To Breathe,
Perchance to Die

In August 1999, I pulled out a several-months-old news story. Scientists had found that proteins which cap the ends of a cell's chromosomes may play a role in cancer.

The caps, called telomeres, "keep a cell's genetic material from unraveling, just as an elastic band keeps braided hair in place," the story said. "When the telomeres become too short, the aging cell stops dividing and begins to die."

Intrigued, I sent an e-mail to a number of University of Kansas researchers. I wrote, "Besides shortened telomeres, why else do we die? At the cellular and molecular levels, what does us in?"

Here's a distillation of the several answers professors sent.

• Small engines in our cells called mitochondria stop manufacturing energy for the cells' use. Our cells run out of gas.
  
  
• As oxygen is broken down in our cells, the breakdown products, called free radicals, cause mischief. That is, breathing kills us.
  
  
• Cell boundaries weaken. Cells lose their ability to regulate the coming and going of calcium and potassium. They can't keep water out, either, and the water dilutes cell constituents. In effect, says Fred Samson, professor emeritus of molecular and integrative physiology, cells drown.

Diana Bigelow, a professor of biochemistry, wrote about these problems in the context of heart and blood-vessel disease, whose incidence increases with aging:

"Some of these diseases are due to narrowing of the arteries and the consequent blockage of blood flow. The molecular basis for both arterial narrowing and the heart damage done by blockage of blood flow involves effects from free radicals. (Heart cells, by the way, like nerve cells, are NOT dividing, and, therefore, telomere shortening is probably of little relevance.)"

One puzzle is that though free radicals are manufactured all our lives, their damage is most strongly manifest in old age: "Free radicals are produced normally by our cells during metabolism," Bigelow writes. "Why their reaction with proteins is greater in the elderly is a focus of much current research. It's possible that the reaction is the same but that the normal repair and recycling of damaged proteins becomes defective, so that more and more damaged proteins accumulate."

Erik Floor, associate professor of molecular biosciences, provided a poetic summary:

"Here's what I'd say if I tried to explain my work to an ordinary person without all the jargon and sophisticated scientific framework.

"We are material beings (dust to dust and ashes to ashes). Our life depends on the most complex collection of molecules and cells in the (known) universe. The body is a self-repairing machine that usually functions very well, thank you, for the better part of a century. But when a component breaks down and cannot be repaired by our body's own resources or cured by modern medicine, we die.

Because I could not stop for death-
He kindly stopped for me-
The Carriage held but just Ourselves-
And Immortality.

-Emily Dickinson

"Early life tamed the energy of fire 2.5 billion years ago, give or take half a billion. At that time cells on an airless Earth first produced oxygen through photosynthesis. Oxygen is able to react with the molecules of life. Leaves burn. So does hair. Cells learned to trap the heat and energy released when molecules react with oxygen. But controlling combustion is not so easy to do.

"For cells, the problem is that some combustion products escape, like sparks from a fire, to the detriment of the cell itself. One of the foremost theories of aging is that this oxidative damage accumulates and somehow, gradually, wears down the self-repairing machine. Even if nothing catastrophic breaks, the body eventually becomes too weak to keep going. This oxidative stress theory of aging is supported by a great deal of evidence.

"Some kinds of cellular damage have been identified, but others remain obscure.

"My research focuses on oxidative damage to cell proteins with the aim of using this as a Rosetta stone to decipher oxidative events that happen inside cells. By finding out what kind of sparks are flying around inside cells and how they attack proteins, we will be in a position to make a flame retardant to protect the fabric of life.

"Antioxidants like vitamins C and E seem to work in this way. But there are probably much better antioxidants that target precisely the types of damage that harm cells most. Discovering these 'super' antioxidants is one of the goals of research in this field."

Other ideas about the cellular basis of our mortality are knocking around out there. No matter what we do to slow the processes of aging, though, I think the point of the exercise called life will remain quality, not quantity. With that in mind, I recommend you read "Seven Lessons from a Dying Man" in the "Excerptional" department of this issue of Explore:.

The late William Bartholome, an ethicist and professor of pediatrics at the KU Medical Center, had a long time to study the approach of his own death -- a cancer killed him in 1999 -- and he made generous use of that time by sharing what he learned, as you'll discover in reading his ruminations.

Roger Martin
Editor
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