Imagine if your cells had a few simple switches that could be turned on in order to rewind their age and convert them back to young cells. Well … it turns out they do.
David Sinclair of Harvard Medical School and a whole bunch of other researchers from Harvard, Yale, UCLA, Massachusetts General Hospital, and the University of New South Wales have teamed up to demonstrate the reversal of aging in real animal tissues. By turning on three genes, they cured both glaucoma-associated and age-related vision loss in mice and demonstrated regeneration in cultured human nerve cells. The results were published December 2 in the journal Nature.
While there has been previous success in halting the progress of degenerative retinal disease, this is something quite different: In whole live animal tissues, without causing the cells to lose their identity or to grow uncontrollably (form tumors), these researchers achieved a remarkable feat. They didn’t just halt the aging process.
They reversed the aging process.
In 2006, four genes called the Yamanaka factors were identified, and Shinya Yamanaka won a Nobel Prize in 2012 because of it. If you turn on those four genes in the adult cells of a mouse or a human — say, nerve cells or muscle cells — you can convert them into stem cells that are pluripotent, meaning they can be reprogrammed to become any other type of cell and in the process become biologically young again. In effect, you hit the “reset” button.
If you turn on all four of those genes in real tissues, though, unfortunately you often induce tumors, and of course the cells also lose their identities and must be reprogrammed. So you couldn’t do this safely or effectively in the real tissues of a human being.
But is there some way we can tap into this “fountain of youth” in the cells of real tissues, preserving their function but reversing their biological age? It sounds crazy, but it isn’t at all.
There are at least a couple of species that have demonstrated the ability to defy aging like this; that is, to be “biologically immortal”: Turritopsis dohrnii, or the “immortal jellyfish”, which is able to return to a young state when it is sick, old, or injured; and Hydra, which takes an easier route by simply not aging at all.
So, organisms like you and me do not necessarily have to be mortal. Not biologically, at least. We just evolved that way to keep mixing up our genes without overpopulating the bejeezus out of our environment by never dying. Most of our cells don’t have the right combination of genes turned on to reset themselves when they are damaged or when they get old — but they could.
The Yamanaka factors include one cancer-causing gene called c-Myc, so our researchers eliminated that gene and only turned on the other three (Oct4, Sox2, and Klf4). Let’s call those three genes collectively OSK to make things simpler.
Turning on OSK does almost everything the full set of Yamanaka factors does, except it doesn’t cause cells to lose their identity and doesn’t cause uncontrolled growth (tumors). OSK just retains the positive aspect of turning back the biological age of live cells.
Sinclair and the rest of the team expressed OSK in mice with glaucoma and in other mice with plain old advanced age, and by doing this, they were able to reset the retinal ganglion cells back to young cells, with all the markers and behavior of young cells (telomere length, DNA methylation, etc.) These cells regenerated and restored vision in these kinds of mice.
Previous research has been able to arrest the progress of optic nerve damage associated with glaucoma or old age, but never to reverse it. Below, a damaged optic nerve from old mice shows that retinal ganglion cells are regenerated when OSK is added. On top is a control where the unrelated gene for green fluorescent protein was inserted, and on the bottom is one with the OSK genes inserted. They stuck a fluorescent label onto cholera toxin B, which binds to molecules on the surface of ganglion cells, so that the ganglion cells light up in the figure below:
You can see that the ganglion cells become more robust near the retina and also extend much farther into the optic nerve after OSK treatment.
They were also able to regenerate cultured human cells this way. Obviously they couldn’t do it in live humans just yet, but they say within a couple years they may be able to go to clinical trials in a glaucoma context.
Here are cultured human nerve cells that have been treated with vincristine, a chemotherapeutic agent that unfortunately also induces damage to neurons. You can see that the addition of OSK causes significant recovery, and, although you cannot see it, also restores the hallmarks of youth to these cells:
There’s “a lot to unpack” here, as they say, and of course the authors had a lot of technical and ethical points to address, but one sentence within their discussion sort of stands out:
OSK promotes a youthful epigenetic signature and gene-expression pattern that causes the neurons to function as though they were young again.
No, we don’t know exactly how to regenerate young tissue in living humans just yet, but I don’t think we’re very far from knowing how, at least conceptually. I don’t know if we can ever eliminate the possibility of being hit by a bus, and new diseases and disorders will always pop up, but one day in the not-too-distant future, we may not need to age anymore.