July 23, 2006
Genes Show Same Aging Pattern Across Species

Humans, mice, and flies show the same patterns of changes in gene regulation with age.

STANFORD ó We can dye gray hair, lift sagging skin or boost lost hearing, but no visit to the day spa would be able to hide a newly discovered genetic marker for the toll that time takes on our cells. ďWeíve found something that is at the core of aging,Ē said Stuart Kim, PhD, professor of developmental biology and of genetics at the Stanford University School of Medicine.

In a study published in the July 21 issue of Public Library of Science-Genetics, Kim and colleagues report finding a group of genes that are consistently less active in older animals across a variety of species. The activity of these genes proved to be a consistent indicator of how far a cell had progressed toward its eventual demise.

Until now, researchers have studied genes that underlie aging in a single animal, such as flies or mice, or in different human tissues. However, a protein associated with aging in one species may not be relevant to the aging function in a different animal. This limitation had made it difficult to study the universal processes involved in aging.

Kimís work overturns a commonly held view that all animals, including humans, age like an abandoned home. Slowly but surely the windows break, the shingles fall off and floorboards rot, but thereís no master plan for the decay.

What we need to know: Which genes first start changing? Or which key regulatory switches start telling genes to start expressing differently? To put it more generally: What is the sequence of events that causes the genes to start behaving differently with age?

One possibility: The genes in the mitochondria (the sub-cellular organelles that generate energy molecules for the rest of the cell) could get mutated and damaged and then the genes in the nucleus start expressing differently due to signals coming out of the mitochondria.

Energy metablolism takes a big hit with age.

In the study, Kim and his colleagues looked at which genes were actively producing protein and at what level in flies and mice in a range of ages and in tissue taken from the muscle, brain and kidney of 81 people ranging in age from 20 to 80. The group used a microarray, which can detect the activity level of all genes in a cell or tissue. Genes that are more active are thought to be making more proteins.

One group of genes consistently made less protein as cells aged in all of the animals and tissues the group examined. These genes make up the cellular machinery called the electron transport chain, which generates energy in the cellís mitochondria.

Kim said the gene activity is a better indicator of a cellís relative maturity than a personís birthday. One 41-year-old participant had gene activity similar to that of people 10 to 20 years older; muscle tissue from the participant also appeared similar to that of older people. Likewise, the sample from a 64-year-old participant, whose muscles looked like those of a person 30 years younger, also showed gene activity patterns similar to a younger person.

Biopsies of many organs in your body might tell you which organs are going to wear out first and which need replacements. With the sort of biotechnology we'll have 10 or 20 years from now we'll be able to start growing replacements for the worn out parts. Ideally, the replacements could be grown inside your own body and then connected up with surgery.

You can read the full article online: Transcriptional Profiling of Aging in Human Muscle Reveals a Common Aging Signature

We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of six genetic pathways; four pathways increase expression with age (genes in the extracellular matrix, genes involved in cell growth, genes encoding factors involved in complement activation, and genes encoding components of the cytosolic ribosome), while two pathways decrease expression with age (genes involved in chloride transport and genes encoding subunits of the mitochondrial electron transport chain). We also compared transcriptional profiles of aging in humans to those of the mouse and fly, and found that the electron transport chain pathway decreases expression with age in all three organisms, suggesting that this may be a public marker for aging across species.

People who had worse muscle function also had gene expression patterns characteristic of more aged muscles.

The authors profiled gene expression changes in the muscles of 81 individuals with ages spanning eight decades. They found 250 genes and 3 genetic pathways that displayed altered levels of expression in the elderly. The transcriptional profile of age-regulated genes was able to discern elderly patients with severe muscle aging from those that retained high levels of muscle function; that is, the gene expression profiles reflected physiological as well as chronological age.

Another use for this information: Study people on different diets and lifestyles and see if particular diets or patterns of living cause particular organs to age more rapidly.

Some day I expect spouses to include DNA tests on body aging to argue that their spouses are aging them too rapidly.

Share |      Randall Parker, 2006 July 23 03:14 PM  Aging Genetics


Comments
Lou Pagnucco said at July 25, 2006 9:36 AM:

After perusing the paper, I have several questions.

First, can we be sure that the gene expression profiles are due to intrinsic tissue aging?
Experiments in tissue transplantation between old and young immune-compatible animals as well as parabiotic coupled animals demonstrate that some manifestations of aging are due to systemic factors. Perhaps when old muscle tissue is transplanted, some of transcription patterns are reversed.

Second, if my interpretation is correct, Kayo, et al , (http://www.pnas.org/cgi/content/abstract/98/9/5093) have shown that adult-onset caloric restriction does not reverse the aged transcriptional activity even though it reverses insulin-resistance, obesity, elevated cholesterol levels, etc., as well as extending life span. So, might a metabolic profile be a better measure of physiological age?

Third, is the level of mitochondrial respiration really a measure of physiological age?
The authors note that reduced mitochondrial function might actually be beneficial to aged animals.
If so, perhaps a lowered, but more stable, level of mitochondrial respiration is not an indicator of aging.

Randall, on the issue of whether certain diets might cause individual organs to age more rapidly, you might want to look at the possible link between soy consumption and brain aging at:
http://starbulletin.com/2000/04/03/news/story1.html
or the evidence that life style changes increase rates of dementia at:
http://jama.ama-assn.org/cgi/content/abstract/276/12/955

Randall Parker said at July 25, 2006 8:24 PM:

Lou,

Maybe a small fraction of the cells get damage in their mitochondrial DNA that cause them to generate free radicals (not my theory btw, Aubrey de Grey has argued this in the past). Then other cells could respond to the free radicals by turning down their own metabolism.

The other cells might be responding to the free radicals due to a mechanism that is there for other purposes. Or maybe it is adaptive. Hard to say.

I find it unlikely that cells would slow down their energy generation unless they had to. The costs of the slowing down are considerable.

If calorie restriction can not reverse the change in transcriptional activity then seems to me the transcriptional activity is a better measure of aging. Aubrey expects that the percent life extension from calorie restriction for humans is a lot less than for mice or rats. He thinks maybe we'll get another year or two from CR.

If an aged animal needs slower mitochondrial metabolism then that fact is a sign of aging.

The Hawaii tofu and Alzheimer's study: Yes, read about it when it came out. But why don't the Japanese have a much higher rate of Alzheimer's?

Lou Pagnucco said at July 26, 2006 9:53 AM:

Randall,

I cannot find any research on whether mitochondrial function is restored in transplanted tissue, so I am still unsure how responsible systemic factors are.

If I properly understand some of the recent findings, reducing mitochondrial respiration, especially in young organisms, extends lifespan. So, while the decline in mitochondrial energy production is definitely associated with aging, reducing it may be beneficial for animals in a lab enviroment that do not have to fend for themselves.

Regarding that Hawaii soy study - it looks like a strong statistical association was uncovered. The sample size was quite large. It may very well be that soy is an innocent bystander and is guilty only by association with some other cofactor. For example, tofu sold in Hawaii seems to be significantly higher in aluminum than Japanese tofu. That certainly doesn't prove aluminum is responsible, but shows that there are either strain or processing differences. The main point, though, is that life style differences have major effects on organ aging. Also note that west African blacks have a much lower rate of dementia than American blacks who are their descendants.

Randall Parker said at July 26, 2006 4:40 PM:

Lou,

Organ transplant between old and young highly inbred mice is such an intriguing experiement to do. Transplant an organ. Wait a month. Then analyse gene expression in the transplanted organ. Does the transplanted organ's gene expression more closely match that of the host or donor?

The experiment can be done in both directions: Transplant from young to old and old to young.

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