August 08, 2005
Gene Expression Patterns Studied In Young And Old Brains

A research team with members from UC Berkeley, the Max Planck Institute in Leipzig Germany, Harvard, and Lawrence Berkeley National Laboratory have examined gene expression patterns of different regions of young and old human and chimpanzee brains using DNA microarrays and found that the frontal cortex where most higher levels of thinking get done ages more rapidly and in ways distinct from other parts of the brain.

No matter how healthy a life one leads, no person has managed to live much longer than a century. Even though the advances of the modern age may have extended the average human life span, it is clear there are genetic limits to longevity. One prominent theory of aging lays the blame on the accumulation of damage done to DNA and proteins by “free radicals,” highly reactive molecules produced by the metabolic activity of mitochondria. This damage is expected to reduce gene expression by damaging the DNA in which genes are encoded, and so the theory predicts that the most metabolically active tissues should show the greatest age-related reduction in gene expression. In this issue, Michael Eisen and colleagues show that the human brain follows this pattern. A similar pattern—which, surprisingly, involves different genes—is found in the brain of the aging chimpanzee.

The authors compared results from three separate studies of age-related gene expression, each done on the same type of DNA microarray and each comparing brain regions in young versus old adult humans. In four different regions of the cortex (the brain region responsible for higher functions such as thinking), they found a similar pattern of age-related change, characterized by changes in expression of hundreds of genes. In contrast, expression in one non-cortical region, the cerebellum (whose principal functions include movement), was largely unchanged with age. In addition to confirming a prediction of the free-radical theory of aging (namely, that the more metabolically active cortex should have a greater reduction in gene activity), this is the first demonstration that age-related gene expression patterns can differ in different cells of a single organism.

Since the paper was published in PLoS Biology you can read the full paper online for free. One section of the paper referring to other studies on brain aging makes mention of some depressing results from another study on brain aging.

Exactly how macromolecules damaged by ROS may lead to aging has been studied in detail in recent years, and the human brain has been intensively examined in this regard because of its overall importance in human senescence. For example, up to one-third of the proteins in the brains of elderly individuals may be oxidatively damaged, and these damaged proteins have been shown to sometimes have diminished catalytic function [3,6]. One recent study of aging in the human brain demonstrated that oxidative damage to DNA can be caused by mitochondrial dysfunction, and tends to accumulate preferentially in some areas of the genome that include promoters, resulting in lower levels of transcription [7] (possibly due to loss of transcription factor or other protein binding [8–10]). In this same study, genome-wide patterns of aging-associated gene expression change in one region of the human brain cortex (the frontal pole; Figure 1) were measured using DNA microarrays, and genes that had decreased transcription with age were shown to be the ones that are most susceptible to oxidative damage [7]. Since different regions of the human brain have been shown to accumulate DNA damage at different rates [11,12], it is reasonable to suppose that these different regions may show different gene expression changes with age as a result.

Leave aside for the moment the fact that aging eventually kills us. Leave aside that we get more illnesses and disabilities as we age. The fact that our brains decline is extremely distasteful to me. Do you love the thoughts in your mind? Do you love learn and take in new experiences and see new sights and form new memories? Do you love to recall old memories or solve new puzzles? Your ability to do all those things declines with age. That such a large fraction of proteins in the brain are oxidatively damage strongly suggests that the extent of brain aging is quite far reaching. Aging is not just a process that happens to our arms and legs and skin and hair. It happens to our minds, to the very core of our identities. We learn a lot and then our brains gradually decay and even while we are alive part of us dies and the rest us our identity becomes impaired. How repugnant.

The cerebral cortex regions showed the same pattern of gene expression changes with aging while other (and notably older) regions of the brain did not show this pattern.

Strikingly, all four regions of cerebral cortex for which we had expression data (prefrontal cortex, Broca's area, primary visual cortex, and anterior cingulate cortex) showed excellent agreement with the aging pattern in frontal pole (Figure 2A; r > 0.8 and p < 0.02 for each). We note that the true similarity of aging patterns in these regions is likely to be even stronger than is indicated by the correlations because, as mentioned above, approximately 15% of our genes are expected to be false positives with no true aging-related changes. In sharp contrast to cortex, the cerebellum and caudate nucleus showed far less agreement with frontal pole (Figure 2A; |r| < 0.1 and p > 0.4 for each). These results have several implications. First, the agreement between frontal pole and four regions of cortex indicates that we were able to accurately measure the direction of gene expression changes with age for most genes, even with only three samples from each region; thus the age range, number of samples, etc., are all sufficient to reflect the pattern of gene expression changes previously reported in frontal pole [7]. Second, we can have even greater confidence in the results from frontal pole [7], because they have been independently reproduced (albeit in different brain regions). Third, and most importantly, the human brain appears to have different aging patterns in cerebellum and caudate nucleus than in cortex. The fact that our four cortex samples all show strong correlations with frontal pole is akin to having a positive control, and it allows us to interpret the lack of correlation in cerebellum and caudate nucleus as evidence suggesting a difference in aging patterns, as opposed to several more trivial explanations (e.g., too few samples).

