Dr. Rodolfo Goya – Could Yamanaka Factors Delay Human Aging?

Elena Milova brings us another interesting interview from the recent International Longevity and Cryopreservation Summit, where she caught up with a senior scientist at the National Scientific and Technical Research Council (CONICET) of Argentina, Dr. Rodolfo Gustavo Goya.

Dr. Goya admits that he used to be a rebel from a young age. At 17, he decided he was not happy about aging and that he wanted to make a difference. He became a biochemist in the hope he could do something about age-related health deterioration, and he continues to rebel against Mother Nature to this day.

Dr. Goya has led a number of studies on cellular reprogramming and restoration of function in important organs, such as the thymus and the brain. He is also daring to challenge death itself by studying different aspects of cryopreservation, and he openly supports cryonics as a logical extension of medicine.

In this short interview, Dr. Goya explains his interest and motivation in aging research as well as his views on the potential of Yamanaka factors and their limitations in relation to human rejuvenation.

Dr. Goya’s team is currently exploring Yamanaka factors in relation to aging. These factors (Oct3/4, Sox2, Klf4, c-Myc) are the four master genes that allow cells to be rejuvenated and reprogrammed [1].

In 2011, Jean-Marc Lemaitre famously reset cells from people aged over 100 back to the state of a 20-year-old’s cells [2]. This is the basis for induced pluripotent stem cell (iPSC) therapy, and our understanding of how these factors work has been refined in the time since then.

Resetting epigenetic alterations – a hallmark of aging

One of the proposed primary hallmarks of aging is epigenetic alterations [3], but what are they?

While the various organs and tissues in the body are so different from each other, they share the same genetic code in our DNA. This is due to the epigenetic information that changes gene expression by either silencing, reducing, or enhancing the expression of particular genes as needed by the different tissue types. This is how, for example, liver cells or lung cells know what they are and how to behave.

You might consider epigenetics to be like a lens that focuses gene expression, and moving the lens around in different ways changes how those genes are expressed and how cells function.

Unfortunately, aging changes our epigenetic information, which is detrimental to our gene expression. This change of gene expression from a pro-youthful one to a pro-aging one is thought to be a major reason that we age. Indeed, iPSC experiments strongly support this notion, as cells can be rolled back from an aged state to a nearly new state by activating the Yamanaka factors.

It was therefore proposed back in 2013 in the Hallmarks of Aging that epigenetic alterations may be a primary reason why we age; however, the authors were unable to confirm this due to a lack of evidence in living animals. That all changed in late 2016.

Reversing epigenetic alterations in living animals

Recently, progress has been made using these factors in living animals, rather than just on cells in a dish, by Juan Carlos Izpisua Belmonte and his colleagues at the Salk institute [4]. Transgenic mice had their epigenetic alterations reset by using the Yamanaka factors in situ to reprogram them. This is very much like iPSC therapy but in a living animal.

This now opens the door for the possibility of reprogramming cells in people to make them functionally younger again. Indeed, Dr. Maria Blasco and her team recently followed up Dr. Belmonte’s experiment and showed that reprogramming cells in vivo also resets telomere length.

Telomere attrition is thought to be another primary aging hallmark and a reason why we age [5]. This is very interesting as it suggests that by resetting epigenetic alterations, we may potentially get a two-for-one deal on reversing aging hallmarks.

Unfortunately, translating this reprogramming to humans is not as simple as in Dr. Belmonte’s experiment, which involved transgenic mice. These mice were genetically engineered to express Yamanaka factors when given a common antibiotic as a trigger. We cannot engineer humans in this way due to ethical considerations, and even if we could, this would have to be done at the embryonic stage. So, the therapy as it is could not be used in already aged people.

Fortunately, we all have the Yamanaka genes in our cells, but they are dormant. Dr. Goya believes the race is now on to find ways to activate them. This could be done by using compounds, gene therapies, or other, more sophisticated, approaches.

Conclusion

If a way to activate these dormant genes can be found, it would mean we could reprogram our cells and reset them to a functionally younger state, which would rejuvenate the body. The debate over whether epigenetic changes are a reason why we age or if they are just a consequence of aging continues, but with rapid progress in this area, hopefully the matter will be settled soon.

If it turns out that epigenetic alterations are a primary cause of aging, this fact will have huge implications for how rejuvenation biotech will play out in the coming decades. This is equally true if it turns out that epigenetic alterations are a consequence of other forms of damage and not a primary driver of aging, as this would also be valuable information.

There is an urgent need to conduct more tests to answer these questions so that future research efforts can be focused on addressing the root of the problem. LEAF is supporting fundamental scientific research via our platform Lifespan.io, a crowdfunding platform where researchers can host breakthrough projects to address gaps in our knowledge and drive progress forward more quickly.

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] Lapasset, L., Milhavet, O., Prieur, A., Besnard, E., Babled, A., Aït-Hamou, N., … & Lehmann, S. (2011). Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes & development, 25(21), 2248-2253.

[3] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[4] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell, 167(7), 1719-1733.

[5] Marión, R. M., de Silanes, I. L., Mosteiro, L., Gamache, B., Abad, M., Guerra, C., … & Blasco, M. A. (2017). Common telomere changes during in vivo reprogramming and early stages of tumorigenesis. Stem cell reports, 8(2), 460-475.