Mitochondria & aging: ‘Remarkable’ effects for nicotinamide riboside in mice, says new study

According to data published in EMBO Molecular Medicine​​, oral supplementation with nicotinamide riboside “resulted in a remarkable induction of mitochondrial biogenesis and oxidative metabolism, with an increase in mitochondrial mass, […] and respiratory chain protein amounts in the muscle”​.

Mitochondria and aging​

It’s already well known that the function of mitochondria declines with age, while aging is a known risk factor for a number of common age-related and neurodegenerative disorders. This led to the proposition that secondary mitochondrial dysfunction may lead to degenerative diseases.

A role for oxidative stress has been proposed to promote mitochondrial dysfunction, leading some researchers to examine if antioxidants such as CoQ10, and vitamins C and E may play a role. For example, San Francisco-based Edison Pharmaceuticals has been exploring the potential of redox control and mitochondrial function using a vitamin E derivative​ (alpha-tocotrienol quinone), with impressive results.

NAD+​

Another approach has been to raise levels of NAD+ in the mitochondria, which is an important cellular co-factor for improvement of mitochondrial performance and energy metabolism.

David Sinclair from Harvard University, who did so much to boost the anti-aging potential of resveratrol into the mainstream, recently published data from a mouse study in Cell​ (2013, Vol. 155, pp. 1625-1638, doi: 10.1016/j.cell.2013.11.037), which concluded that, “raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner”​. SIRT1 is a cellular protein that plays a major role in mitochondrial biogenesis, glucose regulation and protection against age-related disease.

This has led scientists to look at ways to boost NAD+. NAD+ can be made from tryptophan in a biological process that involves about eight steps. Searching for a more efficient pathway, some scientists are focusing on NAD biosynthesis from nicotinamide riboside (NR), which is a no-flush version of niacin (vitamin B3). NR is a precursor to NAD+ in the mitochondria of animals via a two-step process, making for a more efficient and potent NAD+ source.

Building on Dr Sinclair’s mouse data, scientists from the University of Helsinki (Finland), École Polytechnique Fédérale de Lausanne (Switzerland), the University of Eastern Finland, and the Metabolomics Unit at the Institute for Molecular Medicine Finland (FIMM) now report that oral supplementation with NR “efficiently prevented development and progression of mitochondrial myopathy in mice”​.

Delaying disease progression​

Led by Nahid Khan, the authors of the new EMBO Molecular Medicine​ ​paper report that NR supplements for mice with mitochondrial myopathy “effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and [mitochondrial DNA] deletion formation. ​

“NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease.”​

In a ‘close-up’ (editorial) to accompany the Finnish/Swiss paper, Robert Lightowlers and Zofia Chrzanowska-Lightowlers from the Wellcome Trust Centre for Mitochondrial Research at Newcastle University in England wrote: “​The rationale for increasing NAD+ levels in order to increase mitochondrial mass is reasonable, and the results reported here are compelling.​

“It will of course be necessary to evaluate the NR dosage used by Khan et al, as it appears strikingly high (400 mg/kg/day) compared to most commercially available supplements (60–500 mg/person/day). ​

“Whether such a large dosage is viable as a supplement needs to be established; however, it will be exciting to follow new pharmacokinetic data for this potentially therapeutic nucleoside derivative.”​

Niagen​

In the supplement space, nicotinamide riboside is commercialized by Chromadex, which has been accumulating the IP surrounding the ingredient for a couple of years, having licensed patents from Cornell University, Dartmouth College, and Washington University in St Louis.

The Irvine, CA-based company has signed deals with a number of supplement manufacturers to get its Niagen-branded ingredient into finished products, including High Performance Nutrition’s (HPN) N(R) product to support neuroprotection in contact sports, Thorne Research for the healthcare-practitioner channel, and 5LINX for the use of Niagen in dietary supplements exclusively in the network marketing sales channel in the United States, Canada and Philippines.

Numerous academic institutions are researching the potential health benefits of the ingredient, including Scripps, the Mayo Clinic, ULB Brussels, Queen’s University Belfast, Cornell, Harvard, MIT, and Iowa, with the company in discussions with more.

Sources: EMBO Molecular Medicine​​
Volume 6, Issue 6, pages 721–731, June 2014, doi: 10.1002/emmm.201403943
“Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin-B3”​
Authors: N.A. Khan, M. Auranen, I. Paetau, E. Pirinen, L. Euro et al.

Close-up/Editorial:  EMBO Molecular Medicine​​
Volume 6, Issue 6, pages 705–707, June 2014, doi: 10.15252/emmm.201404179
“Salvaging hope: Is increasing NAD+ a key to treating mitochondrial myopathy?”​
Authors: R.N. Lightowlers, Z.M.A. Chrzanowska-Lightowlers