Hunting for clues to healthy aging, from the lab to the sea floor

Researchers are "making an incredible amount of progress" in the search for molecular mechanisms underlying successful aging, says Steven Austad. His own studies are uncovering the secrets of long-lived animals, and investigating the anti-aging effects of the immunosuppressive drug rapamycin.

The longest-lived human on record didn’t make it much past 120 years. That’s nothing compared to the ocean quahog, a fist-sized clam found off the coast of Maine. “They can live 500 years or longer,” said Steven Austad, Ph.D., chair of UAB’s Department of Biology and associate director of the UAB Comprehensive Center for Healthy Aging. “They’ve been sitting out there on the sea floor since before Shakespeare was born.”

Austad’s research focuses on understanding the underlying causes of aging at the molecular level. Although his studies take him in many fascinating directions, it’s the ancient clams that everyone remembers. “I’m known in the field as the guy who works with weird animals,” Austad said.

So what do animals like the quahog know about healthy aging that we don’t? That question drives Austad’s studies in comparative gerontology, which look to long-lived animals to identify new molecular targets to help humans.

Protein Power

Clams — technically, bivalve mollusks — live longer than any other animal group; more than a dozen species have lifespans of a century or more. But they are not all masters of aging. Austad’s lab is studying mitochondrial function, protein stability and stress resistance across seven species of clams, with lifespans ranging from one year to the ocean quahog’s 500-plus years.

Studying long-lived animals is “a way to quickly identify new genes that might be targets for new drugs to keep people healthy longer.”

Austad’s research has convinced him that one key to slowing aging is to protect the proteins inside our cells. “Proteins make everything work in the cell, and to do that, they have to be folded precisely like origami,” Austad said. “But as we get older they get battered about, and ultimately lose that precise shape.”

That’s why Austad is so excited by what he’s found in ocean quahogs. “They keep their proteins in shape century after century,” he said. When Austad takes human proteins and adds them to a mix of tissues from the clams, “they become more stable, less likely to unfold.” His lab is now working to identify exactly what is protecting the clams’ proteins. That mechanism could point to a potential treatment for aging, along with new therapies for Alzheimer’s disease and other conditions caused by protein misfolding, Austad notes.

Enter the Hydra

In addition to clams, Austad studies a tiny freshwater creature called a hydra, which is basically immortal. Or so scientists once thought, until they found one particular species of hydra that begins to age rapidly under the right combination of environmental conditions.

“Under certain conditions, this hydra turns on a symphony of genes that prevent aging; under others, it does not,” Austad said. His lab is working to discover the molecular mechanisms that get switched on, or off, as the hydra’s environment changes. “These kinds of studies are a way to quickly identify new genes that might be targets for new drugs to keep people healthy longer,” Austad said.

He adds that the opportunities for collaborative, translational work in the Comprehensive Center for Healthy Aging, which brings together a wide range of basic and applied scientists from schools across campus, helped draw him to UAB.

Living Longer — and Better

This is a very exciting time to study aging, says Austad, who is in a position to survey the field as the scientific director for the American Federation for Aging Research. “We’re making an incredible amount of progress,” he said. “We know a lot of things from animal work that will slow aging by 20 percent, and that’s the difference between being healthy for 60 years and being healthy for over 70 years.”

Old Friends Austad’s book “Why We Age,” published in 1997 and since translated into eight languages, explained the latest aging research in layman’s terms. Ever since, “publishers have been after me to do an updated version,” he said. “But there are lots of books out there now on that topic.” Instead, he’s working on a book called “Methuselah’s Zoo,” which he described as “a natural history of successful aging.” It will include profiles of his favorite 500-year-old clams, but also 200-year-old whales and 40-year-old bats.

Living longer wouldn’t be much fun if you got progressively sicker, but “what we’re finding is that, if you treat the underlying causes of aging, you can push back cancer, heart disease, blindness, hearing loss — all of these diseases associated with aging,” said Austad.

One particularly intriguing lead, being followed by Austad and other researchers worldwide, is the drug rapamycin, which is FDA-approved to prevent rejection after organ transplants. A series of studies, from yeast, worms and mice, have shown that rapamycin can extend lifespan as well.

Rapamycin has “almost miraculous” effects against aging in mice, Austad says. “It prevents cancer, heart disease, Alzheimer’s — a whole host of things.” His lab is now working to understand how administering rapamycin at different points in an animal’s life affects the aging process.

Curb Your Enthusiasm?

Despite these exciting findings, caution is required, Austad notes. “Nothing I have learned so far has changed my behavior,” he said. “I don’t take a bunch of pills; I’m not even tempted to take rapamycin at this point.” For one reason, rapamycin has several side effects in mouse studies, including an elevated incidence of cataracts, loss of glucose sensitivity and testicular atrophy. Austad believes that the right dosing and formulation could overcome these issues in humans, but “we still don’t know what the best dose is,” he said.

At the moment, the best advice about healthy aging “is still the boring stuff your mother already told you,” Austad said. “‘Eat the right foods; don’t eat too much; exercise.’ But come back in 10 years and it will be a different answer.”

Biology’s Moment The development of ever-better tools for investigating genes has brought about a revolution in biology, Austad says. He believes biology is set to dominate the 21st century the way that engineering and physics shaped the 20th — making vital contributions to everything from personalized medicine to climate change. And UAB’s Department of Biology will take a leading role in training, research and discovery in these areas, he adds. “The human world 50 years from now will be unrecognizable,” Austad said. “People never realized that they could go faster than a horse and suddenly they had airplanes. We haven’t had this fancy DNA technology for more than a decade and a half, and we’ve already come so far.” Learn more at www.uab.edu/cas/biology.

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.