The analysis, published in Aging Cell, also found that changes in muscle mitochondrial DNA content correlated with changes in MEAT-derived epigenetic age acceleration, which suggested a potential relationship between mitochondrial adaptations and epigenetic clock measures.
The analysis included results from a five-month human NR trial (using 1,000 milligrams per day of Niagen nicotinamide riboside from Niagen Bioscience) and independent four-to-six-week HIIT [high-intensity interval training] studies, along with new in vitro data from human muscle cells.
“Our findings provide novel insights by demonstrating that both NR supplementation and exercise can modulate epigenetic aging in muscle, and that these effects appear to be both clock- and intervention-specific,” wrote researchers from academic institutions in Finland, Denmark and Australia.
“While this study is limited with the mechanistic data, it provides evidence for future research aimed at disentangling the molecular mechanisms underlying fluctuations in human biological aging in response to mitochondria targeting interventions.”
The new analysis was welcomed by Rob Fried, CEO of Niagen Bioscience. “This is among the first human studies suggesting that Niagen NR supplementation may alter epigenetic aging in skeletal muscle, rather than simply increasing NAD+ or improving mitochondrial function,” he said. “It strengthens the idea that NAD+ restoration can influence biological aging pathways at the tissue level.”
Nicotinamide riboside
In 2004, Dr. Charles Brenner discovered that nicotinamide riboside – a version of niacin (vitamin B3) – is a potent precursor to nicotinamide adenine dinucleotide (NAD). NAD is an important cellular co-factor for improvement of mitochondrial performance and energy metabolism.
As organisms age, NAD+ levels drop, which leads to a decrease in mitochondrial health; this in turn leads to age-related health issues. Aging muscles in particular tend to lose mitochondrial content and function, contributing to sarcopenia and frailty. NAD+ levels also can be depleted by lifestyle choices such as overeating and lack of exercise. By boosting NAD+, NR can increase mitochondrial health and induce the creation of new mitochondria.
Irvine, CA-based Niagen Bioscience (formerly Chromadex) began accumulating the IP surrounding NR by licensing patents from Cornell University, Dartmouth College and Washington University in St. Louis. This IP has been challenged over the years, but Niagen remains the leading player in this sector.
The potential health benefits of NR are reported in dozens of clinical trials, with the data consistently showing that oral NR supplementation can increase NAD+ levels, including in the brain, improve endothelial function in blood vessels and reduce inflammatory biomarkers.
New analysis
The new study analyzed skeletal muscle and blood samples from three previously published clinical studies, combined with new laboratory experiments in human muscle cells using seven distinct epigenetic clocks (DunedinPACE, PCHorvath, PCHannum, PCPhenoAge, PCGrimAge, GrimAge2, and MEAT) to assess epigenetic age acceleration (EAA), a molecular measure of biological aging.
“Our earlier work showed that Niagen NR can enhance muscle mitochondrial health, and this study shows that these benefits may extend to the epigenetic level,” stated Dr. Eija Pirinen, University of Helsinki and University of Oulu, and a senior author on the study. “It is a meaningful step toward understanding how NAD+ restoration may influence molecular markers of aging in human skeletal muscle; however, additional research must be conducted.”
The new analysis revealed a significant association between EAA and mitochondrial content following Niagen supplementation, with five months of supplementation linked to a reduction of muscle EAA by approximately 2.5 years after five months, as measured by the muscle-specific MEAT epigenetic clock. In addition, significant reductions were observed with the DunedinPACE and PCHannum clocks.
Following Niagen NR supplementation, six of seven skeletal muscle epigenetic clocks showed changes consistent with lower EAA, with statistically significant reductions observed in the MEAT, DunedinPACE, and PCHannum clocks. Three clocks showed significantly lower epigenetic age acceleration after supplementation in blood.
The in vitro experiments found that NR increased NAD+ levels in human myotubes (muscle cells) by 1.52-fold versus control-treated cells, though no significant changes in epigenetic aging markers or mitochondrial DNA quantity (mtDNAq) were observed in this cell model.
On the other hand, HIIT was associated with higher EAA, said the researchers, which may be due to the HIIT-associated inflammation and transient muscle damage working against certain epigenetic aging signals.
“These findings suggest that certain epigenetic clocks, including MEAT and DunedinPACE, respond to NR and HIIT interventions,” wrote the researchers. “Although linked to mitochondrial content and increased NAD+ biosynthesis, the modest correlation coefficient implies that the clocks capture unique cellular adaptations not fully explained by these markers alone. Thus, they may hold potential as tissue level biomarkers for detecting molecular responses to interventions, although the exact drivers of clock changes across tissues and individuals remain to be elucidated.”
Source: Aging Cell, 2026, 25, no. 8: e70638, doi: 10.1111/acel.70638. “The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.” Authors: A. Heikkinen, et al.
