Alterations in Cells May Cause Aging, Study Finds
The wasting that comes with age--wrinkled skin, weakened bones and nagging physical complaints--may result from genetic mistakes that begin in midlife as cells lose their ability to reproduce properly, a new study concludes.
The research, published today in Science, offers a tantalizing--and tentative--explanation for the physical ravages of time. If confirmed in subsequent studies, it would suggest a single underlying factor at work in degenerative maladies ranging from Alzheimer’s disease and arthritis to gum disease, cancer and heart ailments.
From the moment of birth, the human body is under assault by the natural chemistry of the world we inhabit, by the radiation from the sun that nurtures us, from the repetitive stress of moving muscle and bone against the force of gravity. Yet for decades, the body’s cells can shrug off ill effects and flawlessly replace themselves, until inevitably and mysteriously they begin to fail.
Seeking clues to why the human body wears out over time, researchers at the Scripps Research Institute and the Novartis Genomics Institute in La Jolla found that as the years add up, so do the genetic mutations that occur when critical cells lose their gift for making perfect copies of themselves.
By examining how thousands of genes behaved over a lifetime, the researchers discovered that a breakdown in cell machinery spurs genetic mutations, occurring at different rates in different parts of the body, which slowly add up to the complex symptoms of aging.
“While scientists have believed that aging is a disease in which cells stop dividing, this study suggests that aging really is a disease of quality control,” said lead researcher Dr. Richard Lerner, president of the institute. “Our research ties the effects of aging into a single package by identifying a common element in aging tissues throughout the body.”
Unusually sweeping in its scope, the new research is an example of the intriguing biochemical studies made possible by a new generation of DNA-coated “gene chips,” which can detect significant patterns in the chaotic chemistry of life on a scale never before possible, said USC molecular biologist Amy Lee.
Several experts on aging, while impressed with the work, tempered their enthusiasm by warning that any broad conclusions about the biochemistry of aging are premature. Too little is known about how all human genes function and interact, they said, to be certain how time affects the body’s cells.
“This is the first time we have been able to look at that many genes at once,” said Dr. Anna McCormick, chief of the genetic and cell biology branch of the National Institute on Aging. “This is beginning to give us a broad picture and beginning to identify the processes involved in aging.”
Worried that the findings could be “a bit sensationalized,” McCormick cautioned that “they have not uncovered the key to the aging process because there are many aging processes. It is probably not the same in every cell or every tissue in the body.”
USC gerontologist Caleb Finch shared McCormick’s reservations. Calling the new research “valuable,” Finch warned, “It is difficult to extrapolate from studies of dividing cells to tissues that don’t have dividing cells, like the brain.” The cells of some organs normally divide while others do not.
To study the effects of aging, the Scripps researchers compared actively dividing skin cells drawn from young people, the middle-aged and the elderly. They also compared the normal cells to those drawn from two children suffering from a rare premature-aging disorder.
Normally, the body replaces old cells by periodically dividing them in two. The new cells contain complete copies of the chromosomes from the original parent cell.
With age, however, the cells started to go awry at a stage in normal cell division when chromosomes holding the cell’s genetic construction kit are supposed to separate in matching sets, the study found. Those errors, in turn, affected how genes functioned.
The research made public today reported the resulting behavior of about 6,300 genes in cells from people ages 9 to 90. At least 61 genes went through significant changes as a result of the chronic errors that arose from duplication mistakes during the cell cycle.
In subsequent unpublished experiments, the team has examined 35,000 genes in all--about one-third of the entire human genome. Although no one knows yet what all those genes do, the researchers found the same pattern of breakdown in the cells’ quality control, Lerner said.
With time, some genes stopped working, while others showed heightened activity.
The activity of some genes dropped twelvefold by middle age, and diminished even more in extreme old age.
One-quarter of the misbehaving genes were related to the cell cycle itself. Several have been linked to breast cancer and ovarian cancer. Other abnormalities have been implicated in kidney and heart problems, gastric disorders and female infertility--all related to age.
In a sense, Lerner said, aging may be a disease like cancer.
“In cancer you make too many cells; in aging, you make imperfect cells,” Lerner said. “In both cases, you are mucking around with the cell division process.”
Their work was funded by the Skaggs Institute for Chemical Biology at Scripps. Lerner worked with Danith H. Ly and Peter G Schultz at Scripps, and David Lockhart at Novartis. Schultz and Lockhart helped pioneer the technology of gene chip arrays.
(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)
Why We Age
The wrinkles and woes of aging may be caused by a breakdown in quality control as cells duplicate their genetic material, a new study by the Scripps Research Institute says.
Researched by ROBERT LEE HOTZ / Los Angeles Times
Source: Scripps Research Institute
