Several research groups and companies are working on in vivo applications of cellular reprogramming. Today's research materials cover recent work from David Sinclair's team showing off the use of reprogramming to produce regeneration of damaged nervous system tissue in the eye and optic nerve. Glaucoma is a condition in which rising pressure in the eyeball progressively harms the retina and optic nerve. Since nerve tissue doesn't regenerate well in mammals, loss of vision is irreversible. This is one of many conditions for which the ability to regenerate nerve tissue would be a great benefit.
Since its discovery, reprogramming has been used to produce induced pluripotent stem cells from any other type of cell. That process has been found to reverse age-related changes in epigenetic patterns and mitochondrial function characteristic of cells in old tissues. Introducing the factors capable of reprogramming cells into a living animal may produce effects akin to stem cell therapy by converting a small number of cells into induced pluripotent stem cells, followed by stem cell signaling that beneficially affects tissue health more broadly. Alternatively, many cells may have their epigenetic markers reset to a more youthful state without losing their identity to become induced pluripotent stem cells. Or both. Beyond this, there is certainly the threat of cancer or structural damage to tissue through the conversion of too many cells, and this class of therapy will require careful development to ensure safety, even as the mouse data continues to look quite interesting.
David Sinclair has been pushing an epigenetic-centric view of aging of late, with analogies to information systems and computing. The most interesting part of the the supporting work suggests that DNA repair of double strand breaks has the side-effect of driving alteration of the epigenome in characteristic ways with age. That will be an important connection between stochastic nuclear DNA damage and deterministic global effects throughout the body, should the evidence continue to hold up.
As this illustrates, however, epigenetic change is a downstream issue in aging, a reaction to events and a changing environment, not a first cause. Fixing it may or may not turn out to be particularly useful in the broader picture of aging, depending on exactly where it sits in the web of cause and consequence. As a comparable example, hypertension is a major downstream issue in aging. It is far removed from root causes such as cross-link formation and inflammation, but is also a proximate cause of many forms of further dysfunction, such as pressure damage to delicate tissues in the brain. Controlling hypertension without addressing its causes is both possible and beneficial - but the benefits are limited by the fact that those root causes are still there, chewing away at the body in a thousand other ways.
Scientists reverse age-related vision loss, glaucoma damage in mice
Scientists have successfully restored vision in mice by turning back the clock on aged eye cells in the retina to recapture youthful gene function. The team used an adeno-associated virus (AAV) as a vehicle to deliver into the retinas of mice three youth-restoring genes - Oct4, Sox2, and Klf4 - that are normally switched on during embryonic development. The three genes, together with a fourth one, which was not used in this work, are collectively known as Yamanaka factors. The treatment had multiple beneficial effects on the eye. First, it promoted nerve regeneration following optic-nerve injury in mice with damaged optic nerves. Second, it reversed vision loss in animals with a condition mimicking human glaucoma. And third, it reversed vision loss in aging animals without glaucoma.
The team's approach is based on a new theory about why we age. Most cells in the body contain the same DNA molecules but have widely diverse functions. To achieve this degree of specialization, these cells must read only genes specific to their type. This regulatory function is the purview of the epigenome, a system of turning genes on and off in specific patterns without altering the basic underlying DNA sequence of the gene.
This theory postulates that changes to the epigenome over time cause cells to read the wrong genes and malfunction - giving rise to diseases of aging. One of the most important changes to the epigenome is DNA methylation, a process by which methyl groups are tacked onto DNA. Patterns of DNA methylation are laid down during embryonic development to produce the various cell types. Over time, youthful patterns of DNA methylation are lost, and genes inside cells that should be switched on get turned off and vice versa, resulting in impaired cellular function. Some of these DNA methylation changes are predictable and have been used to determine the biologic age of a cell or tissue. Yet, whether DNA methylation drives age-related changes inside cells has remained unclear. In the current study, the researchers hypothesized that if DNA methylation does, indeed, control aging, then erasing some of its footprints might reverse the age of cells inside living organisms and restore them to their earlier, more youthful state.
Reprogramming to recover youthful epigenetic information and restore vision
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. Changes to DNA methylation patterns over time form the basis of ageing clocks, 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. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4, 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.
View the full article at FightAging
