A Brief Tour of Work on Reprogramming as an Approach to the Treatment of Aging

A recent popular science article from the Lifespan.io team provides a high level introduction to cellular reprogramming as a potential approach to the treatment of aging. Since the discovery that somatic cells can be reprogrammed to become induced pluripotent stem cells, essentially the same as embryonic stem cells, most exploration has focused on the cost-effective production of specific cell types for use in research and cell therapies. More recently, however, researchers have applied reprogramming strategies directly to tissues in living animals in order to improve heath and turn back aspects of aging and age-related disease.

Reprogramming is achieved by inducing expression of a few or all of the Yamanaka factors, genes regulating pluripotency. Scientists have observed that reprogramming of cells from old tissues reverses age-related epigenetic marks, gene expression changes, and mitochondrial dysfunction. It is a process that recapitulates some of the rejuvenation that takes place in early embryonic development, as cells clear out molecular damage and reset themselves for the task of building an embryo. Some studies have shown that delivering reprogramming factors into adult animals as a therapy produces benefits to health and signs of reversal of age-related pathology. There are clearly safety concerns in taking this approach to therapy, in that the production of even small numbers of pluripotent cells can lead to cancer, even as those cells improve tissue function via their signaling, in much the same way as the transplanted cells of first generation stem cell therapies. It isn't just a matter of producing a sort of in situ stem cell therapy, however; somatic cells exposed to lesser amounts of reprogramming factors can exhibit improved function without transforming into stem cells.

Reprogramming is not an instant event, not a switch. It is a process of change that requires sustained expression of reprogramming factors over some period of time, typically days. Shorter, lesser exposure to reprogramming factors can improve cell function by reversing age-related epigenetic changes and mitochondrial dysfunction without resulting in a transformation of cell type. This useful outcome of partial reprogramming may or may not prove to be challenging to reliably and safely achieve in living tissues. Different cell types require different timing, different recipes for effective reprogramming, and every aging organ in the body is made up of many different cell types. This is a work in progress.

Yamanaka Factors and Making Old Cells Young

In 2006, a study showed that it was possible to reprogram cells using just four master genes named Oct4, Sox2, Klf4, and c-Myc, or OSKM for short. These four reprogramming factors are often called the Yamanaka factors. This discovery paved the way for research into how these Yamanaka factors might be used for cellular rejuvenation and a potential way to combat age-related diseases. In 2011, a team first reported cellular rejuvenation using the Yamanaka factors. During their life, cells express different patterns of genes, and those patterns are unique to each phase in a cell's life from young to old; this gene expression profile makes it easy to identify an old or young cell.

In 2016, researchers showed for the first time that the cells and organs of a living animal could be rejuvenated via reprogramming. For the study, the researchers used a progeric mouse designed to age more rapidly than normal as well as a normally aging mouse strain. Both types of mice were engineered to express the Yamanaka factors when they came into contact with the antibiotic doxycycline, which was given to them via their drinking water. After just six weeks of this treatment, which steadily reprogrammed the cells of the mice, the researchers noticed improvements in their appearance, including reduced age-related spinal curvature. The treated mice also experienced a 50% increase in their mean survival time in comparison to untreated progeric control mice. It should be noted that not all aging signs were affected by partial cellular reprogramming, and if treatment was halted, the aging signs returned.

In 2020, another study howed that partial cellular reprogramming improves memory in old mice. As the previous studies have shown, partial cellular reprogramming is a balancing act between epigenetically rejuvenating cells and resetting their aging clocks, without completely resetting their cell identity so they forget what kind of cell they are. Also in 2020, researchers published a study that showed that they had managed to restore lost vision to old mice, and mice with damaged retinal nerves, using partial cellular reprogramming.

By far the biggest hurdle to translating partial cellular reprogramming to people is the need to find a way to activate the Yamanaka factors in our cells without needing to engineer our bodies to react to a drug such as doxycycline. Doing this may require us to develop drugs capable of activating OSKM, editing every cell in our body to respond to a particular compound like doxycycline, which would be extremely challenging though plausible. The rapid progress of medical technology could potentially mean that such partial cellular reprogramming therapies may become available in the not too distant future. We certainly hope so.


I would expect the first generation therapies to effect mainly the high-metabolism tissues, as most small-molecule drugs. So the easiest targets would be the liver, lungs and the heart. I hope that most of the damage actually has accumulated in such high-activity/high-turnover tissues and organs so there might be a few low-hanging fruits here

Posted by: Cuberat at September 7th, 2021 4:14 PM

Reason wrote: "By far the biggest hurdle to translating partial cellular reprogramming to people is the need to find a way to activate the Yamanaka factors in our cells without needing to engineer our bodies to react to a drug such as doxycycline."

Using a tame adenovirus to insert an OSKM cassette that is switchable with doxy into the subject's DNA is perhaps OK for animal studies, but there is already an alternative that seems better for humans. T. J Sarkar and his group at Stanford published Nature Communications doi: 10.1038/s41467-020-15174-3,a few years ago, in which they demonstrated that messenger RNA coded for OSKLM and delivered to cells as a burst by liposomes could rejuvenate cell cultures and test animals. They showed that about three days of such transient bursts of the mRNA was about optimal. Turn Biotechnologies is now attempting to turn this academic research into a commercial product.

Posted by: John G. Cramer at September 9th, 2021 2:26 PM

There remains many questions about the safety of cellular reprogramming or partial cellular reprogramming and affect on cell type and age related changes. One question that must be addresses first is the oncogenic pressure that may be driven by such ectopic expression or over expression. For example c-myc and possibly the other Yamanaka factors may drive changes that are beneficial but also antagonistic pleiotropy on aging on cells. We know c-myc plays a role in ectopic expression of cell cycle markers in terminally differentiated neurons in AD. Driving cellular changes to differentiated cells could lead to apoptosis downstream.

Posted by: Dr. Obrenovich at September 11th, 2021 6:28 PM

Extremely interesting. With the further development of delivery tools such as those being worked on at the Broad Institute I can see a road map developing that could move regeneration treatments to the forefront for the proactive treatment of aging.


Posted by: robin at September 12th, 2021 9:16 AM
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