P7C3_structure

Chemical structure of the drug P7C3.

Google’s venture biotech company, Calico, has largely been stealthy about its moves since the initial announcement of its founding a year ago. Last week, Calico broke this relative silence with an announcement that it has acquired the rights to a class of drugs labeled “P7C3”, and in the process offered the first strong indications of where the venture might be headed in the near future. It is now clear that Calico, in collaboration with pharmaceutical partner AbbVie, will move forward to develop P7C3 as one of its first anti-aging interventions. But what are P7C3 drugs, and why do we care about them?

P7C3 was first discovered in 2010 when scientists at the University of Texas Southwestern Medical Center were looking for compounds that enhance the formation of new neurons in the brains of mice. In the process, the researchers found that P7C3 had both protective and regenerative functions in the brain. This observation had strong potential implications for neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s diseases. Despite the importance of this finding, the mechanism behind the drugs’ activity remained unknown until last week, when researchers published a report in the journal Cell indicating that P7C3 binds and activates nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme in the synthesis of nicotinamide adenine dinucleotide (NAD+).

NAD+ is an essential metabolite for many cellular functions including energy production, protein deacetylation, calcium signaling, and DNA repair. NAD+ levels decline in many tissues with age. With so many different processes dependent on this molecule, it is not surprising that loss of NAD+ could cause problems in neurons of the brain with age. Earlier this year, researchers at Washington University in St. Louis showed that NAMPT levels – and therefore NAD+ – declined in the brains of mice with age. Supplementation with an NAD+ precursor was able to restore NAD+ levels, enhancing regeneration in the brains of aged mice. Since P7C3 elevates NAD+ levels through activation of NAMPT, it is likely that this pathway is responsible for the protective and regenerative effects of this drug in the brain.

However, implications of NAD+ decline with age extend far beyond the brain. Last December, a study out of Harvard found that loss of NAD+ in muscles with age resulted in a loss of mitochondrial function, and administration of an NAD+ precursor restored function to the muscles of aged mice. Prior to this, loss of NAMPT activity was linked to type II diabetes in mice that were fed a high fat diet. Administration of an NAD+ precursor restored glucose tolerance and protected against the diabetic effects of high fat diets. These studies indicate that loss of NAMPT and NAD+ are key events in the development of a host of disorders that arise during the aging process.

In each of these studies, loss of NAD+ resulted in decreases in sirtuin activity. The sirtuins are a class of proteins that have been linked to aging and longevity in a broad spectrum of animals, from yeast, to worms and flies, to mammals. Sirtuins consume NAD+ as part of their activity, and loss of NAD+ is directly linked to loss of sirtuin function. This past July, it was shown that NAD+ also acts to stabilize the anti-aging protein BubR1 in a sirtuin-dependent manner, and this process can extend the lifespan of mice. Since BubR1 prevents age-related disease in multiple tissues, NAD+ is likely to be involved in other aspects of aging that have yet to be fully studied.

It is still unknown why NAMPT levels decline with age in multiple tissues, but until we can identify the mechanism behind this, enhancing the activity of the NAMPT that remains may prove an effective tool for combating one of the most common underlying molecular mechanisms of aging that we have identified so far. No wonder, then, that Calico moved so swiftly to acquire P7C3 technology, which holds promise as a NAD-based intervention not only for neurodegenerative disease, but also for so many other disorders of aging.