Short Exposure To Reprogramming Factors Causes Dramatic Rejuvenation

In potentially one of the biggest findings of the year, researchers have found that brief, cyclical treatment of mice with a cocktail of proteins used to create stem cells extends life and causes significant rejuvenation

In 2006 Shinya Yamanaka and his team released a paper detailing a technique able to create induced pluripotent stem cells from adult mouse fibroblast cells. These factors, Oct3/4Sox2Klf4c-Myc (OSKM) are present in embryonic stem cells, and applying them to adult cells is able to trigger a similar transformation process - turning them into a type of cell with very similar abilities and qualities as embryonic stem cells do: induced pluripotent stem cells (IPSCs). 

Further analysis of these factors revealed that they are able to reverse some of the marks of the aging process, partially by removing many of the epigenetic marks that change with age. The degree they are able to do this is debatable and appears to vary, but the process seems to trigger some form of clock reset, regardless of how potent the reset is. A word of caution however; over exposure to these factors can causes cancerous tumours. After all, embryos are required to go through rapid growth.

A startling discovery

Keen to replicate these rejuvenative effects on a live organism, researchers decided to test a smaller dosage in a mouse model of the accelerated aging disorder progeria.  Progeria patients display many early onset signs of aging, one of them being early epigenetic changes. 

"Our study shows that aging may not have to proceed in one single direction. It has plasticity and, with careful modulation, aging might be reversed"

Partial cellular reprogramming reverses cellular signs of aging such as accumulation of DNA damage. (Left) Progeria mouse fibroblast cells; (right) progeria mouse fibroblast cells rejuvenated by partial reprogramming. Credit: Salk Institute

The researchers injected these mice embryos with a sequence of DNA containing the code for these 4 OSKM factors, under control of a promoter that could be turned on by a chemical called doxycycline. This means that when the mice were fed doxycycline, the genes would turn on and produce the OSKM proteins. They knew that trying to trigger long term exposure to these OSKM factors effectively kills mice by trigger large scale tumour growth, but they theorised that a brief burst of exposure may cause rejuvenation - without turning adult cells into stem cells and causing unregulated growth. 

First off, the team exposed cells in culture to OSKM factors for a period up to 12 days. They found this was enough to cause some reversal without triggering stem cell transformation. Emboldened, they moved onto live progeric mice genetically altered to be responsible to doxycycline. When they attempted short rounds of OSKM induction, in repetitive cycles, the results were striking. 

Aging isn't inevitable

While we should of course be careful not to overhype the discovery, mice that experienced this cyclical treatment displayed obvious reversal of many aging phenotypes: showing decreased DNA damage, improved mitochondrial health, improved muscle and skin health meaning they looked visibly younger. They also lived 30% longer and appeared to recover from many of the signs of progeria, as well as other wider signs of aging beyond progeria. More importantly, when they tested the procedure on certain tissue in normal mice, they showed that the strategy improved regeneration and healing in pancreatic, muscle and heart tissue. We'll have to wait for further research to find out more. 

"This work shows that epigenetic changes are at least partially driving aging. It gives us exciting insights into which pathways could be targeted to delay cellular aging. Obviously, mice are not humans and we know it will be much more complex to rejuvenate a person. But this study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought"

When they tested the OSKM factors with a molecule that inhibits epigenetic alterations, they found many of the benefits melted away. This provides strong evidence that maladaptive epigenetic regulation plays an important role in the aging process. 

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