To their surprise, the scientists at The Jackson Laboratory in Bar Harbor, Maine, a nonprofit mammalian genetics research facility, found a gene known to incite death among cells also can prevent their demise. Studies of specially engineered mice suggest the gene, called apoptosis inducing factor or AIF, protects certain nerve cells in the brain and eye.
The AIF gene can keep a damaging biochemical process called oxidative stress at bay and avert cellular deterioration. Oxidative stress, resulting from an unchecked proliferation of erratic molecules called free radicals, has been implicated in a lengthening list of human ailments. Its effects include both the superficial and deadly -- from wrinkled skin to cancer, heart disease, stroke and a host of chronic progressive or degenerative disorders, including Lou Gehrig's disease, also known as amyotrophic lateral sclerosis or ALS.
"The authors describe a study in which (AIF) ... staves off cell death in neurons of the retina and certain regions of the brain (cerebellum) when these cells are exposed to conditions of oxidative stress," Ed Levine, assistant professor of ophthalmology and visual sciences at the Eccles Institute of Human Genetics at the University of Utah in Salt Lake City, told United Press International.
"This is somewhat surprising since AIF has previously been shown to be involved with promoting cell death," Levine said. "(The study's) connection to oxidative stress is interesting because oxidative stress is a common cause of cellular damage and death that is associated with aging. Thus, targeting treatments to promote AIF activity in specific neurodegenerations may have promise."
The work establishes the first such link to free radicals. They are wildly unstable molecules with a missing or impaired electron -- a negatively charged particle that bonds atoms together -- which they seek to replace at all cost.
Generally, an unbalanced radical plunders the nearest stable molecule, leaving it, in turn, one electron short, and ready to avenge the theft. This domino-like chain reaction -- rampaging radicals grabbing electrons from their neighbors that then themselves turn radical -- can cascade until the entire cell is disrupted or destroyed, setting the stage for disease.
Radicals arise as oxygen reacts with other molecules in biochemical process that normally are life-sustaining. Some also spawn from environmental factors, such as pollution, radiation, cigarette smoke and herbicides. These biochemical "bad boys" can play the good guy role equally well, however. They can serve the body's disease-fighting immune system by neutralizing viruses and bacteria.
The body tries to keep the damaging effects of free radicals in check with protective mechanisms called antioxidants. Antioxidants contribute one of their own electrons to stabilize the radicals, bringing the "stealing" game to a halt.
These beneficial scavengers -- which help prevent cell and tissue injury that could lead to chronic disease -- remain stable with or without a full set of electrons and so do not turn into radicals upon making their donation.
If antioxidants are not available or if the free-radical production becomes excessive, oxidative stress occurs, leading to cell damage, which accumulates with age.
Radicals may have a hand in cognitive degeneration, the study suggests, implying that one might forestall the onset of dementia by eating the right foods rich in antioxidants -- such as strawberries, blueberries and broccoli -- taking supplements of vitamins C and E and beta carotene and exercising regularly. Research has indicated such antioxidant-employing measures might prevent cell damage, potentially slowing the aging process and protecting against disease.
"The study ... provides additional evidence suggesting that better control of oxidative damage may be effective in preventing or treating (neurodegenerative) disease," Greg Cole, associate professor of medicine and neurology at the University of California, Los Angeles, told UPI.
"Many people are already interested in preventing age-related oxidative damage using antioxidant supplements like vitamins E and C. An ongoing clinical trial with a vitamin E supplement should soon help answer questions about vitamin E supplements," said Cole, who is also associate director of the UCLA Alzheimer's Disease Research Center.
"However, two recent ... papers suggest that for Alzheimer's prevention, it may be more important to consume more natural antioxidants in the diet.
Alternatively, researchers need to identify an optimum supplement."
The new research shows the Aif gene provides an antioxidant defense against free radicals, protecting certain types of aging nerve cells or neurons, he added.
The study with specially formulated, "harlequin" mice -- so called for their patchy hair pattern and clownish or harlequin appearance -- carries major implications for research into age-related dulling of mental acuity, said Susan Ackerman, staff scientist at Jackson and lead author of the paper, which will be published in the Sept. 26 issue of the British journal Nature.
"While there are many types of mutant mice with nervous system defects, only a few show major age-dependent neuron loss, a phenomenon found in human diseases including Alzheimer's, Parkinson's, Huntington's, ALS and types of retinal degeneration," Cole told UPI.
Ackerman and her team pinpointed the molecular basis for why the much-analyzed harlequin rodents serve as a useful model for late-onset neurodegenerative disease. The ailment is characterized by progressive degeneration of neurons in the cerebellum, a large brain region that coordinates voluntary movements, posture and balance. Additional damage appears in the retina, a light-sensitive component of the eyeball that receives the image produced by the lens.
"We have focused on identifying mouse strains that have genetic defects that lead to degeneration of neurons in the aging brain, and by studying these mice we can go on to identify the gene that is disrupted. This allows us to identify molecules that are necessary for neuron survival (in the adult brain)," Ackerman told UPI. "Degenerative disorders of neurons in the brain and of the retina of the eye affect many people, particularly those in the aging population."
It turns out the mice have a mutation in their AIF gene. The mutation severely curtails production of the corresponding AIF protein, a scavenger of free radicals in the brain and retinal neurons, the investigators discovered. With the protein numbers diminished, the radicals remain free to roam, leading to oxidative stress and, eventually, nerve cell death. This is a scenario increasingly painted for the development of Alzheimer's disease, said Dr. Gary Small, Parlow-Solomon Professor on Aging and professor of psychiatry and biobehavioral sciences at UCLA.
"What's interesting in this study is that it touches on free radicals and oxidative stress and damage and antioxidation as a mechanism of prevention," Small, who is also director of the UCLA Center on Aging, told UPI.
"You have antioxidants in foods like broccoli, strawberries and blueberries or in supplements of vitamins E and C," Small explained. "Some studies show if you take these, your risk of Alzheimer's is reduced. This study goes along with these theories and gives us hope that some of these antioxidant strategies can maximize brain health and decelerate future brain aging."
Copyright © 2002 LexisNexis, a division of Reed Elsevier Inc. All rights reserved.