Monday, February 4, 2013

Epigenetics, aging and cancer

We used to talk about how "the blueprint" for the human body was encoded in genes. These long chains of DNA held the instructions for the building of proteins, which made up the body's structures and carried its messages. End of story, right?  Actually, it's just the beginning.

Recent research has shown that genes, while crucially important, represent just one aspect of the human genetic system. The human body achieves its unique level of complexity by putting the same genes to many uses. In this light, mechanisms that "decide" when and where genes are turned on and off become central to human health and disease.

Interestingly, one set of these regulatory mechanisms, epigenetic changes, contribute to our genetic regulatory finesse without changing the instructions encoded in the DNA we inherit from our parents. Epigenetic mechanisms are chemical reactions that turn genes on and off during our lifespan, and largely thanks to our interactions with the world around us. Evidence is mounting that environmental factors like the foods we choose to eat constantly change the performance of our genetic material, and in ways that drive the aging process and cancer risk.

Such changes were the focus of a recent UAB Epigenetics Symposium, and The Mix – the UAB research blog – sat down with some of the presenters. Today's guest is Trygve Tollefsbol, Ph.D., professor of in the UAB Department of Biology, and an expert on the relationships between epigenetics, cancer and aging.


Show notes for the podcast: 

:53 Epigenetics is defined as changes in human gene expression caused not by changes in the order of base pairs, the DNA "letters" making up our genes. Epigenetic changes are instead the result of chemical reactions that determine whether or not the instructions encoded in a given stretch of DNA are read and followed..

2:20 If a person is born with a cancer-causing mutation, a permanent change in the order their DNA code within a gene, current medicine cannot often or easily reverse it. Physicians try to treat the cancer, but cannot easily address the underlying genetic problem.

2:39 One of the most exciting things about epigenetic changes, Tollefsbol said, is that they are easily reversible. Researchers hope they will soon be able to manipulate epigenetic mechanisms to reverse disease processes. This becomes especially relevant when you consider that perhaps "half of cancer cases" are caused by epigenetic changes instead of mutations in the DNA code, Tollefsbol said.

3:54 Two important epigenetic mechanisms that regulate when genes are turned on or off are DNA methylation and histone acetylation. Methylation is the chemical attachment at a certain point on the DNA chain of a methyl group (one carbon atom bonded to three hydrogen atoms). This attachment can make it possible for other proteins to bind to the DNA chain such that the surrounding gene is silenced.

5:40 In addition, DNA does not just float around lose in the nuclei of human cells. Long chains of DNA are wrapped around protein "spools" that help to organize, protect and regulate them. Part of DNA regulation is spatial, and works by controlling when certain parts of DNA chains are able to unravel from their spools. The unraveling makes a stretch of code accessible to the protein-making machinery. The spools are proteins called histones, and the attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible.

6:50  Enzymes, protein catalysts in the body, which encourage epigenetic changes include DNA methylase and histone acetyltransferase. They serve as editors of the proteins that are controlling gene expression. Researchers in the future may be able to manipulate such enzymes with drugs that reverse epigenetic processes contributing to many diseases.

8:26 Epigenetics is a central interest in Tollefbol's lab, especially with respect to cancer and aging.  His team is interested in countering the epigenetic changes that contribute to the aging process, many of which appear to be influenced by diet. Both the quality and the quantity of the food we eat affects our gene expression. Evidence is mounting that caloric restriction, the hard choice to consume fewer calories, contributes to longer life and protects against cancer through epigenetic processes.

10:47  Whether or not a person gets cancer as they age in part comes down to a battle between genetic mechanisms that encourage cell growth (and that get broken to create abnormal growth) and others that suppress tumors by countering growth. It's a gas pedal versus the brakes. Evidence is emerging that epigenetic changes brought about by environmental factors (diet, sunlight exposure, air quality) can shift the balance from health toward disease as we age.

12:10  In the car analogy, oncogenes are the gas pedal for abnormal growth, while tumor suppressor genes are the brakes. Oncogenes encourage cell division. Each cell divides to become two, the number of cells goes up and growth occurs. Tumor suppressors block cell division. Taking the car analogy further, one then has to consider how much gas is in the tank. DNA within a human cell, packaged in chromosomes, can be copied into a new generation of cells only so many times. Each time a cell divides, the tail end of the chromosome called the telomere gets a little shorter until it is gone. Like the amount of gas in a tank, this serves as a physical limit on cell division, limiting the lifespan of a line of cells and its ability to drive tissue growth. Limited telomere length also serves as another protection against tumors as cancer cells seek to become immortal.

12:27 The older we get, the more likely we are to acquire problems with telomerase, the enzyme that sets telomere length in the womb, and then shuts down in most normal adult cells. Cancer cells are "addicted" to telomerase, which extends the length of their telomeres indefinitely. This fills the gas tank and makes the cells "immortal" as they divide and multiply indefinitely. Evidence suggest that many of the mechanisms that contribute to abnormal telomerase activity are epigenetic chemical modifications, said Tollefsbol.

14:02 While telomeres get shorter and shorter as a measure of aging, you can't just give telomerase to a person and think they will live for seven hundred years.The same process that causes aging via the suppression of telomerase after we leave the womb protects us from cancer.

15:29 Drug designers have seized on the realization that cancer cells depend on telomerase to become immortal and that normal cells don't use it. Selective telomerase inhibitors have been developed and some are in clinical trails. While the arrival of effective drugs in this class would be a boon, Tollefsbol's lab has determined that many compounds in common foods epigenetically prevent the activation of telomerase.  Broccoli, Brussels sprouts, cabbage, green tea and avocados are examples of foods containing compound that epigenetically turn of the gene that encodes telomerase.

17:37  The main thrust of Tollefsbol's presentation at the recent UAB Epigenetics Symposium was the concept of the "Epigenetics Diet," a term coined by his team. Specifically, Tollefsbol and colleagues are looking closely at the action of the chemical called solforaphane found in broccoli, cabbage and Kale that has beneficial epigenetic effects, including the turning down of the gene that expresses telomerase. While long-term studies need to be done, it may that eating more of these foods from childhood on protects a person against cancer later in life.

19:17 Tollefsbol also presented the results of a study that showed feeding isolated human cells less sugar (caloric restriction) not only enabled the cells to live longer but also to killed precancerous cells in their midst via epigenetic mechanisms. The finding may have implications for ongoing public health and policy debates surrounding the proposed causes of the U.S. obesity epidemic and potential remedies.

1 comment:

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