The field of epigenetics has always been very interesting to me. In cancer treatment, it was observed that certain drugs that allowed the accumulation of acetyl groups on histone proteins (these drugs were called histone deacetylase (HDAC) inhibitors). Histone proteins bind tightly to DNA, and are associated with tightly wound DNA (chromatin) that is not actively expressed. The acetylation of histones is thought to be a reversible chemical switch – where low acetylation is associated with loosely wound chromatin and high levels of gene expression – and high acetylation is associated with tightly wound chromatin and low levels of gene expression. (This oversimplifies things, but it's good enough as a simple intro to this topic.)
I made it my business to learn as much as I could about epigenetics, a very complex topic. Let me try to define it at the simplest level. All of our cells have the same genes and chromosomes. Yet, we have many very different types of cells and tissues in our bodies. How do some cells become brain tissue, and other cells become lung, skin, bone, muscle, etc? In biology, this process is called differentiation or development. The theory has been that different genes get expressed (turned on) or silenced during different stages of development. In the field of cancer, the theory is that epigenetic changes during development & differentiation can sometimes run amok, leading to tumors where normal development had been interrupted or defective.
In the lab, these drugs could induce certain human leukemia cell lines (HL60 cells, derived from the blood of leukemia patients) to stop being cancer cells. These cells typically divide rapidly (about once every day) while growing in liquid suspension cultures. They are known to be descended from bone marrow cells, the precursors of many types of red & white blood cells. But these leukemia cells don't do any of the cell functions that you would expect of those cells. They just divide and divide.
At high enough concentrations, above 5 µM (micromolar, 5 parts per million), these drugs killed the leukemia cells. But at about 1 µM, these drugs allowed the leukemia cells to survive, but stopped their rapid cell division. They also stopped growing in liquid suspension (typical of many tumor cells), and settled onto plastic surfaces if they had been coated with certain proteins (growth while adhering to surfaces is a feature common to many non-tumor cells).
Interestingly, at the same time these HL60 cells stopped dividing and switched from growing in suspended cultures to adherent cultures, these leukemia cells also started to produce hemoglobin, a protein expressed by mature red blood cells. It was as if the treatment made the HL60 cells stop being rapidly dividing cancer cells, and acquire at least one normal function. This became known in the cancer world as "differentiation therapy", where you don't aim to burn or poison the tumor cells, but try to trick them into abandoning their worst cancer cell traits and differentiate into something more like normal cells.
I followed this field very closely as 2 or 3 generations of these histone deaceytlase inhibitor drugs were developed. The National Cancer Institute encouraged their development, and ran a number of clinical trials with them. The early forms of HDAC inhibitors weren't very potent. In the lab they worked at 1-5 millimolar concentrations (mM, 1 to 5 parts per thousand). No patient could take enough of these drugs, given IV or orally, to come close to those concentrations.
At least two of the next generation of HDAC inhibitor drugs were more potent. But it was still difficult to get enough into patients' blood stream to achieve a concentration of 1 µM. Both were approved for use in treating cutaneous T-cell lymphoma (CTCL), but in other more common forms of cancer these drugs were effective, but not effective enough for approval.
For example, clinical trials of Zolinza (an HDAC inhibitor made by Merck) were done in advanced lung cancer, multiple myeloma, and a number of other types of cancer. Zolinza was given in combination with other standard chemotherapy drugs. In the lung cancer trial, that HDAC inhibitor was combined with standard chemotherapy (carboplatin & paclitaxel), and appeared to work better than the standard chemotherapy alone. But about 40% of those patients experienced fatigue so severe that they couldn't get out of bed, often requiring hospitalization. Most of those patients quit the trial rather than go through 8 full weeks of treatment. It's been well known that carboplatin & paclitaxel treatment can temporarily stop lung tumors from growing, even shrinking them, but it requires the full 8 weeks of treatment. Combining them with an HDAC inhibitor worked well in the lab and in mice, but in humans, it caused too much fatigue. It was very frustrating for me, as this was my baby for a number of years. It was frustrating for Merck too, not to mention those lung cancer patients.
Interestingly, the whole field of epigenetics came about from scientists who studied the genetics of development in fruit flies. Typical of insects, fruit flies have 4 stages of life: eggs, larvae, pupae, and adults. These scientists used classic old-school genetic methods to identify a large number of mutations that interrupted the normal development of fruit flies between these stages. Decades later, these mutations were found to be in genes involved in the epigenetic control of gene expression during insect development. Similar genes are higher mammals, including humans. And now, they are active topics in cancer and aging research. This is a good reason why we must always fund basic science research. You never can predict where it takes you.
All this background on epigenetics is complex enough that I never read much about epigenetics with regard to aging. Once I get my hands on this paper, I'll read it with interest.
Sorry for such a long post.