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Diving into the fountain of youth

Lab & Library — A health scientist explains why ageing may no longer be Nature's law

Who doesn’t want to live forever? Who doesn’t want to have eternal time to enjoy life? For thousands of years, humans have been searching for the magic ingredient that will restore youth. Legendary tales of the existence of fountains with rejuvenating powers have been told for centuries.

Lab and Library

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It all began in Ethiopia where it was speculated that people could prolong their lives by the use of magical waters. These stories became even more prominent during the 16th century when the famous explorer Juan Ponce de Leon began his search for the fountain that would help him regain his youth.

Although these stories are nothing but tales, they served one purpose: They fed people’s hope for finding ways to reverse ageing. Since then, science has developed tremendously, and it is now known that some organisms hold a powerful mechanism to regenerate themselves. Interestingly, organisms such as planaria can fully grow their head back if it is cut; a salamander can re-grow their limbs. Even in humans, organs with heavy work load such as intestine, liver and skin continuously replenish their cells in order to maintain proper function. In addition to this, in case of an injury the body has the capacity to heal itself. But how is this happening? Is it possible to mimic the body and engineer ways to develop and replace damaged or aged organs in order to restore youth?

Stem cells for tissue regeneration

The body seems to hold a powerful reservoir of cells that can form specialized cell types whenever there is a need. These cell types are called Stem Cells and, to a large extent, are responsible for our body’s regeneration ability. Unfortunately, as we age so do our stem cells and their function declines. In addition the reservoir is gradually getting exhausted and stem cells become less and less frequent. Whether loss of stem cells is the result or the cause of aging still remains an open question.

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Stem cells can be divided into two broad categories depending on their origins: embryonic or adult. Embryonic stem cells can be isolated from the early stages of the embryonic development and can give rise to all the cell types of the body and eventually all organs. In addition, embryonic stem cells can grow indefinitely, and they do not age. These properties make them ideal cell source for tissue regeneration.

However, since they can only be isolated during embryonic development, they cannot be found in adults who mostly need stem cells. In addition to unsolved ethical concerns, if they are isolated from other embryos and implanted back into adults they may cause an immune response and ultimately rejection. Last but not least, they are considered highly tumorigenic. Thus, the development of methods enabling culture of human embryonic stem cells generated a lot of hope that the current limitations prohibitting their clinical use could be overcome.

Embryonic stem cell mimicry

In contrast, adult stem cells are more accessible since they can be isolated directly from the patient (in what is commonly known as patient specific therapy) thus avoiding a possible immune reaction. They are not tumorigenic and have been successfully used clinically.

However, adult stem cells have restricted differentiation capacity. In other words they can specialize only in certain cell types. For example, Mesenchymal Stem Cells that are located in adult bone marrow can only give rise to cells that can form fat, bone, cartilage and muscle. Furthermore, they have limited growth capacity and aging has a profound effect on their function.

Due to the limitations of adult stem cells, an alternative approach was recently proposed. Scientists hypothesized that adult cells or stem cells can be modified in a way that mimics embryonic stem cells. If this were true, then a patient could use his own cells to transform them into embryonic stem cells which have the capacity to form all types of organs and they never age.

Smooth muscles

Indeed, this was achieved by Yamanaka and co-workers and because of this work he was awarded with the 2012 Nobel Prize in physiology and medicine. These stem cells are called Induced Pluripotent Stem Cells, and resemble embryonic stem cells to a large extent. Up until this study, scientists believed that cells (regardless of whether they are specialised cells or stem cells) have certain functions that cannot be changed.

Now it is known, that with the right twist all the cells can become different cell types. For example, in the near future it might be possible to take blood cells and transform them into heart cells or neurons. However, induced pluripotent stem cells cannot be used clinically just yet, as there is a possibility of tumor formation similar to embryonic stem cells. What is more, the method of generating them requires genetic modification using viruses which further increase the tumorigenic potential of the resulting cells.

Here at the Andreadis’ lab at the Chemical & Biological Engineering department of University at Buffalo we study the effect of aging on adult stem cells. We focus our attention on the role of aging on a specific adult stem cell type that is called Mesenchymal Stem Cells that can specialize into smooth muscle cells.

Nanog: the land of the young

Smooth muscle cells are the building block for several organs such as arteries and bladders and their ultimate role is to generate force; in other words the can constrict or dilate. In this direction, by using Mesenchymal Stem Cell derived smooth muscle cells we aim in developing an artificial artery that can be used for patients that have damaged arteries.

As you can imagine, the majority of the patients who suffer from cardiovascular diseases are elderly. However we have shown that as the people age the capacity of Mesenscymal Stem Cells to form smooth muscle cells declines. We also demonstrated that aged cells lose the ability to generate force. In addition, the engineered arteries are much weaker and this is a huge drawback since the arteries should be able to sustain the high-pressure environment of the bloodstream. Thus, there was a need to make the aged Mesenchymal Stem Cells young again.

Inspired by the Yamanaka study, we tried to twist Mesenchymal Stem Cells so that they can regain their ability to make muscle. To achieve this we carefully followed the studies on embryonic stem cells in order to identify what makes them immortal and unaffected by aging. The gene named Nanog (which literally means the land of young) was a key player in this process. Interestingly, by introducing Nanog into aged Mesenchymal Stem Cells we showed that the smooth muscle forming capacity was regained to the same extent as young Mesenchymal Stem Cells.

Steps in the right direction

The cells also recovered the ability to generate force and could grow for longer periods of time, another strong indication that the aging effects have been reversed. Currently we try to understand how Nanog reverses the aging effects on Mesenchymal Stem Cells. This will give a boost to pharmaceutical companies to design novel therapeutics that target aging.

Collectively, using this method we have managed to eliminate to a large extent the effects of aging on Mesenchymal Stem Cells. This process does not require transforming them into embryonic stem cells and in that way this approach is more clinically relevant.

Have we discovered the fountain of youth yet? Perhaps not, but we are now starting to understand how the stem cell ages and how can we reverse this process. Can we translate these findings into more complicated systems such as tissues or organs or even whole organisms? We are on our way to doing that, starting from building blood vessels that nourish the whole body. We are definitely on the right track.

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