolism.
The researchers further found that cells dial up the expression of the Slc12a8 gene when NAD levels fall. When they deliberately lowered NAD levels inside cells and then gave NMN to compensate, the resulting NAD manufactured in the cell overshot the amount they expected 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.
The researchers highlighted the importance of the interaction of NMN and its transporter, and suggested a role for both supplementing NMN and enhancing the function of Slc12a8, the NMN transporter, in therapies.
Previous study 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. Studies also found that the benefits of supplementing NMN were seen only in 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," said Shin-ichiro Imai, a professor of developmental biology at Washington University School of Medicine in St. Louis. "With aging, we see a bottleneck in NAD production. If we can give NMN and aid its transport into cells, it may be a way to bypass the bottleneck."
The technology has been licensed to a Japanese company that is working on new therapies targeting the chronic diseases of aging.