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partial_cellular_reprogramming_reverse_aging

The Road to Reversing Epigenetic Aging

Steve Hill March 13, 2020

Today, we are going to take a look at the companies working on resetting cellular aging through a reprogramming approach that directly targets a core reason we age.

Cellular reprogramming resets aging in cells

As we age, our cells experience alterations to their epigenetic markers, and this, in turn, changes gene expression; this process is a primary hallmark of aging. These age-related changes lead to a decline of function and ultimately contribute to the loss of homeostasis, or balance, which allows age-related diseases to develop.

Recently, there has been considerable interest in resetting these epigenetic markers to potentially reverse cellular aging and restore youthful function to tissues and organs. In 2006, Drs. Takahashi and Yamanaka showed that a cell’s age or type is not something set in stone; rather, it is flexible and can be manipulated.

The researchers demonstrated that it is possible to reprogram cells from one type to another using just four master genes: Oct4, Sox2, Klf4, and c-Myc (OSKM), which are also known as Yamanaka factors. Exposing cells to these factors appears to reset the aging clock, making these cells forget their roles and their age while reverting them to a youthful, flexible, and embryonic state from which they can become any cell type.

This discovery turned the scientific world upside down, as prior to this, it was believed that egg cells (oocytes) must contain a complex range of factors needed to turn a somatic cell into an embryonic cell. It became the basis of induced pluripotent stem cell (iPSC) therapy, which we use today to produce transplant cells of different types.

Some researchers suggest that it may be possible to expose aged cells to reprogramming factors for just long enough so that they reset their epigenetic state and work like young cells again — but not long enough to erase their cell identify and make them forget what cell type they are. This approach is known as partial cellular reprogramming, and it could keep tissues and organs free from many of the damages that aging causes and help us to stay healthy and free from age-related diseases for longer.

Researchers are now investigating if it might be plausible to separate the reversal of cell identity from the reversal of cell age, and recent animal studies suggest that it is. In December 2016, Professor Juan Carlos Izpisua Belmonte and his team of researchers at the Salk Institute reported the conclusion of their study, which showed for the first time that the cells and organs of a living animal could be rejuvenated using the Yamanaka factors [1].

This has created a surge of interest in developing therapies that use these reprogramming factors. There are a number of labs and companies now involved in exploring the exciting possibilities of this approach.

Turn.Bio

Turn.Bio is one of a number of companies working on resetting cellular aging using the partial cellular reprogramming approach. In March 2019, the Turn.Bio team published a study showing the potential of using transient mRNA to trigger partial cell reprogramming and has been busy building on that research since.

In their study, the researchers claim that the cellular memory erasure and the resetting of epigenetic aging markers can be separated because the reversal of aging markers happens first in the reprogramming process; in other words, they believe that if they can expose cells just long enough to the reprogramming factors, it should be possible to reverse their epigenetic aging without resetting their type, which would obviously be bad news inside your body.

The unique thing about their approach is that they have added two additional factors, LIN28 and Nanog, to the four reprogramming Yamanaka factors; the combined cocktail is called OSKMLN. According to their research, this combination is more effective and spurs greater cellular rejuvenation.

Additionally, LIN28 also reduces the activity of Let-7, an mRNA that facilitates cell differentiation. Reducing its presence helps to reinforce cellular identity and may also further boost the rejuvenation process.

We think that the direction Turn.Bio is taking is particularly fascinating, especially its decision to use six reprogramming factors. If you would like to learn more about Turn.Bio, we interviewed Professor Vittorio Sebastiano last year about the company and the exciting research that it is doing.

Youthereum Genetics

While Turn.Bio is using more than the usual four Yamanaka factors, Youthereum Genetics is doing the opposite; this company is taking a minimalist approach and plans to use just a single factor, Oct4, to partially reprogram cells. Indeed, a number of studies suggest that Oct4 is the initiating reprogramming factor that kickstarts the entire process of cellular reprogramming. It could be the case that just this single factor is enough to achieve the goal of resetting epigenetic aging markers.

The company believes this streamlined approach is the best course to ensure safety while still resetting cellular aging. The basis for this line of thinking is that while OSKM has been demonstrated to reverse cellular aging in living animals, it is not without risk. Youthereum thinks that with the Yamanaka factors, there is a narrow therapeutic window between erasing aging markers and potentially overstimulating them, which could invite cancer. In an experiment in which mice were engineered to express OSKM for more than three days or so, they start to develop teratomas and die.

Clearly, there is a line to walk between rejuvenation and out-of-control cells prone to becoming cancerous, which is why Youthereum is opting to take this route. The risks of using more than one factor could possibly be mitigated, but this company has chosen a single factor in order to reduce those risks.

We are intrigued to see if the use of one factor will be enough to reset epigenetic aging markers and are following this company’s work closely. If you are interested in learning more about the work of Youthereum Genetics, we interviewed its CEO, Yuri Deigin, last year.

Conclusion

The promise of partial cellular reprogramming is considerable, and if it can be successfully translated to people, it has the potential to keep tissues and organs functionally younger and free from the diseases of aging. We are likely a number of years away from this happening, but perhaps in the next decade or so, we will see these approaches arriving at the clinic as treatments for age-related diseases.

Literature

[1] Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JLXJ, Rodriguez-Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P, Izpisua Belmonte JC. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell. 2016;167:1719–33.

