To understand the process Sinclair has developed, you have to go back to a discovery made by a Japanese researcher named Shinya Yamanaka, who in 2012 won the nobel prize for his discovery of how to transform ordinary adult skin cells into stem cells, cells that are capable of developing into any cell in the human body. Yamanaka accomplished this by adding just four genes into the adult skin cells of mice.
Flash forward to this year, where Sinclair discovered that by eliminating just one of these Yamanaka genes, you could control a slow roll back in the age of a cell - not all the way back to a stem cell but to a much younger version of the same cell. The question is how would the cell know what younger version to become? How would it know what methylation to discard from the epigenome and which to keep in order to become young again?
We all know that DNA contains all our genes, but which genes are turned on or off is controlled by the epigenome. Using methyl markers on DNA, genes are either turned on or off so that the right combination can form various cells such as liver, brain, or any other cell in the body. But over time, extraneous methylation on the DNA occurs from smoking, too much sun, poor diet, lack of exercise, or any other number of factors until the DNA becomes hard to read, like scratches on a CD. So how can we ever hope to become young again if the CD is so scratched that we have lost much of the original information from our youth?
In what is probably the most stunning revelation in his new book, Sinclair believes that the body has actually made a backup copy of the epigenome from a very young age, perhaps even when we were still in the womb. Sinclair doesn't yet know where on the DNA this backup copy resides but it is probably made up of markers using methylation, a protein, an RNA, or even a novel chemical attached to DNA that we haven’t yet discovered. However Sinclair is virtually certain this backup copy exists because without it the cell wouldn't have any idea what version of itself to turn into in order to become young again, no blueprint.
Sinclair's method involved inserting the Yamanaka genes (minus one) into an empty virus shell and then injecting them into the optic nerves of older mice with cloudy vision, blind mice, and younger mice that have had their optic nerves crushed. Optic nerves were chosen because they are the most difficult to improve and results are easier to isolate. The injected genes then somehow communicate with the ancient backup copy of the epigenome to slowly roll back the extraneous methylation (scratches) that have clouded the DNA and return the epigenome to a younger version, restoring vision. Once the virus has been injected into the mice the Yamanaka factors are turned on by injecting mice with an antibiotic called doxycycline. The cellular rollback in time begins and can be stopped at any point by simply discontinuing doxycycline injections, say when the cells reach the equivalent human age of 21.
As we learn how to manipulate the factors that reset our cells, we may one day be able to move away from using viruses to inject Yamanaka factors to simply taking a month’s course of pills. We may also develop a way to treat the entire human body instead of one organ at a time. In any case, the roadmap towards a fountain of youth is starting to shape up and it may be years rather than decades before we begin to see the benefits.
Reading the book gave me some background I didn't have before that makes it more believable.
I used to think Dr Sinclair kind of "lucked" into his role with Resveratrol, somewhat like Dr Brenner did in discovering NR pathway to NAD+.
But he actually had a major Eureka breakthrough at Dr Guarantes lab in late 90's where he first postulated his information theory of aging that is behind his "scratched CD" analogy, and also showed it was excessive burden on sirtuins due to DNA repair playing a key role in aging way back then.
So it wasn't just Resveratrol, and leveraging the fame from that to take the lead on NAD, then having the platform to get people to pay attention to his theory. He had these theories for decades and has been discovering things that support his theories.
The doxycycline is only used as a trigger for the virally inserted genes. It’s not being used for it’s antibiotic properties, but instead because it’s a safe and specific chemical that they are able to use (in ways that don’t entirely understand) as a sort of key to activate the inserted (and “locked”) genes.
There are other chemicals that can be used as a key/lock system, they just happened to choose doxycycline for this experiment.
The idea is: if the genes are left on for too long, cells might get de-methylated all the way back to pluripotent stem cells and now you’re just a bag of undifferentiated cells and nobody wants to turn back into an embryo. But a few days activating the genes with the doxycycline trigger is just enough to rewind the cells back to youthful levels.