You may recall the work linking DNA double strand break repair to epigenetic changes characteristic of aging. Repeated cycles of this repair cause some form of depletion of necessary factors or other disarray in the mechanisms controlling gene expression. This is a compelling way to link random DNA damage, largely occurring in parts of the genome that are inactive in any given cell, largely occurring in cells that will not go on to divide many times, and occurring in completely different locations from cell to cell, to a consistent, characteristic aspect of aging. Beyond the question of cancer risk, the only other compelling way to connect stochastic DNA damage to the general declines of aging is to consider somatic mosaicism emerging as a result of mutational damage to stem cells, as that mutation spreads throughout a tissue.
In today's materials, researchers describe a way to accelerate this epigenetic change caused by repair of breaks in DNA, and characterize a mouse lineage engineered to undergo a great deal of DNA damage, but damage that occurs only in inactive portions of the genome, and should thus produce no harm to the genomic information needed for cell function. The result appears to be accelerated aging, occurring though the mechanism of epigenetic change noted above. This allows researchers to more readily test the use of partial reprogramming as a means to reverse this epigenetic change, and better understand how this reversal works.
As ever, one should be cautious about declaring models that focus on just one mechanism of aging to actually exhibit accelerated aging. Any form of biological damage run amok, such as occurs for DNA damage in progeroid syndromes, can produce outcomes that bear a strong resemblance to normal aging - but they are not normal aging. The details as to how exactly they are different are important when it comes to drawing conclusions from these models about the best approaches to treating aging. It is a little early in the research into DNA repair and epigenetic change for a good understanding as to how this sort of model will differ from normal aging, as researchers have for progeroid mice.
A component of epigenetics is the physical structures such as histones that bundle DNA into tightly compacted chromatin and unspool portions of that DNA when needed. Genes are inaccessible when they're bundled up but available to be copied and used to produce proteins when they're unspooled. Thus, epigenetic factors regulate which genes are active or inactive in any given cell at any given time. By acting as a toggle for gene activity, these epigenetic molecules help define cell type and function. Since each cell in an organism has basically the same DNA, it's the on-off switching of particular genes that differentiates a nerve cell from a muscle cell from a lung cell.
The team's main experiment involved creating temporary, fast-healing cuts in the DNA of lab mice. These breaks mimicked the low-grade, ongoing breaks in chromosomes that mammalian cells experience every day in response to things like breathing, exposure to sunlight and cosmic rays, and contact with certain chemicals. In the study, to test whether aging results from this process, the researchers sped the number of breaks to simulate life on fast-forward. The team also ensured that most of the breaks were not made within the coding regions of the mice's DNA - the segments that make up genes. This prevented the animals' genes from developing mutations. Instead, the breaks altered the way DNA is folded.
The researchers called their system ICE, short for inducible changes to the epigenome. At first, epigenetic factors paused their normal job of regulating genes and moved to the DNA breaks to coordinate repairs. Afterward, the factors returned to their original locations. But as time passed, things changed. The researchers noticed that these factors got "distracted" and did not return home after repairing breaks. The epigenome grew disorganized and began to lose its original information. Chromatin got condensed and unspooled in the wrong patterns, a hallmark of epigenetic malfunction. As the mice lost their youthful epigenetic function, they began to look and act old. The researchers saw a rise in biomarkers that indicate aging. Cells lost their identities as, for example, muscle or skin cells. Tissue function faltered. Organs failed.
Next, the researchers gave the mice a gene therapy that reversed the epigenetic changes they'd caused. The therapy delivered a trio of genes - Oct4, Sox2, and Klf4, together named OSK - that are active in stem cells and can help rewind mature cells to an earlier state. The ICE mice's organs and tissues resumed a youthful state. The therapy set in motion an epigenetic program that led cells to restore the epigenetic information they had when they were young. How exactly OSK treatment achieved that remains unclear. At this stage, the discovery supports the hypothesis that mammalian cells maintain a kind of backup copy of epigenetic software that, when accessed, can allow an aged, epigenetically scrambled cell to reboot into a youthful, healthy state.
All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.