Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner

Aging is a universal process, yet it does not wear down every part of the body in the same way, nor does it affect men and women identically. At the heart of this biological decline is a molecule called NAD+, which acts as a vital fuel for the enzymes that keep our cells running, repair damaged DNA, and manage energy. As mammals grow older, the levels of this essential fuel drop significantly, sometimes by half, leaving cells struggling to maintain their function. Scientists have long suspected that replenishing this fuel might slow the aging process. To test this, researchers have turned to a specific precursor molecule known as NMN, which the body naturally converts into NAD+. While previous studies in mice and humans have shown that taking NMN can improve various health markers, such as metabolism and physical endurance, a critical question remained unanswered: does taking NMN for a long time actually extend the total number of years a mammal lives?

A large team of researchers set out to answer this by feeding NMN to mice for the majority of their natural lives. They started giving the supplement to mice at thirteen months of age, which is roughly middle age for a rodent, and continued the treatment until the animals died of natural causes. The study involved hundreds of mice, split evenly between males and females, and was designed to be rigorous and long-term. The researchers did not just count how long the mice lived; they also tracked how healthy the animals were as they aged, measuring things like frailty, physical strength, and metabolic health. They also looked deep inside the bodies of these mice, examining their gut bacteria, their blood chemistry, and the activity of genes in their muscles and livers to understand exactly how the supplement worked.

The results revealed a striking difference between the sexes. In female mice, the long-term treatment with NMN extended their median lifespan by 8.5 percent. This means that the typical female mouse lived longer than her untreated peers. The treatment also delayed the onset of frailty, keeping the female mice healthier for a longer portion of their lives. However, the story for the male mice was different. While the male mice treated with NMN did not live longer than the untreated males, they did show significant improvements in their health. They maintained better metabolic health, gained less body fat as they aged, and remained more physically active, particularly during their active night cycles. Both male and female mice treated with NMN showed a delay in the general decline of physical function, suggesting that the supplement helped them stay robust even if it did not extend the life of the males.

To understand why the supplement helped females live longer but only helped males stay healthier, the researchers investigated the biological mechanisms at play. They discovered that the gut bacteria played a crucial role. In both male and female mice, the NMN treatment caused a massive increase in a specific type of beneficial gut bacteria called Anaerotruncus colihominis. This bacterium is known to produce butyrate, a substance that supports gut health and reduces inflammation. The researchers found that this bacterium can actually consume NMN and convert it into NAD+ within its own cells, which helps the bacteria grow and thrive. The presence of this bacterium was strongly linked to better health and longer life in the mice, suggesting that the supplement works partly by reshaping the gut microbiome to support the host.

The researchers also looked at how the mice's bodies processed the supplement at a genetic level, and here the sex differences became even clearer. In the female mice, the NMN treatment boosted the activity of genes related to mitochondrial function. Mitochondria are the power plants of the cell, and keeping them working efficiently is essential for longevity. The female mice showed increased energy production and better DNA repair mechanisms in their tissues. In contrast, the male mice showed a different response. Their bodies increased the activity of genes involved in DNA repair, which helped them maintain metabolic health and muscle size. However, this benefit came with a trade-off: the male mice also showed increased activity in genes related to inflammation and immune response. The researchers suggest that this heightened inflammatory response in males might have prevented them from living longer, even though it helped them stay physically healthier.

The study also examined how the mice metabolized the NMN. The researchers found that the body does not simply absorb NMN and turn it directly into NAD+ in a straight line. Instead, a significant portion of the NMN is processed by gut bacteria, which strip away a chemical group to turn it into a different molecule that is then reassembled into NAD+ by the body. This pathway, known as the Preiss-Handler pathway, appeared to be more active in the female mice, potentially explaining why they saw a greater benefit in terms of lifespan extension. The male mice, while also benefiting from the supplement, seemed to experience a more complex mix of effects where the benefits of improved metabolism were balanced by the costs of increased inflammation.

This research provides the first clear evidence that long-term NMN supplementation can extend the lifespan of female mice, but it also highlights that the effects are not uniform across sexes. The treatment successfully delayed frailty and improved health in both male and female mice, but it only extended the total lifespan of the females. The findings suggest that while boosting NAD+ levels is a powerful strategy for improving health in aging, the specific biological response depends heavily on whether the subject is male or female. For the males, the supplement improved metabolic health and physical activity but triggered an inflammatory response that may have limited its ability to extend life. For the females, the treatment enhanced mitochondrial function and reduced frailty, leading to a longer life.

The study also points to the gut microbiome as a key player in the aging process. The increase in the beneficial bacterium Anaerotruncus colihominis was a consistent finding in both sexes and was directly linked to better health outcomes. This suggests that the way a person or animal processes supplements like NMN is deeply connected to the community of microbes living in their gut. The researchers propose that in the future, therapies might be tailored to account for these sex differences and microbiome variations to maximize the benefits of NAD+ boosting.

Ultimately, this work moves the field of aging research forward by demonstrating that a simple dietary supplement can have profound, long-term effects on health and longevity in female mice, but it also serves as a reminder that biology is complex and often different for men and women. The researchers did not find a single magic bullet that works the same way for everyone. Instead, they found a nuanced picture where NMN helps both sexes stay healthier, but the path to a longer life involves different biological mechanisms for males and females. The study underscores the importance of considering sex differences in aging research and suggests that future treatments may need to be customized to achieve the best results for each individual.