Fight Aging!

Cell reprogramming was first induced by expression of the Yamanaka factors, a way to access the program of rejuvenation and dedifferentiation that takes place in the early embryo. A small fraction of cells in culture exposed to reprogramming factors will change into induced pluripotent stem cells while ohers will undergo an epigenetic reset to adopt a youthful set of behaviors and capabilities. This involves removing age-related changes in gene expression that lead to mitochondrial dysfunction, for example. By virtue of the way in which cellular biochemistry is very interconnected, there should be many ways to access the embryronic program of rejuvenation, and hopefully ways to separate the process of dedifferentiation from the epigenetic reset. It is just a matter of finding those other ways.

An important part of the reprogramming field as it stands today is the expansion from genetic means of provoking reprogramming to the discovery of small molecules that can achieve the same outcome. While gene therapy is the future of medicine, the gene therapy industry of today remains a rounding error next to the size of the small molecule industry. With this in mind, most of the noteworthy organizations involved in the development of reprogramming therapies have a small molecule program. Today's open access paper is a illustrative report from one of the associated research groups in the field, a starting point for a small molecule drug discovery program aimed at producing efficient reprogramming without genetic modification.

Chemically induced reprogramming to reverse cellular aging

Starting in 1962, researchers demonstrated that nuclei contain the necessary information to generate new individuals with normal lifespans. In 2006, researchers demonstrated that the expression of four transcription factors, OCT4, SOX2, KLF4, and c-MYC (collectively known as the Yamanaka factors or OSKM), reprograms the developmental potential of adult cells, enabling them to be converted into various cell types. These findings initiated the field of cell reprogramming, with a string of publications in the 2000s showing that the identity of many different types of adult cells from different species could be erased to become induced pluripotent stem cells, commonly known as "iPSCs".

The ability of the Yamanaka factors to erase cellular identity raised a key question: is it possible to reverse cellular aging in vivo without causing uncontrolled cell growth and tumorigenesis? Initially, it didn't seem so, as mice died within two days of expressing OSKM. But later work confirmed that it is possible to safely improve the function of tissues in vivo by pulsing OSKM expression or by continuously expressing only OSK, leaving out the oncogene c-MYC. In the optic nerve, for example, expression of a three Yamanaka factor combination safely resets DNA methylomes and gene expression patterns, improving vision in old and glaucomatous mice. Numerous tissues, including brain tissue, kidney, and muscle, have now been reprogrammed without causing cancer. In fact, expression of OSK throughout the entire body of mice extends their lifespan. Together, these results are consistent with the existence of a "back-up copy" of a youthful epigenome, one that can be reset via partial reprogramming to regain tissue function, without erasing cellular identity or causing tumorigenesis.

Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases, rely on the delivery of genetic material to target tissues. This is achieved through methods like adeno-associated viral (AAV) delivery of DNA and lipid nanoparticle-mediated delivery of RNA. These approaches face potential barriers to them being used widely, including high costs and safety concerns associated with the introduction of genetic material into the body. Developing a chemical alternative to mimic OSK's rejuvenating effects could lower costs and shorten timelines in regenerative medicine development. This advancement might enable the treatment of various medical conditions and potentially even facilitate whole-body rejuvenation.

In this study, we developed and utilized novel screening methods including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells. We identify a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression. Thus, it is possible to reverse aspects of aging without erasing cell identity using chemical rather than genetic means.