NR is a supplement that affects energy generation in mitochondria and gene regulation through the same pathway as resveratrol and caloric restriction.  It has been promoted in recent months, and this month is featured in Life Extension Magazine.  But evidence for its life expectancy benefit is indirect.  There have been no positive results for fruit flies, let alone mice.  If it works in humans, benefits will likely be limited to people who are overweight.  And there are reasons to expect only limited benefits from the pathways through which NR works.

Reading about a new life extension supplement, I get excited when I see “we fed it to mice and they lived X% longer”, or better yet, “In preliminary human trials, mortality was found to be Y% lower.”  The articles about NR are full of biochemical pathways and chains of genes that promote other genes.  In my way of thinking, all the biochemistry is important for generating ideas, but the proof of the pudding is in life extension trials.  Lab experiments on live mice run hundreds of thousands of dollars to test a single compound.  We can’t be testing everything under the sun, so we rely on biochemistry for plausible candidates.  But jumping from biochemical theory to marketing of a supplement is a leap of faith that leaves me behind.

Worms and flies are much cheaper to breed than mice, and the experiments last weeks instead of years.  Furthermore, genetics of these lower animals is well-understood, and easy to manipulate.  Experiments with worms and flies provide an intermediate proving ground for ideas before the expensive life span trials with rodents.  The ultimate yield is low.  There are many interventions that work well to extend life in flies that don’t work in mammals.

 

NR and Resveratrol

Resveratrol, which works along similar biochemical pathways to NR, was all the rage from about 2003 to 2006.  First discovered in yeast, its mechanism of action was mapped out.  Len Guarente at MIT and others from his lab put the SIR gene on the  map, and coined the term “sirtuins” for substances that activate these genes.

Excitement mounted as resveratrol was shown to extend life span in worms, and then flies.  A young scientist in Italy launched his career by introducing a short-lived African fish to laboratory genetics.  Nothobranchius lives only a few months, one of the shortest life spans of any vertebrate.  For his PhD dissertation, Dario Ricardo Valenzano (2006) safaried to Africa to bring back samples of Nothobranchius, figured out how to breed them in the lab, and demonstrated they live 60% longer with resveratrol in their food.

Incidentally: Valenzano found best results for an intermediate dose of resveratrol, not the highest or the lowest dose.  This has been a recurrent theme in resveratrol research: a little is better than none, but a lot isn’t better than a little.

Soon after Valenzano’s fish, it was reported that resveratrol failed to extend life span in mice.  We were all disappointed.  The result came from the Harvard lab of David Sinclair, Guarente’s most famous student, who was highly motivated to get good results because he had commercial ambitions for resveratrol derivatives.  Sinclair reported that overweight mice that were fed a high-fat diet could be brought back to a normal life expectancy with resveratrol, but that normal-weight mouse received no life extension from the same treatment.

 

NR in experiments with lab animals

Almost all the literature on NR is about yeast cells.  I can’t find a single study on flies or fish.  I found one study of Alzheimer’s Disease in mice that did not look at life span, but the measured the plaques in the brain that are a symptom of AD.  These are mice that are genetically engineered to be vulnerable to AD, because normally AD is absent in mice.  They showed that feeding these mice NR slowed the progress of their mental decline, a good result that traces dietary cause all the way to behavioral effect, its ultimate benefit.  Another mouse study showed metabolic benefits for mice that were fed to obesity.  This was similar to the result for resveratrol, but not as strong because life extension for obese mice was recorded from resveratrol, but not from NR.  The only study in worms showed a 16% life extension.  This kind of performance would be impressive in mice, but there are many ways to double and triple the life span of worms that don’t work in mammals.  (the record is tenfold increase in a genetically modified worms).;

 

Biochemistry of NR and NAD+ / NADH

Biomolecules are a huge variety of different geometric structures, based mostly on covalent bonds between carbon and carbon or between carbon and hydrogen.  But the body’s energy metabolism is based on ionic bonds, because they store more energy in each bond.  Ionic bonds form between atoms that are very different from each other, like sodium and chlorine in table salt.  The standard biological energy repository is in phosphate bonds.

Every cell has hundreds of mitochondria, which are tiny energy factories that burn sugar and produce  phosphates for the cell’s use.  This energy generation process is an ancient biochemical trick called the Krebs Cycle, and is shared by all plants and animals today.  NAD+ has a role to play in the Krebs Cycle, where it absorbs an electron to become NADH, and then is recycled to NAD+ again.

As we age, we lose mitochondria, and the mitochondria we have become less active.  We have less of all the chemical intermediates of the Krebs Cycle, including CoQ10 and NADH.  CoQ10 is an important anti-oxidant, soaking up ROS and converting their energy to useful form.  CoQ10 has been found to improve heart health, but it has failed to extend life span in mice.

In addition to its role in the Krebs Cycle, NAD+ works through sirtuins.  These are high-level chemical signals that can close up DNA into tight balls (facultative heterochromatin) selectively in certain places to block expression of many genes at once.  NAD+ can turn on sirtuins in order to turn off a panoply of pro-aging genes.  This has been shown to work well to slow aging in obese lab animals, but not normal animals.  It works by some of the same pathways as caloric restriction, but without the restriction.

 

Saturation of the CR pathway

Life span is programmed in a flexible way, so as to respond to external mortality.  Famine is one of the deadliest dangers for populations in nature, and so evolution has provided extra ruggedness in the face of starvation.  Death from aging takes a vacation just when the death rate from starvation is highest, helping to level out the overall death rate and protect against extinction.

The fact that life span is extended by hunger was first discovered in the 1930s, and many years later, the genes and biochemical pathways associated with sensing food scarcity have proven to be the most accessible, the easiest to manipulate.

Underfeeding, and tricking the body into thinking it is underfed, are the simplest, most fertile, and most reliable strategies for extending life span.  On a percentage basis, these strategies work best in short-lived species.  With caloric restriction we can double the life span of worms, add 40% to the life span of mice, but only 15% to dogs and 5% or less in Rhesus monkey experiments reported last year.  So 3 to 5 years is an optimistic range for the available flexibility in humans via the caloric restriction pathway.

There are many ways to activate this pathway, either by eating less, exercising, or taking metformin or resveratrol, for example.  The benefit you get from each of these do not add together; rather you are getting the same 3 years over and over again.  So NR is likely to work best for people who are overweight and not taking metformin or resveratrol.

 

The bottom line

It may be that there have already been experiments feeding NR to mice or rats, but sometimes negative results don’t get published.  I am going to wait and see before jumping on the NR bandwagon.