Credit: Juan Carlos Izpisua Belmonte Lab /Salk Institute.

Credit: Juan Carlos Izpisua Belmonte Lab /Salk Institute.

A first of its kind study performed cellular reprogramming on live mice and the results have been simply breathtaking. The rodents had a mutation which made them age prematurely, but when the researchers from the Salk Institute of Biological Science altered or reprogrammed chemical marks in the genome, the signs of aging were drastically reduced. The lifespan of the mice was improved by 18 to 24 weeks, suggesting the aging process is heavily influenced by epigenetics — environmental changes that alter the structure of DNA, without affecting its sequence.

“We did not correct the mutation that causes premature aging in these mice,” says lead investigator Juan Carlos Izpisua Belmonte, a professor in the Salk Institute of Biological Science’s Gene Expression Laboratory. “We altered aging by changing the epigenome, suggesting that aging is a plastic process.”

In other words, Belmonte seems to suggest, the aging process can be altered, possibly even reversed.

Cellular reprogramming sounds pretty intense — and it is. Previous efforts which involved cellular reprogramming caused mice to die immediately or develop tumors. The team from Salk, however, used a partial cellular reprogramming approach and the mice survived.

When scientists talk about cellular reprogramming, what they mean is the conversion of a type of cell into another. Specifically, it typically entails the conversion of a somatic cell type, such as a fibroblast, to a pluripotent cell type known as an induced pluripotent stem cell, or iPS cell.

You may have heard about iPS cells. These are like stem cells, in the sense that they can be coaxed to turn into any type of cell, with the notable distinction that you don’t have to harvest them from live embryos. Rather, any type of cell can be programmed to turn into an iPS. It’s how some scientists make or print whole organs in a petri dish or controlled environment starting from nothing but a patient’s skin cells and a scaffold.

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Reprogramming cells involves the expression of four factors in the cells called Yamanaka factors. To reach pluripotency or the ability to turn into a specialized cell, the factors have to be expressed for two to three weeks. The Salk researchers, however, only expressed the Yamanaka factors for just 2 to 4 days, resulting in a partial cellular reprogramming. So what happens to the cell? The skin cell is still a skin cell, i.e. it retains the same function, but it’s not the same cell anymore.

The study’s authors found the partially reprogrammed cells had less DNA damage accumulation and showed a restored nuclear structure. This is the result of epigenetic remodeling in the cell, the authors say.

There are thousands of genes coded by our DNA, but not all are active. Genes are regularly switched ‘on’ or ‘off’ during our lifetimes through chemical changes called methylation. These so-called ‘epigenetic’ changes can happen for a lot of reasons, and it all depends on the environment. The epigenetic marks are tasked with regulating and protecting the genome and in our study’s case, some peculiar things happened.

After the cells were inserted back into the rodents, several organs improved. The scientists mention in their paper that tissue from skin, spleen, kidney, and stomach looked rejuvenated when inspected under the microscope. Most importantly, the cardiovascular system, which is the first cause of failure in prematurely aging mice, also showed improved structure and function.

“It is difficult to say specifically why the animal lives longer,” says co-first author Paloma Martinez-Redondo. “But we know that the expression of these factors is inducing changes in the epigenome, and those are leading to benefits at the cellular and organismal level.”

Interestingly, when the same experiment was made on injured mice, the rodents showed enhanced regeneration of muscle tissue and beta cells in the pancreas. Next, the researchers plan on exploring which marks specifically are driving and changing the aging process.

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There’s a lot we need to learn but what seems clearer by the day is that epigenetics — the environments and chemical changes our genome suffers during our lifetimes and some of which we pass on — is heavily involved in aging and longevity. Previously, we reported how epigenetic changes in the genome can predict how long people can live or what they ‘real’ or biological age is.

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