NMN vs. NR: Why NMN May Be Better for Older and Obese Adults

Highlights

• In both obese and older adults, the activation of a gene for an enzyme that converts NR to NMN is reduced. 
• In both obesity and aging, the activation of a gene for sirtuin-5, an age-promoting enzyme, is reduced. 
• The alterations in NAD+ metabolism are associated with poor health conditions, such as excess fat and inflammation. 

Researchers from the University of Helsinki in Finland hypothesized that obesity and aging have kindred effects on NAD+ metabolism. To test this, they examined fat tissue samples taken from identical twins, as published in a new study in the International Journal of Obesity. The fat tissue was analyzed for changes in mRNA, which reflects changes in gene activity. According to their results, both aging and obesity are associated with deficits in NAD+ metabolism, but in different ways. 

Effects of Obesity and Aging on NAD+ Synthesis 

To assess the effect of obesity, the fat tissue of leaner twins was compared to that of their heavier twin siblings (average age: 46). To examine the consequences of aging, the fat tissue of young (average age: 30) participants was compared to that of old (average age: 65) participants. By measuring changes in mRNA from the participants’ fat tissue, the Finnish researchers found alterations in NAD+ synthesis genes that could point to the differential effectiveness of NAD+ precursors. 

One of the NAD+ synthesis pathways (the Preiss-Handler pathway) begins with the NAD+ precursor nicotinamide, which is converted to NAD+ upon entering cells. In both obesity and aging, at least one enzyme responsible for this conversion was reduced. Namely, the mRNA for the enzymes NMNAT and NADSYN1 were significantly reduced in obesity and aging, respectively. 

Another NAD+ synthesis pathway (the salvage pathway) begins with NR or NMN entering cells. When NR enters cells, it is converted into NMN before being converted into NAD+. In both aging and obesity, the mRNA for NRK1, an enzyme that converts NR into NMN, was significantly reduced. Additionally, the enzyme that converts NMN into NAD+, NMNAT, was only reduced in obese participants. 

Together, these findings suggest that obesity and aging differentially alter NAD+ synthesis genes. The only exception is NRK1, the gene responsible for converting NR to NMN, which was downregulated in both obesity and aging.  

Effects of Obesity and Aging on NAD+ Consuming Enzymes 

There are several families of enzymes that utilize NAD+ as fuel to function. Aside from the NAD+ synthesis genes, the researchers measured genes for these enzymes. 

Sirtuins

Sirtuins are a family of seven enzymes, and some of them tare linked to promoting healthy aging. The researchers found that sirtuin-5 was reduced in both obesity and aging. Animal studies suggest that sirtuin-5 is involved in activating brown fat cells, which convert calories into heat instead of cellular energy. However, the role of sirtuin-5 in humans is not well characterized. 

In obesity, sirtuin-1 and sirtuin-3 were reduced, potentially contributing to inflammation, mitochondrial dysfunction, and other drivers of aging. Additionally, sirtuin-6, involved in protecting DNA and reducing inflammation, was increased in obesity. This increase may have been a compensatory response, but further research is needed, as sirtuin-6 has previously been shown to be reduced in obesity.  

Poly Adenosinediphosphate Ribose Polymerases (PARPs) and CD38 

PARPs are a family of enzymes involved in repairing DNA. The most abundant PARP, PARP-1, was increased in older participants but not in obese participants. Elevations in PARP-1 are associated with inflammation in animal models and neurodegeneration in humans, likely as a compensatory response. Additionally, an enzyme called CD38, which is thought to be the primary consumer of NAD+ in old age, causing NAD+ depletion, was increased in older participants, as expected, but not in obese participants. 

NAD+ Alterations are Associated with Metabolic Aging 

To gain further insights, the researchers assessed the relationship between the observed gene alterations and measured health parameters in obesity and aging. They found that alterations in NAD+ and sirtuin metabolism were associated with having more subcutaneous, abdominal, and liver fat. These gene alterations were also associated with pro-aging factors like low “good” HDL cholesterol, insulin resistance, and inflammation. Elevations in PARP1 were also associated with liver fat, insulin resistance, and inflammation. 

Along those lines, the heavier twins had 65% more subcutaneous fat tissue, double the abdominal fat, and 360% more liver fat than their lean counterparts. The heavier twins also exhibited increased inflammation, insulin resistance, and low HDL cholesterol. The older participants had larger fat cells, more abdominal fat, higher “bad” LDL cholesterol, and were more insulin resistant than their younger counterparts. Together, these findings suggest that the gene alterations in aging and obesity, while not exactly the same, lead to similar pro-aging effects. 

Study Limitations 

The study has several limitations, one being that only mRNA was measured. While alterations in mRNAs reflect the activity of their corresponding proteins, this is not always the case. Therefore, it is necessary to determine the functional outcomes of the changes in mRNA observed in the fat tissue of obese and older adults. Another limitation is that the fat tissue samples were retroactively analyzed from previous longitudinal studies. For this reason, we don’t know if the mRNA alterations are a cause or consequence of obesity and aging. 

Is NMN Better than NR? 

The study showed that, in the fat tissue of obese and older adults, there was a downregulation of NRK1 mRNA. NRK1 is an enzyme that converts NR into NMN, and this downregulation suggests that NRK1’s activity could be reduced. This means that the conversion of NR into NMN could be less efficient in obese and older adults. If NRK1 is less efficient at converting NR to NMN, the conversion of NR to NAD+ may also be less efficient, as NR must first be converted to NMN before being converted to NAD+. 

Moreover, NMNAT mRNA was downregulated in obese but not older adults. NMNAT is an enzyme that converts NMN to NAD+, so its downregulation could point to a reduction in the conversion of NMN into NAD+. If so, the conversion of NR to NAD+ in the fat tissue of obese individuals may be blunted by the reduced activity of both NRK1 and NMNAT. In contrast, the conversion of NR into NAD+ in the fat tissue of older adults may only be blunted by a lack of NRK1 activity.  

With that being said, there is still no consensus on what happens to NMN and NR before they reach our cells. At least one study has shown that NMN is converted into NR before it enters cells. Another study showed that NMN’s conversion to NAD+ is dependent on NRK1. Still, a more recent study showed that NMN and NR are converted to nicotinic acid, another NAD+ precursor, in the gut before reaching the bloodstream. If NMN is converted to NR or other NAD+ precursors before entering cells, then reduced NRK1 activity may not make a difference if choosing between NMN and NR.