A study in rats matching the activity of 146 genes with brain aging and impaired learning and memory produces a new picture of brain aging and cognitive impairment. The research, by scientists at the University of Kentucky, uses powerful new gene microarray technology in a novel way to match gene activity with actual behavioral and cognitive performance over time, resulting in the identification of this wide range of aging- and cognition-related genes (ACRGs). Importantly, the changes in gene activity had mostly begun in the mid-life of the rats, suggesting that changes in gene activity in the brain in early adulthood might set off cellular or biological changes that could affect how the brain works later in life.
The report (embargoed for release until May 7, 2003, at 5 p.m. ET) appears in the May 2003 issue of The Journal of Neuroscience. It provides more information on genes already linked to aging, including some involved in inflammation and oxidative stress, and also describes additional areas in which gene activity might play a role in brain aging. These include declines in energy metabolism in cells and changes in the activity of neurons (nerve cells) in the brain and their ability to make new connections with each other. In addition, other areas in which genes appear to play an influential role involve increases in cellular calcium levels which could trigger cell death, cholesterol synthesis (also implicated in Alzheimer's disease in other research), iron metabolism and the breakdown of the insulating myelin sheaths that when intact facilitate efficient communication among neurons.
Note that this study does not explain why energy metabolism declines. Is the decline caused by damage to the genes that code for proteins involved in energy metabolism? Does junk accumulate in the cells and crowd out the space which would otherwise be used for energy metabolism? Does the circulatory system decline in its ability to deliver the nutrients needed to feed the machinery of energy metabolism in the mitochondria. Or it could be that the energy metabolism be getting down-regulated because there is too much oxidative stress on the aged cells for other reasons (e.g. accumulated junk in the cells could be reacting with compounds in the cell to create free radicals). There might be a regulatory mechanism in cells to down-regulate energy metabolism when there is a lot of oxidative stress so that the cell no longer has to handle the additional free radical stress caused by high levels of energy metabolism. There are a lot of other possibilities. Some of those possibilities are a lot more likely than others and there are obvious experiments that could be tried to test them.
One obvious avenue of investigation would be experiments to try to introduce replacement genes for the mitochondrial genes involved in energy metabolism. If the replacement genes helped then one explanation for declining energy production might be accumulated damage to mitochondrial DNA.
The study was conducted by a team led by Philip W. Landfield, Ph.D., and colleagues Eric M. Blalock, Kuey-Chu Chen, Keith Sharrow, Thomas C. Foster, and Nada M. Porter at the University of Kentucky, Lexington, and James P. Herman at the University of Cincinnati, Ohio. It was supported primarily by the National Institute on Aging (NIA). Additional support was provided by the National Institute of Mental Health (NIMH). Both are parts of the National Institutes of Health at the U.S. Department of Health and Human Services.
"Gene microarrays, which can measure activity of thousands of genes simultaneously, provide the most advanced genomics technology. This has allowed us to do what no other study has done before – use large numbers of microarrays to relate genes and behavior over the lifespan of the animals on a scale that can identify most of the important players," says Landfield. "The good news is that we have a new, more comprehensive model of brain aging at the genetic level; the downside is that this model shows just how very complex that process may be." "This study makes it very clear that it is not a single gene or even several genes that are responsible for brain aging. Here, we are presented a picture of age-related changes in multiple cellular pathways and systems which interact with one another to change the brain's structure and how it functions," notes Brad Wise, Ph.D., Program Director, Fundamental Neuroscience, NIA.
This fellow's phrasing is unfortunate and can leave readers with a misimpression of the meaning of these results. Just because the expression of a large number of genes changes as we age does not mean that all those genes are contributing to the process of aging. The expression of many of those genes may be changing in order to compensate for changes that aging is causing. The changing of the gene expression might simply be symptoms rather than causes of aging. This is why gene microarray studies to study changes in gene expression by themselves provide only a very incomplete picture of what causes aging.
The microarrays do not provide an indication of what is causing each gene to be turned on or off in the cells in the sample. The biggest missing element in this kind of study is a way to measure what molecules are turning each gene on and off and, in turn, what molecules are regulating those molecules. Gene arrays do not show the chains of cause-and-effect that are responsible for the levels of gene expression that they measure.
In the study, young, middle-aged, and aged rats were trained on two memory tasks, learning to navigate a water maze and remembering familiar objects in their cages. After training, the scientists examined the brain tissue of the rats, specifically the hippocampus, an area associated with memory and cognition. RNA (ribonucleic acid, which carries out the DNA's instructions for making proteins) was isolated from each rat and selectively bound to a separate chip containing over 8,700 fragments of genes to generate gene expression, or activity, profiles. One important step was further refining of the analyses to reduce false positives and false negatives while statistically assessing changes in gene activity. The researchers then homed in on genes that changed with aging and, finally, on genes involved in age-related changes in the performance of the rats on the two memory tests. Ultimately, they zeroed in on 146 ACRGs (aging- and cognition-related genes), which were then assigned to functional categories representing different cellular processes in the brain. A complete listing of the genes and what they do appears in the original journal article.
Offering one model of brain aging, the researchers suggest that loss of neuronal processes and the compromise of their insulating myelin sheaths may trigger brain inflammation, eventually leading to loss of the cells' function. The changes in gene expression for the most part were seen in mid-life, before cognition was impaired, suggesting that changes in gene activity in the brain in early adulthood might initiate cellular or biological changes that could lead to functional changes later in life.
An increase in the expression of genes that are involved in inflammation responses is characteristic of other aged cell types that have been studied with gene microarrays. I think these guys are just guessing that the inflammation might be causing the loss of myelin sheath. My guess is that the inflammation is causing a number of other problems in neurons as well.
The NIA leads the Federal effort to support and conduct basic, clinical, and social and behavioral studies on aging and on age-related memory change and dementia. It supports the Alzheimer's Disease Education and Referral (ADEAR) Center, which provides information on research on age-related memory change and Alzheimer's disease. ADEAR's website can be viewed at www.alzheimers.org. ADEAR may also be contacted at 1-800-438-4380. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information website www.nia.nih.gov.
What we need are experiments that try a variety of interventions to find ways for aged cells to be repaired. As mentioned above, genes could be introduced to try to replace mitochondrial genes that are more susceptible to damage. Also, genes that code for “xenohydrolases” could be introduced in animal models to see if clearing out the accumulated junk in neurons would allow them to function more like younger cells. A number of other approaches are possible. What we need, as Aubrey de Grey explains, is a shift toward more of an engineering mindset to develop tools and techniques that can undo the damage caused by aging (PDF file).
If you want to get up to speed on the most radical thinking on how to stop and reverse human aging then take the time to read all of Aubrey de Grey's publications on Strategies for Engineered Negligible Senescence.
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