Reversing the clock of ageing
Nicholas Wade, Dec 20, 2016, The New York Times
Regeneration
At the Salk Institute in La Jolla, California, USA, scientists are trying to get time to run backward. Biological time, that is. In the first attempt to reverse ageing by reprogramming the genome, they have rejuvenated the organs of mice and lengthened their life spans by 30%. The technique, which requires genetic engineering, cannot be applied directly to people, but the achievement points towards better understanding of human ageing and the possibility of rejuvenating human tissues by other means. The Salk team’s discovery, reported in the recent issue of the journal Cell, is “novel and exciting,” said Jan Vijg, an expert on ageing at the Albert Einstein College of Medicine in New York, USA.
Leonard Guarente, who studies the biology of ageing at Massachusetts Institute of Technology, USA said, “This is huge,” citing the novelty of the finding and the opportunity it creates to slow down, if not reverse, ageing. “It’s a pretty remarkable finding, and if it holds up it could be quite important in the history of ageing research,” Leonard said. The finding is based on the heterodox idea that ageing is not irreversible and that an animal’s biological clock can in principle be wound back to a more youthful state. The ageing 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 fertilised egg is free of all marks of age.
Powerful genes
Ten years ago, 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 reprogramme even the genome of skin or intestinal cells back to the embryonic state. Shinya’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 fertilised 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, 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, Juan 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.
Beneficial effects
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 ageing, healthier organs, and at the end of the experiment we could see they had lived 30% longer than control mice,” Juan 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. Juan believes these beneficial effects have been obtained by resetting the clock of the ageing 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 past few years have biologists come to realise that the state of the epigenome may be a major cause of ageing. If the epigenome is damaged, perhaps by accumulating too many marks, the cell’s efficiency is degraded. Juan sees the epigenome as being like a manuscript that is continually edited.
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,” Jan said. But he cautioned the fast-ageing mice used in the study might not be fully representative of ordinary ageing.
Leonard Guarente, who studies the biology of ageing at Massachusetts Institute of Technology, USA said, “This is huge,” citing the novelty of the finding and the opportunity it creates to slow down, if not reverse, ageing. “It’s a pretty remarkable finding, and if it holds up it could be quite important in the history of ageing research,” Leonard said. The finding is based on the heterodox idea that ageing is not irreversible and that an animal’s biological clock can in principle be wound back to a more youthful state. The ageing 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 fertilised egg is free of all marks of age.
Powerful genes
Ten years ago, 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 reprogramme even the genome of skin or intestinal cells back to the embryonic state. Shinya’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 fertilised 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, 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, Juan 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.
Beneficial effects
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 ageing, healthier organs, and at the end of the experiment we could see they had lived 30% longer than control mice,” Juan 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. Juan believes these beneficial effects have been obtained by resetting the clock of the ageing 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 past few years have biologists come to realise that the state of the epigenome may be a major cause of ageing. If the epigenome is damaged, perhaps by accumulating too many marks, the cell’s efficiency is degraded. Juan sees the epigenome as being like a manuscript that is continually edited.
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,” Jan said. But he cautioned the fast-ageing mice used in the study might not be fully representative of ordinary ageing.
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