Aging is one of the reasons that scientists work hard to do biomedical research, however, rejuvenation is an unreachable dream. Especially in fiction movies, rejuvenation is always a key element. Is it possible to let people keep young-looking forever? How does it work? If so, how does it change the current biomedical industry or even the cosmetic industry?

The first thing I would like to introduce is “Yamanaka factors,” which brought Kyoto University researcher Shinya Yamanaka to win the Nobel prize in 2012. What are Yamanaka factors? Four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) are the Yamanaka factors, and they could be applied to reprogram somatic cells into pluripotent stem cells. In other words, with Yamanaka factors, we could generate unlimited stem cells from people or any patients who need organ transplantation. We could think of the stem cells as age zero because every fetal is grown from embryonic stem cells, and the Yamanaka factors could induce the cells from a mature state to the original condition. This fact allows scientists to think about rejuvenation; what if we only partially reprogram the cells? Is it possible to make the cells younger? In 2020, Dr. Sinclair and his group used the adenovirus-associated virus (AAV) to deliver three Yamanaka factors to restore vision in mice, and this work has been published in Nature. Also, Dr. Vittorio Sebastiano and his group demonstrated how Yamanaka factors with two additional factors (LIN28 and NANOG) reverse the epigenetic methylation of cytosine-guanine dinucleotides (CpG) on DNA to make the human cells younger with restored regeneration. Here, I would like to explain what epigenetic methylation is and what epigenetic clock is? First, CpG islands are the region on DNA that could be added a methyl group (CH3 group), and the DNA methylation could regulate gene expressions. In this hypothesis, stem cells would have less methylation of CpG on DNA. Second, with epigenetic methylation, a new definition of age is epigenetic clock/age, calculated and measured by the change in DNA methylation and the biomarkers of age. It is different from the chronological age counting by time, but epigenetic age is measured by the methylation of DNA. An exciting discovery is that the rate of epigenetic aging is slower in supercentenarian and their descendants. This might explain why those people could live longer than others. On the other hand, previous studies give us hope that if we could use the Yamanaka factors to partially reverse epigenetic methylation frequently, we might make dreams come true that we all become centenarians and have young-looking forever.

With the potential as therapeutics, several companies have been found to develop anti-aging as rejuvenation therapy. For example, Calico Life Sciences/Alphabet, which was founded by Bill Maris and Arthur Levinson in 2013, focuses on basic research in partial reprogramming mechanisms. Life Biosciences which was found by David Sinclair and Tristan Edwards in 2017, focuses on using AAV to deliver reprogramming factor genes. Turn Biotechnologies which was found by Vittorio Sebastiano, Marco Quarta, and Jay Sarkar in 2019, focuses on mRNA-based delivery of reprogramming factors. Last, a newly launched biotechnology company, Altos Labs, which is invested by the founder and former CEO of Amazon, Jeff Bezo, focuses on transforming medicine through cellular rejuvenation programming. The company has three Altos Institutes of Science based in the San Francisco Bay Area, San Diego, and in the UK (Cambridge). In the increase in aging research and newly launched biotech companies, maybe rejuvenation is a potential therapeutic to extend average human life; however, the current research only accomplished the epigenetic reprogramming in a rodent model and human cells in vitro. I believe it will not be an easy task to reverse the epigenetic methylation in non-human primates and also in humans. The four Yamanaka factors are not enough to completely reprogram the cells in the body. Therefore, there will be a lot of things we could do in the aging research, especially after the COVID-19 pandemic, mRNA therapeutic becomes a very popular tool to deliver genes in the human body, for instance, the COVID vaccine.

In sum, rejuvenation was a myth story to us, but with accelerated development in biotechnology, anti-aging would be accomplished and improve human health in the next decade.

Reference:

1. Michael Eisenstein, nature biotechnology 2022 https://doi.org/10.1038/d41587-022-00002-4
2. Sarkar, T.J., Quarta, M., Mukherjee, S. et al. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun 11, 1545 (2020). https://doi.org/10.1038/s41467-020-15174-3
3. Lu, Y., Brommer, B., Tian, X. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). https://doi.org/10.1038/s41586-020-2975-4
4. Chiavellini P, Canatelli-Mallat M, Lehmann M, Gallardo MD, Herenu CB, Cordeiro JL, Clement J, Goya RG. Aging and rejuvenation – a modular epigenome model. Aging (Albany NY). 2021; 13:4734-4746. https://doi.org/10.18632/aging.202712
5. Altos Labs company website

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Jason(Yen-Chun) Lu, All right reserved.