Nov. 11, 2011 UCLA life scientists have identified a gene that slows the aging process. The biologists, working with fruit flies, activated a gene called PGC-1, which increases the activity of mitochondria, the tiny power generators in cells that control cell growth and tell cells when to live and die.
"We took this gene and boosted its activity in different cells and tissues of the fly and asked whether this impacts the aging process," said David Walker, an assistant professor of integrative biology and physiology at UCLA and a senior author of the study. "We discovered that when we boost PGC-1 within the fly's digestive tract, the fly lives significantly longer. We also studied neurons, muscle and other tissue types and did not find life extension; this is telling us there is something important about the digestive tract."
The research appears in the current online edition of Cell Metabolism, the leading journal in its field, and will be published in an upcoming print edition. Co-authors are from Walker's laboratory, the Salk Institute for Biological Studies in La Jolla, Calif., and the department of biology at UC San Diego.
"By activating this one gene in this one tissue -- the intestine -- the fly lives longer; we slow aging of the intestine, and that has a positive effect on the whole animal," said Walker, a member of UCLA's Molecular Biology Institute. "Our study shows that increasing PGC-1 gene activity in the intestine can slow aging, both at the cellular level and at the level of the whole animal."
The biologists delayed the aging of the flies' intestines and extended their lives by as much as 50 percent.
Fruit flies, or Drosophila melanogaster, have a life span of about two months. They start showing signs of aging after about one month, and they slow down, become less active and die, Walker said. They are a great model for studying aging, he said, because scientists know every one of their genes and can switch individual genes on and off.
What are the study's implications for human aging?
"We all think about protecting the brain and the heart, but the intestine is a vital tissue type for healthy aging," Walker said. "If anything goes wrong with the mitochondria in cells, the consequences could be devastating, and if anything goes wrong with our intestines, that may have devastating consequences for other tissue types and organs. Not only is the intestine essential for the uptake of nutrients that are a vital source of energy, but it is also an important barrier that protects us from toxins and pathogens in the environment. The intestine has to be well-maintained.
"No one yet knows what causes aging at the cellular or tissue level," Walker said. "As we age, our mitochondria become less efficient and less active. That has far-reaching consequences, because if the mitochondria decline, then all of our cellular functions may be compromised. However, it's a dangerous road to travel to say, 'This is the cause of aging.'"
The PGC-1 gene activates the cells' mitochondria and regulates mitochondrial activity in mammals and flies. The gene is a potential target for pharmaceuticals to combat age-related diseases, Walker said.
The study raises the question of whether increasing mitochondrial activity is an effective strategy to delay aging. If so, increasing the PGC-1 gene may prove key, Walker said.
The first question Walker and his colleagues asked was whether the fruit fly version of PGC-1 has the same function as the mammalian version. They found it does.
The biologist increased levels of expression of the fly version of the PGC-1 gene and found that this made mitochondria more active. They then tested whether boosting PGC-1 activity would slow aging and, again, they found that it did, when they focused on the fly's digestive tract.
The fly's intestine is maintained by adult stem cells, previous research has shown. The biologists also asked what would happen if they used genetic and molecular tools to boost PGC-1 gene expression within only the stem cells and their immediate "daughter" cells.
"Collaborating with a stem cell group at the Salk Institute for Biological Studies, we boosted the gene expression within just the stem- and the immediate daughter-cell types and found that was sufficient to extend the life span of the flies," said Walker, who studies the basic underlying mechanisms of the aging process.
In addition, increasing the fruit fly's version of PGC-1 delays the onset of cellular changes within the intestine, thereby establishing a link between mitochondria, tissue stem cells and aging, the new study shows.
"Many scientists study the diseases of aging, and they tend to do so individually," Walker said. "One group will study Alzheimer's disease, another group will study cardiovascular disease, another will study cancer. We take a different approach. We don't single out any of these specific diseases of old age. We study the aging process itself. Aging is the No. 1 risk factor for most cancers, heart disease, Alzheimer's disease, Parkinson's disease and many others."
Co-authors on the study included Michael Rera, a UCLA postdoctoral scholar in Walker's laboratory; Sepehr Bahadorani, a former postdoctoral scholar in Walker's laboratory; and Jaehyoung Cho, a former postdoctoral scholar in Walker's laboratory.
Walker's research was funded by the National Institutes of Health and the Ellison Medical Foundation. Walker is an Ellison Medical Foundation New Scholar in Aging.
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- Michael Rera, Sepehr Bahadorani, Jaehyoung Cho, Christopher L. Koehler, Matthew Ulgherait, Jae H. Hur, William S. Ansari, Thomas Lo, D. Leanne Jones, David W. Walker. Modulation of Longevity and Tissue Homeostasis by the Drosophila PGC-1 Homolog. Cell Metabolism, 2011; 14 (5): 623 DOI: 10.1016/j.cmet.2011.09.013
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