Researchers find ageing is reversible in mice

New research suggests it is possible to slow or even reverse ageing, at least in mice, by undoing changes in gene activity, the same kinds of changes that are caused by decades of life in humans (Scientific American, 2016).

By tweaking genes that turn adult cells back into embryonic-like ones, researchers at the Salk Institute for Biological Studies reversed the ageing of mouse and human cells in vitro, extended the life of a mouse with an accelerated-ageing condition and successfully promoted recovery from an injury in a middle-aged mouse, according to a study published on Thursday in Cell.

The study adds weight to the scientific argument that ageing is largely a process of epigenetic changes. Over the course of life cell activity regulators get added to or removed from genes. In humans those changes can be caused by smoking, pollution or other environmental factors, which dial the genes’ activities up or down. The new study suggests the possibility of reversing at least some of these changes, a process researchers think they may eventually get to work in living humans. Juan Carlos Izpisua Belmonte, the study’s senior author and an expert in gene expression at Salk, said “Ageing is something plastic that we can manipulate.”

In their study Juan Carlos Izpisua Belmonte and his colleagues rejuvenated cells by turning on, for a short period of time, four genes, known as Yamanaka factors, that have the capacity to convert adult cells back into an embryonic-like state. This approach rejuvenated damaged muscles and the pancreas in a middle aged mouse, and extended by 30% the life span of a mouse with a genetic mutation responsible for Hutchinson–Gilford progeria syndrome, which causes rapid ageing in children. Dosing the animals with doxycycline reduced several signs of old age, including thinning of the skin (Science, 2016). It also delayed the deterioration of the animals’ kidneys and spleens and kept their hearts beating at a sprightly pace. Switching on the stem cell genes also boosted the mutant mice’s life spans by more than one third.

Because the Yamanaka factors reverse changes made to gene regulators, some scientists see the study as further evidence that ageing is driven by epigenetic changes. David Sinclair, a Harvard University geneticist and anti-ageing researcher who was not involved in the study but is doing similar work, said “I do think that epigenetic reprogramming is the ultimate way to reverse ageing. My lab has a lot of evidence that the primary driver of what we call the hallmarks of ageing is the epigenetic change.” He said his lab is preparing a paper explaining what causes these changes.

To determine whether activating stem cell genes restores this capacity, the researchers tested healthy, middle aged mice whose insulin making β cells they had removed. Turning on the stem cell genes increased the rodents’ ability to replace their lost β cells. Juan Carlos Izpisúa Belmonte and colleagues also tested how well a different group of middle aged mice could repair muscle damage. If the stem cell genes were active, the animals were better at mending muscle injuries caused by an injection of cobra venom. The study’s first author Alejandro Ocampo, said in theory, reprogramming epigenetics should work on mice and people at any age, adding that even cells from human centenarians could eventually be rejuvenated. Alejandro Ocampo and Juan Carlos Izpisua Belmonte said they think they can improve the efficiency and results of the technique with more research, and that they can undo the epigenetic changes responsible for ageing by using easier to handle chemicals instead of the Yamanaka factors, hopefully moving toward the possibility of treatment for people.

Matt Kaeberlein, a molecular biologist at the University of Washington who studies ageing but was not part of the work, said other researchers have found that the Yamanaka factors can rejuvenate cells so in some ways this study is not surprising. But he said no one else had yet shown that the factors can treat age related diseases in an animal by making the same changes. He said “That’s the wow factor.” He said the study suggests it may be possible not just to slow ageing but to actually reverse it.

He said “That’s really exciting—that means that even in elderly people it may be possible to restore youthful function. Plus, it is easier to imagine a treatment that makes changes to the epigenome than to consider going into every cell and changing its genes. He also notes that the results of the new study are very similar to those seen when senescent cells—those that have lost function due to ageing—are removed from an organism…[It is not clear if] this is another way to shut down or maybe reprogram senescent cells.”

Manuel Serrano, an expert on senescence at the Spanish National Cancer Research Center in Madrid who was not associated with in the new research, said he is impressed with the study and its results. He said “I fully agree with the conclusions. This work indicates that epigenetic shift is in part responsible for ageing, and reprogramming can correct these epigenetics errors. This will be the basis for future exciting developments.”

The study also showed how fine the line can be between benefit and harm. When the researchers treated mice continually, some developed tumours and died within a week. When the scientists cut the treatment to two days out of seven, however, the mice benefited significantly. David Sinclair said this should be taken as a note of caution by anyone trying to increase the human life span. He said “We’ve all been playing with fire”, adding that this fine line will make it challenging to get a drug approved by regulatory agencies. He added “This is going to be what we spend the next 10 years figuring out: how to reprogram cells to be young again without taking it too far so they become tumours.”

Both David Sinclair and Matt Kaeberlein say they wish Juan Carlos Izpisua Belmonte’s lab had shown that a normal mouse could live longer after the gene tinkering, instead of just reversing an ageing related illness.

Juan Carlos Izpisua Belmonte, like some other anti-ageing researchers, said his initial goal is to increase the “health span”, the number of years that someone remains healthy. Extending life span, the number of years someone remains alive, will likely take longer to achieve. Most major killers, including heart disease, cancer and Alzheimer’s, are diseases of ageing that become far more common past middle age. Alejandro Ocampo said “This is not just a matter of how many years we can live but how well we can live the rest of our life.”

Juan Carlos Izpisua Belmonte said his team is also trying to determine whether or not ageing is a process that occurs simultaneously throughout the body. He said “Is there some tissue that regulates ageing—and when that goes bad, the entire organism goes bad?” He said they currently think the brain’s hypothalamus, the seat of control for hormones, body temperature, mood, hunger and circadian rhythms, may also act as a regulator of ageing.

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