Partial Cellular Reprogramming to Reverse Cellular Aging

Steve Hill March 20, 2019

We have talked about the potential of partial cellular reprogramming in previous articles, and today, we want to draw attention to a new paper that promises to further refine reversal of epigenetic aging in cells.

As we age, our cells experience alterations to their epigenetic markers, and this changes gene expression, which is proposed to be a primary reason we age. Recently, there has been considerable interest in resetting these epigenetic markers to reverse cellular aging, and this paper builds on that.

Three of the study’s authors, Prof. Vittorio Sebastiano, Jay Sarkar, and Marco Quarta, have founded Turn.bio, a biotech company that is working to bring partial cellular reprogramming to humans. The company is also currently enjoying the leadership of Gary Hudson from Oisin Biotechnologies, who is standing in as CEO to help the company get off the ground and funded.

It is worth noting that this paper is a preprint, has not yet been peer reviewed, and is published in bioRxiv in the interest of sharing knowledge faster.

The birth of cellular reprogramming

Back in 2006, Drs. Takahashi and Yamanaka discovered that it was possible to change cells from one type to another by reprogramming them using just four master genes: Oct-4, Sox2, Klf4, and c-Myc (OSKM) [1]. These four factors are commonly known as the Yamanaka factors.

Prior to this discovery, it was generally thought that cells, once specialized, could not change into a different cell type. However, once cells were exposed to the four reprogramming factors expressed by these genes, they reverted back to a younger developmental state and regained the potential to become any other cell type in the body. This state is known as pluripotency.

This is the basis of creating induced pluripotent stem cells (iPSCs), which are used in current stem cell therapies. This process allows cells such as skin cells to be taken from a patient and reprogrammed back into this flexible, pluripotent state; these cells are then guided using other chemical triggers to change into the cell type that the patient needs.

Another interesting aspect of cellular reprogramming is that cells also experience a reversal of the epigenetic markers that develop as we age, thereby reverting back to a younger state. In a very real sense, cells have their age reset and become functionally young again.

Partial cellular reprogramming

This discovery showed that it is possible to reprogram cells to become whatever cell type is needed and that cellular aging is not a one-way process, allowing for the rejuvenation of cells.

However, inducing pluripotency in the cells of a living person would be a very bad idea indeed; imagine if a heart cell forgot it was a heart cell and became a bone cell but was still in the heart! Also, making cells pluripotent in the body carries the risk of causing teratomas, which are tumors made up of multiple types of tissue, such as hair, muscle, or bone. Therefore, we need a solution that can rejuvenate our cells without them forgetting what jobs they are supposed to be doing and without promoting cancer.

One potential answer is partial cellular reprogramming.

In a nutshell, partial cellular reprogramming involves exposing aged cells to OSKM for just long enough that they reset the epigenetic markers that determine if they are young or old but not long enough that the cells forget what they are and become pluripotent. As of late 2016, this approach was successfully demonstrated in living animals [2].

Turn.bio is using transient messenger RNA (mRNA) that mimics the effects of OSKM but includes some factors that help to refine the reprogramming process. Messenger RNA (mRNA) is a family of RNA molecules that relay genetic information from the DNA to the ribosome, where they determine the amino acid sequences of the proteins that are produced as the end result of gene expression.

This approach emulates OSKM expression in that it changes the epigenetic aging markers of the target cells. In doing so, it reverses the age of the cells without the risk of changing their type or causing a teratoma to form.

  Abstract
  Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging is associated with the progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. The technology of nuclear reprogramming to pluripotency, through over-expression of a small number of transcription factors, can revert both the age and the identity of any cell to that of an embryonic cell by driving epigenetic reprogramming. Recent evidence has shown that transient transgenic reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of epigenetic rejuvenation would apply to physiologically aged cells and, importantly, how it might translate to human cells. Here we show that transient reprogramming, mediated by transient expression of mRNAs, promotes a rapid reversal of both cellular aging and of epigenetic clock in human fibroblasts and endothelial cells, reduces the inflammatory profile in human chondrocytes, and restores youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity. Our method, that we named Epigenetic Reprogramming of Aging (ERA), paves the way to a novel, potentially translatable strategy for ex vivo cell rejuvenation treatment. In addition, ERA holds promise for in vivo tissue rejuvenation therapies to reverse the physiological manifestations of aging and the risk for the development of age-related diseases.

Conclusion

We have already seen partial cellular reprogramming used safely in living animals, and Turn.bio’s approach has the potential to further refine that process to make it safer and easier to translate to humans.

This approach has great potential given that epigenetic alterations are likely a primary reason we age, and reversing the epigenetic aging markers in our cells could rejuvenate our organs and tissues as it did in animal studies. That is not to suggest that reversing epigenetic aging is the only problem to solve, because the other hallmarks continue to accrue, but given that it is a primary aging process, some optimism is in order for this and similar approaches.

The key take-home from this paper is that their mixture of reprogramming factors can change the gene expression and function of aged cells back to those of younger cells while avoiding the loss of cell identity and cancer. The next step for these researchers will be to move their technique to animal studies, which is the first step towards bringing it to people.

Literature

[1] Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.

[2] Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JLXJ, Rodriguez-Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P, Izpisua Belmonte JC. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell. 2016;167:1719–33.

partial_cellular_reprogramming_reverse_aging.txt · Last modified: 2020/05/30 05:43 by admin