Image courtesy of Pixaby

It’s been all over the news for the last two weeks. Diljeet Gill and colleagues at the Babraham Institute in England are investigating a novel way to reverse aging of skin, opening the door to creating a new possible cell therapy.

Their work largely originates from the Nobel prize-winning work of Shinya Yamanaka. In 2006 Yamanaka found that, by activating four genes, adult fibroblast cells can be transformed into an embryonic stem cell state. Reversing the age of an adult cell to an embryonic state involves transcriptional and methylation changes in the DNA. You can predict biological age based on which particular genes are switched on, and which genes are switched off (this is called the transcriptional clock). You can also predict age based on the amount and pattern of methylation on the DNA (this is called the methylation clock as the amount of methyl groups on DNA changes over time).

Adult cells such as fibroblasts, neurons and heart cells have a limited capacity to make new and different cells. In contrast, embryonic stem cells are pluripotent, which means they have the potential to differentiate into any cell type. Once fibroblast cells are reprogrammed into an embryonic state, these cells are called induced pluripotent stem cells (IPSCs) and they can grow into all of the body’s numerous tissues. Due to their pluripotent nature, IPSCs have unlimited regenerative capacity and they carry the promise for tissue replacement to counter age-related decline.

However, there is a major hurdle in reversing aging in cells using this method: full iPSC reprogramming results in the loss of original cell identity and function. The process of fully reprogramming an adult skin cell into an embryonic-like stem cell typically takes 50 days in the lab. Attempts to use this full reprogramming method to create iPSCs in vivo have resulted in the formation of cancers and teratomas in the body (teratomas are a specific type of tumour that contain a combination of many different types of tissue including muscle, teeth and hair that originate from pluripotent cells).

Nevertheless, consequences such as cancers and teratomas can be eliminated by controlling the duration and amount of the Yamanaka factors expressed.

For example, a pivotal study led by Ocampo et al. demonstrated that mice that displayed rapid aging (progeria mice) could be genetically engineered in such a way that the Yamanaka factors could be artificially switched on when the mice were exposed to a chemical in their drinking water and switched off when the chemical in the drinking water was removed. Instead of causing the cells to express Yamanaka factors continuously, they switched on the factors for only two days and switched it off for five days. This cyclical treatment, which induces only transient reprogramming, extended lifespan and improved cellular function without teratoma formation by about three years.

During his PhD in the Reik lab, Dr. Gill wanted to know whether a longer reprogramming session could reverse aging more effectively than a two-day induction could. He took skin fibroblasts from three middle-aged women (two of them 53, one of them 38). The Yamanaka factors were switched on when exposed to a certain chemical and could be switched off at will. Instead of reprogramming for 50 days, the process was switched off at around two weeks.

Once the factors were switched off the cells underwent the process of reverting back to their original differentiated state as a fibroblast. However, these cells didn’t just revert back to exactly how they were. Collagen production, the transcriptional clock, and the DNA methylation clock were restored back to youthful levels after transient reprogramming. The results were substantial as they were able to turn back time (~thirty years) while retaining original cell identity.

Partially reprogrammed cells remember their initial cell type because “the methylation at enhancer regions [small sections of our DNA that help switch on genes at the right time and in the right cell type] is the same as the original cell from where it started,” Dr. Gill explained. Therefore, a part of the original cell identity remains as a memory throughout the short duration of reprogramming. For a pluripotent cell, methylation identity is lost and so is the ability to remember which cell they used to be; this gives them the potential to create random cell types, or proliferate as cancer cells.

Like all good science, Dr. Gill’s work has sparked more questions. He is now investigating whether there is a difference in the level of rejuvenation between males and females, how stable this rejuvenation is in the long term, and how to go from lab to clinic.

A possible clinical therapy would be to first isolate and reprogram your cells to youthful levels in the lab and then transplant them back into the skin.

“But we are also thinking of an alternative. We could look downstream of the reprogramming factors that actually cause the cell to rejuvenate and identify those targets. By activating those targets, if they exist, we may be able to activate rejuvenation without reprogramming cells at all. And that can be exciting from a drug development point of view. If you can develop a molecule that targets these pathways, you may be able to induce rejuvenation in cells in vivo without even having to take them out [of the skin] first. So, this is a very long-term goal but it’s a direction we are very interested in following,” says Dr. Gill.

When asked about using this cell therapy as a topical cosmetic for reducing signs of skin aging Dr. Gill responded: “I think these cells are going to be useful due to their supportive role [in building collagen]. Although cosmetics are an interesting line of thought, right now these rejuvenated cells we have created would be used to support the skin cells already there and would aid in the wound healing process [which declines with age] of serious cuts, burns and ulcers. That would be a more realistic goal.”

In the end, the intention for much of this work is about ensuring that old age is enjoyed and not endured. Most do not want to extend their lifespan if all that means is another 30 years of poor health. Studies like Ocampo et al. and Gill et al. contribute to a quest to increase health span, not lifespan.

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Krystal Jacques

Krystal Jacques completed her Master’s degree in the Institute of Medical Science department at the University of Toronto. For her Master’s she studied the embryonic origin of pancreatic stem cells under the supervision of Dr. Derek van der Kooy, where she developed an interest in both photography and science communication. She is currently building her own business as an artist. As a scientist turned artist, she hopes that she can tell stories through visual and written media. You can find her on Instagram @krystaljacques

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