Injecting Three Genes Could Make Cells Young Again? Rejuvenation Around The Corner?


This is the year when genetic engineering is on its way to save millions of lives: messenger RNA vaccines are a success… Some other attempted vaccines against COVID have rather failed (the rather traditional Sanofi-Pasteur is an example). 

And maybe more than millions, but even billions of lives may be in the process of being saved from COVID. Because, after all, the coronavirus could well mutate in a more contagious and more lethal way. More contagious mutations of the coronavirus have been discovered (“56%” more contagious in the latest UK estimate). More lethal coronavirus could happen any time. Increased lethality is apparently what happened to smallpox in the last millennium: as human populations augmented, the virus could become more lethal, while surviving as a species. This is the gist of studies of Viking corpses, who seemed to have lived with a less lethal version of smallpox.

The injection of messenger RNA wrapped in exotic Lipid Nanoparticles (LNP) in hundreds of millions of people has brought alarms in some circles. Some evoke “Site-Directed Mutagenesis” (CRISPr falls into that…) 

Spooky name, SDM! Well done STM will cure thousands of diseases. For example, all cancers. SDM is developed by some companies as a cure for infarctus and angina. The idea is to promote the growth of blood vessels by an injection of the appropriate genes in the distressed area of the heart.

One could hope that mutating genes causing aging could well bring rejuvenation. It is pretty obvious that aging is gene related, because even closely related species of rodents can age at strikingly different rates. Considerhe house mouse (Mus musculus) and the white-footed mouse (Peromyscus leucopus): the latter has a greater than 2-fold greater life span and metabolic potential than the former.. Thus science is increasingly confirming that aging is a selected mechanism, not just fate, entropy and inertia. 

Rejuvenation has already been achieved with neurons in the eye. At least so is the claim in a peer reviewed paper in Nature: “Reprogramming to recover youthful epigenetic information and restore vision” by

Yuancheng Lu, Benedikt Brommer, etc, December 2, 2020. The gist is that cellular ageing is essentially epigenetic. Turning back the clock with three genes (OSK) restores vision in mice. Three genes may make cells young again.

Abstract: “Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity [1,2,3]. Changes to DNA methylation patterns over time form the basis of ageing clocks [4], but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity [5,6,7]. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by DNA methylation—that can be accessed to improve tissue function and promote regeneration in vivo.”

Turning Back The Clock, Advancing Civilization

As Nature puts it [Biology adverse types can jump to my conclusion below]:

Sight restored by turning back the epigenetic clock:

Neurons progressively deteriorate with age and lose resilience to injury. It emerges that treatment with three transcription factors can re-endow neurons in the mature eye with youthful characteristics and the capacity to regenerate. Ageing has negative consequences for all the cells and organs in our bodies. Our brains are no exception. Neurons in the developing brain form circuits that can adapt to change and regenerate in response to injury. These capacities have long been known to diminish over time, but the molecular shifts that underlie this deterioration have remained mysterious. Lu et al.2 show in a paper in Nature that neurons of the eye can be programmed to revert to a youthful state in which they reacquire their ability to resist injury and to regenerate. The authors’ findings shed light on mechanisms of ageing and point to a potent therapeutic target for age-related neuronal diseases.

Retinal ganglion cells (RGCs) reside in the eyes and thus outside the skull, but they are bona fide brain neurons. They initially develop as part of the forebrain. Subsequently, RGCs extend projections called axons out of the eye to make connections with neurons in the brain itself. These axons — which join together to form the optic nerve — survive and regenerate if they are damaged early in development, but not after they reach maturity3,4. Evidence indicates3,5 that this shift is intrinsic to RGCs, rather than reflecting changes in the surrounding cells.

Myriad studies have searched for factors that can prevent or promote RGC survival and regeneration. 

Lu et al. asked whether it is possible to revert RGCs to a younger ‘age’, and whether doing so would allow the cells to regenerate. They infected RGCs in mice with adeno-associated viruses. These harmless viruses had been genetically engineered to induce expression of three of the ‘Yamanaka factors’ — a group of four transcription factors (Oct4, Sox2, Klf4 and c-Myc) that can trigger mature cell types to adopt an immature state6. Such an approach normally comes with hazards in vivo: Yamanaka factors can cause cells to adopt unwanted new identities and characteristics, leading to tumours or death7. Fortunately, Lu and co-workers found that they could circumvent these hazards by expressing just Oct4, Sox2 and Klf4 (together called OSK)….

Why might reprogramming old RGCs to a younger state promote regeneration and restore vision? An emerging model in the field of ageing is that, over time, cells accumulate epigenetic noise — molecular changes that alter patterns of gene expression8, including transcriptional changes and shifts in the patterns of methyl groups on DNA. Collectively, these changes cause cells to lose their identity and so to lose the DNA-, RNA- and protein-expression patterns that once promoted their youthful resilience9,10. Given the growing excitement about DNA methylation as a marker of cell age, the authors asked whether OSK expression somehow counteracts the negative effects of ageing or axon injury on DNA methylation.

The RNA components of a cell’s protein-synthesizing machine, called the ribosome, are encoded by ribosomal DNA genes that steadily accrue methyl marks with age. The ribosomal ‘DNA methylation clock’ is therefore considered to be a reliable estimate of cell age11. Lu et al. found that damaging the axons of RGCs accelerated ribosomal DNA methylation in a way that mimicked accelerated cellular ageing, whereas OSK expression counteracted that acceleration, indicating that tissue injury in general might be a form of accelerated ageing…

For decades, it was argued that understanding normal neural developmental processes would one day lead to the tools to repair the aged or damaged brain. Lu and colleagues’ work makes it clear: that era has now arrived.

***

Preventing ageing, replacing it with rejuvenation, will have tremendous consequences. It is not just tremendously desired by those who love life. It is also tremendously needed, for philosophical-psychological reasons. To be developed, another time.

Patrice Ayme

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