At the Salk Institute in La Jolla, California, scientists are trying to get time to run backwards, that is, biological time. In the first attempt to reverse aging by reprogramming the genome, they have rejuvenated the organs of mice and lengthened their life spans by thirty percent. The technique, which requires genetic engineering, cannot be applied directly to people, but the achievement points towards better understanding of human aging and the possibility of rejuvenating human tissues by other means. The Salk team's discovery, reported in the journal 'Cell', is 'novel and exciting', said Jan Vijg, an expert on aging at the Albert Einstein College of Medicine in New York. Leonard Guarente, who studies the biology of aging at MIT, said, "This is huge". This finding is based on the heterodox idea that aging is not irreversible. The aging process is clock-like 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 fertilised egg is free of all marks of age.
In 2006, the Japanese biologist Shinya Yamanaka amazed researchers by identifying four critical genes that reset the clock of the fertilised egg. The four genes are so powerful that they will reprogram even the genome of skin or intestinal cells back to the embryonic state. Scientists next began to wonder if the four 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 process suggested to him that reprogramming is a stepwise process, and that a small dose of the Yamanaka factors might rejuvenate cells without the total re-programming that converts cells to the embryonic state. With Alejandro Ocampo and other Salk researchers, Izpisua Belmonte has spent five years devising ways to deliver a non-lethal 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 thirty percent longer than control mice", Belmonte said. He believes these effects have been obtained by re-setting the clock of the aging process. The clock is created by the epigenome, the system of proteins that clads the cell's DNA.
The epigenome is involved throughout life in maintaining each cell and letting it switch genes on and off as required. 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 realise 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. What the Yamanaka genes are doing in his mice, belmonte believes, is eliminate extra marks, thus reverting the cell to a more youthful state.
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