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Where Next for Cellular Reprogramming and Regenerative Medicine?

Over the past decade researchers have gained ever more expertise in reprogramming cells from one type to another. The most useful form of reprogramming devised so far is the change from normal differentiated somatic cell, fixed in its role, to pluripotent stem cell, capable of generating any type of cell given the right instructions. Surprising recent developments in this line of research include (a) evidence that performing this transformation in a living animal is beneficial rather than cancerous, producing effects similar to those resulting from a stem cell transplant, and (b) that reprogramming cells to pluripotency erases some of the markers of age in cells from old tissues.

This repair is thought to be much the same process as takes place in early embryonic development: the mechanism by which old parents can produce young children, or perhaps conceptually similar to the constant, aggressive repair and regeneration that takes place in the immortal hydra. What can be done with this knowledge? Can portions of these mechanisms be split off from the whole, understood, tamed, and selectively applied? Will that replace the current paradigm for regenerative medicine in the near future? Some people are thinking along these lines, as illustrated by this interview with a researcher in the field.

What impact will your work have on aging research?

I'm studying whether we can separate the process of functional reprogramming of cells from the process of aging reprogramming of cells. Typically these two processes happen at the same time. My hypothesis is that we can induce cellular rejuvenation without changing the function of the cells. If we can manage to do this, we could start thinking about a way to stall aging.

What is the difference between functional and aging reprogramming?

The function of a skin cell is to express certain proteins, keratins for example that protect the skin. The function of a liver cell is to metabolize. Those are cell-specific functions. Reprogramming that function means that you no longer have a liver cell. You now have another cell, which has a totally different function. Age, on the other hand, is just the degree of usefulness of that cell, and it's mostly an epigenetic process. A young keratinocyte cell is younger than an older keratinocyte but it is still a keratinocyte. The amazing thing is that if you take an aged cell that is fully committed to a certain function, and you transplant its nucleus into an immature egg cell called an oocyte, then you revert its function to a pluripotent, embryonic one, which means it can become any other cell of the body-and you also revert the age of that cell to the youngest age possible. It's mind-blowing to me.

How close are we to using pluripotency induction in therapies?

The production of induced pluripotent stem (iPS) cells in mice was described in 2006, and in humans in 2007, so it's been already 10 or 11 years. The first clinical trials using iPS cells are just about to get to early phase I and phase II. There has been a lot of hope and promise but it's been a little slow. The reason being that when it comes to clinical applications, you have to consider a number of complications. You need to know how to make the cells very efficiently, and then they need to be safe. There will be more clinical trials coming up based off iPSs. For example, I am collaborating with an iPS-based platform for the cure of a skin disease called epidermolysis bullosa. We're trying to move this to the pre-clinical stage over the next few years, and then if we pass that, we will potentially start moving into a phase I clinical trial. Things are moving forward pretty fast now.

Are germ cells immune to aging?

Yes and no. They definitely do age, but not to the same extent as other cell types. In males, spermatogenesis continues all the way from puberty to old life. If you take a 90-year-old man, there are still germ cells and spermatogonial stem cells. They do age, because it's clear that the sperm of an older man is different from the sperm of a younger man, but they do not age as heavily as other cells. This is fascinating because we do not understand the process. Female cells do age, and the consensus is that there are no germ stem cells in the ovary so these cells lack a molecular program to stay young. But once you put together an egg and a sperm, then there is an aging erasure mechanism, which is embryonic-specific, that we also do not understand.

Why are you interested in separating aging reprogramming from functional reprogramming?

The experiments of somatic cell nuclear transfer and iPS cell derivation clearly indicate that both functional and aging reprogramming can be achieved. However, these technologies are very inefficient and cannot be used as whole-body anti-aging measures because the process of reprogramming to an embryonic stage can lead to tumorigenic cells. Instead, if we could separate the two types of reprogramming and achieve only reprogramming of age without touching the function of a cell, then in principle we could apply reprogramming in vivo to every single cell in the body and rejuvenate them. This could be a paradigm shift in the way we approach aging.

Link: http://nautil.us/issue/57/communities/does-aging-have-a-reset-button

Comments

This is a pretty amazing idea, and Age-X appear to be moving rapidly along this path with their induced tissue regeneration small molecule approach.

Posted by: Mark at February 3rd, 2018 3:01 AM

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