The aging process is clocklike in the sense that a steady accumulation of changes eventually degrades the efficiency of the body’s cells. In one of the deepest mysteries of biology, the clock’s hands are always set back to zero at conception: However old the parents and their reproductive cells, a fertilized egg is free of all marks of age.
Ten years ago, the Japanese biologist Shinya Yamanaka amazed researchers by identifying four critical genes that reset the clock of the fertilized egg. The four genes are so powerful that they will reprogram even the genome of skin or intestinal cells back to the embryonic state. Dr. Yamanaka’s method is now routinely used to change adult tissue cells into cells very similar to the embryonic stem cells produced in the first few divisions of a fertilized egg.
Scientists next began to wonder if the four Yamanaka genes could be applied not just to cells in glassware but to a whole animal. The results were disastrous. As two groups of researchers reported in 2013 and 2014, the animals all died, some because their adult tissue cells had lost their identity and others from cancer. Embryonic cells are primed for rapid growth, which easily becomes uncontrolled.
But at the Salk Institute, Juan Carlos Izpisua Belmonte had been contemplating a different approach. He has long been interested in regeneration, the phenomenon in which certain animals, like lizards and fish, can regenerate lost tails or limbs. The cells near the lost appendage revert to a stage midway between an embryonic cell, which is open to all fates, and an adult cell, which is committed to being a particular type of cell, before rebuilding the missing limb.
This partial reprogramming suggested to him that reprogramming is a stepwise process, and that a small dose of the Yamanaka factors might rejuvenate cells without the total reprogramming that converts cells to the embryonic state.
With Alejandro Ocampo and other Salk researchers, Dr. Izpisua Belmonte has spent five years devising ways to deliver a nonlethal dose of Yamanaka factors to mice. The solution his team developed was to genetically engineer mice with extra copies of the four Yamanaka genes, and to have the genes activated only when the mice received a certain drug in their drinking water, applied just two days a week.
The Salk team worked first with mice that age prematurely, so as to get quick results. “What we saw is that the animal has fewer signs of aging, healthier organs, and at the end of the experiment we could see they had lived 30 percent longer than control mice,” Dr. Izpisua Belmonte said.
The team also saw improved organ health in normal mice but, because the mice are still living, could not yet say if longevity was extended.
Dr. Izpisua Belmonte believes these beneficial effects have been obtained by resetting the clock of the aging process. The clock is created by the epigenome, the system of proteins that clads the cell’s DNA and controls which genes are active and which are suppressed.
When an egg develops into a whole animal, the epigenome plays a critical role by letting a heart cell, say, activate just the genes specific to its role but switching off all the genes used by other types of cells. This process lets the embryo’s cells differentiate into all the various types of cells required by the adult body.
The epigenome is also involved throughout life in maintaining each cell and letting it switch genes on and off as required for its housekeeping duties. The epigenome itself is controlled by agents that add or subtract chemical groups, known as marks, to its proteins.
Only in the last few years have biologists come to realize that the state of the epigenome may be a major cause of aging. If the epigenome is damaged, perhaps by accumulating too many marks, the cell’s efficiency is degraded.
Dr. Izpisua Belmonte sees the epigenome as being like a manuscript that is continually edited. “At the end of life there are many marks and it is difficult for the cell to read them,” he said.
What the Yamanaka genes are doing in his mice, he believes, is eliminating the extra marks, thus reverting the cell to a more youthful state.
The Salk biologists “do indeed provide what I believe to be the first evidence that partial reprogramming of the genome ameliorated symptoms of tissue degeneration and improved regenerative capacity,” Dr. Vijg said.
But he cautioned the fast-aging mice used in the study might not be fully representative of ordinary aging.
Dr. Guarente said it was more likely that the Yamanaka genes were not erasing the epigenomic marks directly, but rather were activating the genes which are responsible for the immense health and vitality of embryonic cells. This gene activation is a natural function of the Yamanaka factors. It is these embryonic pro-health genes that are rejuvenating the tissues in the mice, Dr. Guarente suggested, and causing changes in the epigenome through their activity.
Thomas A. Rando, an expert on stem cells and aging at Stanford, said that it should be possible in theory to uncouple the differentiation program and the aging process, and that “if that’s what’s happening, this is the first demonstration of that.”
Dr. Izpisua Belmonte said he was testing drugs to see if he could achieve the same rejuvenation as with the Yamanaka factors. The use of chemicals “will be more translatable to human therapies and clinical applications,” he said.