In my opinion, this was the “Top Anti-aging Story” of 2013 – The story of how mitochondrial dysfunction is not due to intrinsic mitochondrial degeneration (i.e. the Free Radical Theory of Aging or the Wear and Tear theory) but due to inadequate expression of mitochondrial encoded genes which are controlled by cell nuclear factors. Specifically, when nuclear levels of NAD are low, a sequence of events occurs in the cell nucleus that ultimately results in a lack of adequate expression of mitochondrial DNA genes that are required for Complex I, III, and IV in mitochondrial electron transport. In this scenario, the nuclear-encoded proteins required for mitochondrial electron transport chain are still expressed, but the proteins whose genes are encoded only by mitochondrial DNA are not expressed. Thus, mitochondrial electron transport cannot occur and cells develop a metabolic picture which is typical in cancer, which is called the
Warburg effect. With Warburg-type metabolism, cells do not generate ATP from the mitochondria and instead, become dependent on cytoplasmic generation of ATP via aerobic glycolysis.
The primary driver of this “metabolic reprogramming” is the transcription factor, Hypoxia Inducing Factor 1 alpha (HIF-1α), which normally only activates Warburg-type metabolism when oxygen levels are low. Unfortunately, when nuclear NAD+ levels are low, HIF-1α is stabilized and is not degraded by
VHL as would normally be the case. As a result, cells are “metabolically reprogrammed” to use aerobic glycolysis in the presence of normal oxygen. HIF-1α inhibits a chain of events that ultimately results in a reduced expression of the mitochondrial transcription factor, TFAM, which normally migrates from the cell nucleus to the mitochondria to stimulate mitochondrial DNA replication. As a result, mitochondrial encoded genes are expressed. When HIF-1α inhibits TFAM, this does not occur. The nuclear encoded mitochondrial proteins are still created via the transcription factor Nrf1, but because TFAM is suppressed by HIF-1α no mitochondrial-encoded protein components of the electron transport chain are expressed. This results in mitochondria that cannot make ATP but still have defective electron transport chains that “run in reverse”. This “reverse electron transport” results in the production of uncontrolled amounts of free radicals from the mitochondria, which then create the “Universal Signature of Aging” which is mitochondrial dysfunction with high free radical production. All of these events can be traced back to inadequate NAD+ in the nucleus. Without adequate NAD+ in the nucleus, SIRT1 cannot function, since NAD+ is a mandatory co-factor for all of the Sirtuins. What David Sinclair and colleagues from both Harvard and Australia showed in a
landmark publication late in 2013 was that supplementation with an NAD+ precursor could reverse this mitochondrial dysfunction and “Warburg-like” metabolic state in mice in one week. Sinclair and associates used an NAD+ precursor called NMN, but previous work showed that another NAD+ precursor could also work, Nicotinamide Riboside (NR). NMN is only one step away from NAD+, but is difficult to make and is very expensive. NR is two steps away from NAD+, but is much easier to make, is much less expensive, and is already available for sale under the proprietary name,
Niagen. To date, no studies in humans have replicated the findings from Sinclair’s mice studies. Until these are done, we must “hold our breath”. However, in Sinclair’s studies, all of the mitochondrial dysfunction seen in aging mouse skeletal muscle was reversed (with the exception of muscle strength).
In summary, deficiency of NAD+ in the nucleus of muscle cells produces a state of “pseudohypoxia”, where there is adequate oxygen but high levels of HIF-1α. This results in the inhibition of the mitochondrial transcription factor, TFAM, which inhibits the expression of mtDNA. As a result, mitochondria do not produce the proteins encoded in mitochondrial DNA that are required for “forward electron transport” and ATP production. “Reverse electron transport” occurs and high levels of free radicals are produced, giving the exact picture of aging. In this picture cells are dependent on aerobic glycolysis in the cytoplasm and cannot burn fat. They develop the exact metabolic picture of cancer, called the Warburg effect. The mitochondrial dysfunction and this Warburg-type metabolism are fully reversible with the supplementation of NAD+ precursors.