The Present Popularity of Epigenetic Reprogramming to Treat Aging

A fair number of research groups are presently working on ways to force large numbers of cells in the body to adopt more youthful epigenetic profiles. Much of this research is an outgrowth of the discovery of induced pluripotency, the ability to reprogram any cell into a pluripotent stem cell that is largely indistinguishable from an embryonic stem cell, capable of generating any of the cell types in the body. This process also happens to reset many of the epigenetic markers of age that are found in cells in old tissues, alongside restoring mitochondrial function by clearing out damaged mitochondria, and a few other interesting changes. The article here focuses on one representative project, but readers here might be more familiar with the work of in the same space, since it was covered recently.

The important question to be addressed here is this, since it is frequently mentioned: are epigenetic changes a cause of aging? To my eyes the answer is no, a thousand times no. They are - they must be - a downstream consequence of the true cause, which is the molecular damage that accumulates with age as a normal side-effect of the operation of cellular metabolism. However, since these epigenetic changes themselves cause further harm, one can, in principle and in animal studies, produce benefits by forcing cells to adopt a more youthful epigenetic profile for various genes of interest. But this does nothing to address the cause of aging, the underlying damage.

Without repair, the underlying causative damage of aging will continue to cause all of the problems that cannot be ameliorated by forcing a mass change in epigenetic programming and consequent cellular behavior. Consider the presence of molecular waste that the body cannot effectively clear, such as persistent cross links degrading extracellular matrix elasticity, or hardy constituents of lipofuscin making autophagy inefficient in long-lived cells, or potentially cancerous nuclear DNA damage. I predict that epigenetic reprogramming is not going to meaningfully address these line items, because youthful cells and tissues cannot meaningfully address these forms of damage if present. Reprogramming may well turn out to be as useful a tool as stem cell therapies for the purpose of regeneration of functional tissues, though with a very different focus on the type of functional improvement obtained. But be wary of those who claim that epigenetic change is the cause of aging, and that turning it back will fix all issues.

Has this scientist finally found the fountain of youth?

Izpisúa Belmonte, a shrewd and soft-spoken scientist, has access to an inconceivable power. These mice, it seems, have sipped from a fountain of youth. Izpisúa Belmonte can rejuvenate aging, dying animals. He can rewind time. But just as quickly as he blows my mind, he puts a damper on the excitement. So potent was the rejuvenating treatment used on the mice that they either died after three or four days from cell malfunction or developed tumors that killed them later.

The powerful tool that the researchers applied to the mouse is called "reprogramming." It's a way to reset the body's so-called epigenetic marks: chemical switches in a cell that determine which of its genes are turned on and which are off. Erase these marks and a cell can forget if it was ever a skin or a bone cell, and revert to a much more primitive, embryonic state. The technique is frequently used by laboratories to manufacture stem cells. But Izpisúa Belmonte is in a vanguard of scientists who want to apply reprogramming to whole animals and, if they can control it precisely, to human bodies.

Izpisúa Belmonte believes epigenetic reprogramming may prove to be an "elixir of life" that will extend human life span significantly. Life expectancy has increased more than twofold in the developed world over the past two centuries. Thanks to childhood vaccines, seat belts, and so on, more people than ever reach natural old age. But there is a limit to how long anyone lives, which Izpisúa Belmonte says is because our bodies wear down through inevitable decay and deterioration. "Aging is nothing other than molecular aberrations that occur at the cellular level." It is, he says, a war with entropy that no individual has ever won.

The treatment Izpisúa Belmonte gave his mice is based on a Nobel-winning discovery by the Japanese stem-cell scientist Shinya Yamanaka. Starting in 2006, Yamanaka demonstrated how adding just four proteins to human adult cells could reprogram them so that they look and act like those in a newly formed embryo. To many scientists, Yamanaka's discovery was promising mainly as a way to manufacture replacement tissue for use in new types of transplant treatments. Researchers at the Spanish National Cancer Research Centre took the technology in a new direction when they studied mice whose genomes harbored extra copies of the Yamanaka factors. Turning these on, they demonstrated that cell reprogramming could actually occur inside an adult animal body, not only in a laboratory dish. The experiment suggested an entirely new form of medicine. You could potentially rejuvenate a person's entire body. But it also underscored the dangers. Clear away too many of the methylation marks and other footprints of the epigenome and "your cells basically lose their identity."

To others, however, the evidence for rejuvenation is plainly in its infancy. Jan Vijg, chair of the genetics department at the Albert Einstein College of Medicine in New York City, says aging consists of "hundreds of different processes" to which simple solutions are unlikely. Theoretically, he believes, science can "create processes that are so powerful they could override all of the other ones. We don't know that right now." An even broader doubt is whether the epigenetic changes that Izpisúa Belmonte is reversing in his lab are really the cause of aging or just a sign of it - the equivalent of wrinkles in aging skin. If so, Izpisúa Belmonte's treatment might be like smoothing out wrinkles, a purely cosmetic effect. "We have no way of knowing, and there is really no evidence, that says the DNA methylation is causing these cells to age," says John Greally, another professor at Einstein. The notion that "if I change those DNA methylations, I will be influencing aging has red flags all over it."