Slowing down old age

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McGill Reporter
March 6, 2003 - Volume 35 Number 11
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Slowing down old age

Biologist Siegfried Hekimi shot into the public eye a few years ago with his amazingly long-lived worms. These nematodes, small enough to wriggle on the head of a pin, lived up to five times longer than their normal lifespan thanks to a bit of genetic tinkering.

Now Hekimi has shown that aging -- across species -- can be more controlled than previously imagined. He's the primary author of a research review for Science, written with MIT biologist Leonard Guarente (whose genetic experiments made yeast reproduce many more times than expected). Dozens upon dozens of studies indicate that genes hold the key to slowing the progress of aging, and by extension, the progress of all age-dependant diseases. It starts with the stuff of life: oxygen.

Tissues need oxygen to produce energy, Hekimi explained, and in this production process, oxygen can be chemically modified to become a Reactive Oxygen Species (ROS). These toxic compounds attack the various parts of the cell -- lipids, proteins, DNA —and impair the cell's function. It's one of life's ironies that although oxygen is crucial to mitochondria's functioning, it inevitably creates ROS, which weakens it.

Antioxidants are the molecular compounds that scavenge ROS and detoxify them. This is why there is such a hoopla about the antioxidant properties of vitamins, leafy green veggies, and those expensive facial creams.

What is so exciting about Hekimi and Guarente's literature review is that the mass of studies they refer to definitively show a connection between ROS and aging in animals. By working genetically to minimize ROS and lower oxidative stress, scientists can lengthen lifespan in one fell swoop.

"ROS are also intracellular messengers," Hekimi says. "They are not just toxic molecules, but are normal molecules that contribute to the physiological regulation of bodies and cells. When you start playing around with them, you change a lot more things than just decreasing toxic attack."

Both Hekimi and Guarente found the genes that affect the level of ROS by focusing on longevity rather than disease. If a mutant without a certain gene lives longer, it means the presence of the gene in the non-mutant animal actually limits lifespan, Hekimi says.

Thanks to a genetically prompted reduction in oxidative stress, Hekimi's worm mutants lived five times longer than normal. "That you can make any organism live five times longer would have been impossible to predict. It means that all the things you imagine might contribute in killing you, all can function five times longer."

"Lifespan, in people, manifests itself by a collection of diseases," Hekimi says. "Age increases the probability of development of disease. So if you cure people of atherosclerosis, you may increase the average lifespan by 10 years. If you cure them of cancer, you may increase the lifespan by five years, and you will have to cure them of one disease after another to have a serious effect."

Hekimi expects the insight from the study to help find new ways to cure specific diseases.

"By finding new genes in worms we find novel ways to manipulate the level of ROS. Suddenly the model system becomes a way to find a new target for possible therapeutic approaches to lower oxygen stress. It's a way to find new ways to intervene with disease." Age-related diseases such as Parkinson's, cancer, Alzheimer's, diabetes are partly due to damage produced by ROS.

"If there's one observation about centenarians that holds true, it's that they did not have all the major diseases. Nobody who had atherosclerosis, cancer or diabetes -- any of the major killers —lives to 120." People that old die from diseases relating to the slow degradation of organs, like renal failure, or their skin loses its protective barrier and simple wounds don't heal properly.

Before we get all excited about living long enough to dance at our great-grandkid's wedding, Hekimi reminds us that "the way to increase lifespan on the planet is to feed everybody properly. When you look at lifespan in European countries over the last 300 years, there's a one-to-one relationship, a straight line, between the amount of calories per person and lifespan."

To live longer, Hekimi adds, "You just do better or more of the things we already know to do. Many of these things our grandmothers knew: Don't smoke. Don't work too hard. Don't eat too much. And the newest thing to add is don't sunbathe."

Does Hekimi work too hard? Pretty hard, he admits, but nothing compared to the physically demanding work of a miner, he says. He anticipates a long-enough life, despite having got too much sun as a youngster.

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