By Barry Nguyen, Biochemistry & Molecular Biology 

Authors note: I have always been interested in the aging research field. So much so, I watched ALL 8 podcasts episodes of Dr. David Sinclair’s aging podcast during the summer (which can be found on Spotify–highly recommend). A lot of the discussion is centered around developments in rejuvenating research and the various biological pathways associated with aging that can be activated depending on one’s lifestyle. 

As we age, not only does our outward appearance change, but the biological clock hidden within our cells does too. The biological clock, an intrinsic feature shared among cells, allows for partial genetic reprogramming, creating an opportunity to defy the concept of time and aging [2]. This recent development of gene therapy is our closest bet to finding the Fountain of Youth. 

About a decade ago, Shinya Yamanaka had shared the Nobel Prize for discovering a cocktail of proteins with the potential to revert somatic cells back into stem cells. These transcription factors are Oct 4, Sox2, Klf4, and cMYC and are now known as Yamanaka Factors [1]. Typically referred to as OSKM genes, the Yamanaka Factors play a significant role in regulating the developmental signaling network necessary for stem cell pluripotency (defined as the capacity to differentiate to virtually all types of cells) and therefore can revert the identity of virtually any cells in the body. 

Recent advancements in the study of aging at the molecular level have been significant according to Dr. Diljeet Gill, a postdoctoral researcher at the Salk Institute’s Reik Lab, which conducts research on rejuvenation.“These developments have led to techniques that enable researchers to measure age-related biological changes in human cells,” says Dr. Gill [3]. 

Scientists have identified two defining phenomena of the aging process to assist in characterizing signs of aging. The first is the epigenetic clock, which describes the chemical tags present throughout the genome. The second hallmark is the transcriptome, which encapsulates all the gene readouts produced by the cells. 

As an organism ages, the epigenetic markers become widely different. Epigenetic modifications are an intrinsic biological feature of aging, with older organisms showing a significantly different epigenetic profile than younger organisms [1]. Because Yamanaka Factors are able to alter the epigenetic landscape of somatic cells, reprogramming-induced rejuvenation strategies using the OSKM genes are made possible. Furthermore, an animal’s epigenome can be entirely reset by chemically modifying DNA and proteins that help regulate gene activity. Essentially, this form of gene editing allows scientists to revert the aging of cells. 

Cells that have undergone cellular reprogramming not only appear younger, but also function like young cells. In a new study conducted in a collaboration between Dr. In Izpisua and the Altos Lab at the Salk institute have found that mice receiving long-term treatments of Yamanaka factors expressed a gene expression and metabolism profile that resembled that of much younger mice [2].

Results of the study may open up a future of therapeutic possibilities. Researchers observed notable effects in the APBA2 gene, a gene associated with Alzheimer’s Disease and the MAF gene, a gene associated with cataract development, in their transcriptional profile; both displayed a more youthful, more abundant level of transcription, meeting one of the criteria of reverse aging. The results were promising and, according to Dr. Gill, “proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells.” Moreover, Professor Reik, the group leader, stresses that future work can move towards targeting rejuvenating genes to reduce effects of aging. 

The prospects of this new facet of aging research are extraordinary. However, it should be noted that yamanaka factors have the capacity to induce Teratomas, a germ cell tumor. Despite a limit in studies investigating the extent to which Yamanaka Factors can induce cell tumors, the ability for Yamanaka Factors to induce pluripotency and stem cell-like properties allow cells to reach a cancer-like state. Cancers are typically characterized as uncontrolled cell division. Furthermore, the differentiated cell’s ability to revert to pluripotency significantly increases the possibility for cells to take on cancer-like states. 

Nevertheless, studies within this field are exciting, and researchers are united by a common goal of identifying methods to slow or even reverse the processes that lead to disease. As research continues, society is at a rapid pace in reaching a point where predicting, preventing, and even treating diseases through cellular rejuvenation becomes a reality.

References: 

1. Cellular rejuvenation therapy safely reverses signs of aging in mice. Salk Institute for Biological Studies. (2023, January 5). Retrieved February 5, 2023, from https://www.salk.edu/news-release/cellular-rejuvenation-therapy-safely-reverses-signs-of -aging-in-mice/

2. Fan, S. (2022, April 4). Scientists used cellular rejuvenation therapy to rewind aging in mice. Singularity Hub. Retrieved February 5, 2023, from https://singularityhub.com/2022/04/06/scientists-used-cellular-rejuvenation-therapy-to-re wind-aging-in-mice/

3. Garth, E. (2022, May 12). Research reverses aging in human skin cells by 30 years. Longevity.Technology – Latest News, Opinions, Analysis and Research. Retrieved February 5, 2023, from https://longevity.technology/news/research-reverses-aging-in-human-skin-cells-by-30-ye ars/

4. Two research teams reverse signs of aging in mice | science | AAAS. (n.d.). Retrieved February 5, 2023, from https://www.science.org/content/article/two-research-teams-reverse-signs-aging-mice