Think about this result from an evolutionary perspective. The frontal lobe has developed most recently. Its development was a big selective advantage. One way to see this result is that our frontal lobes have been "overclocked" because making ourselves think faster allowed us to get more food, defend ourselves, and leave more progeny. I'm speculating here but perhaps our frontal lobes operate faster and wear out more quickly because there was a net selective advantage to turning up the metabolic rate of the frontal lobe because the faster thinking helped us more than the accelerated aging hurt us.

I see the brain as by far the toughest challenge for the development of rejuvenation therapies. For many parts of the body the simplest approach to rejuvenation will be parts replacement. Once tissue engineering and stem cell research advance far enough we'll be able to replace bad parts just as mechanics do with old cars. Got old failing kidneys dodgy lungs ruined by emphysema? Grow new ones. Is your liver shot? If you don't want to get a whole new liver then send in stem cells that programmed to gradually replace the existing cells with new ones. Got liver scar tissue that doesn't want to go away? Send in cells programmed to eat it up to make room for new liver cells made from stem cells. But the brain's three dimensional network of neural connections defines who you are. Put a new brain in place of your own and that body will no longer be you for most practical purposes.

To rejuvenate the brain each cell in the brain must be repaired. But the scope of such a repair job is enormous. While estimates on the number of neurons in a human brain vary the range goes from 10 billion to 100 billion or 100 billion to 200 billion with the number of neuroglial support cells ranging from 5 to 10 times the number of neurons or perhaps 50 to 100 time sthe number of neurons. So we might have a half trillion or even a trillion cells in our brains, all aging and accumulating DNA mutations, intracellular lysosomal junk, and other damage. To develop methods repair all those cells right in the brain is an enormous scientific and engineering challenge.

While stem cell therapy gets a great deal of press (and deservedly so) and while stem cell therapy does have a crucial role to play in brain rejuvenation stem cells can not do most of the brain repair job. Much of brain rejuvenation probably requires highly advanced gene therapy delivery methods and basically DNA programs to send into cells to carry out repair tasks. Future advances in nanotechnology will eventually produce nanobots that can carry out many brain repair tasks. But to repair DNA we need gene therapy to send in corrective sequences to replace mutated sequences and deleted sequences.

If you treasure your ability to think and your mental identity then support a rapid increase in the rate of development of gene therapies and other therapies aimed at brain rejuvenation.

Share |      Randall Parker, 2005 August 08 02:17 PM  Aging Studies

crush41 said at August 8, 2005 3:48 PM:

When does the effect of a deteriorating frontal lobe start to be palpable to the individual? Roughly the mid-forties, around the same time as "mid-life crises" when people turn towards more existential pursuits, when worker productivity peaks, and when recall speed starts to noticeably decrease?

Brett Bellmore said at August 8, 2005 5:17 PM:

I wonder to what extent your personality could survive the *gradual* replacement of many of your brain cells? Certainly you'd lose a lot of memories, but not as many as you would in dying. And there'd be continuity of a sort, anyway.

So far as we know, the glial cells are not so critical, they're more or less interchangable; Could they be engineered into "life support" mechanisms for the neurons?

PacRim Jim said at August 8, 2005 10:30 PM:

Your article has inspired me to...what was I thinking about?

David Govett said at August 8, 2005 10:33 PM:

The answer is obvious: Use nanobots to diagnose defects and restore functionality. You also could "scan" the 3D structure, slip in a new brain, and then restore the connections. But would it be you?

Lei said at August 8, 2005 11:26 PM:

This is so depressing. I'd hate the idea that as my frontal lobe begins to age, part of me ages and is potentially lost. It's like Thomas Hobbes said--our thoughts, ideas, and soul are merely the result of brain activity--without a functional brain, we are not only not ourselves, we're not human.

David Govett said at August 9, 2005 3:17 AM:

If you think that's depressing, how about the fact that, except for some brain cells, every cell in your body is replaced many times during your life, so you are quite literally a different person several times a year.

Lei said at August 9, 2005 6:33 AM:

David - That actually doesn't depress me so much because I'm in need of a lot of repair. I think of it as natural plastic surgery. The brain, however, is a different matter....

sr said at August 9, 2005 9:31 AM:

Or you could do something to actually help yourself. Start trying to fast every other day. Throw in a tablespoon of turmeric each day (fasting days included). That will modify your brain RIGHT NOW and delay age-related changes. Oh, wait -- it would be EASIER to WHINE about NANOTECHNOLOGY. Aubrey de Grey is a punk-a** b****.

remo williams said at August 9, 2005 9:49 PM:

Maybe instead of starving yourself 150 days a year, you could cut more fat from your diet. I also doubt we have to 'support' gene therepy research considering that the field is burgeoning right now. Bill gates is busy saving Africa, but people are investing in age reversing technologies.

PacRim Jim said at August 9, 2005 11:58 PM:

Baby boomers, give money now for such research and you might add years or even decades to your life. Send your donations (cashiers checks only) to...

Eric Pobirs said at August 10, 2005 12:13 AM:

Then there is the issue, even if you can keep the brain in perfect working order, of the brain's memory capacity. What happens when it is filled? Do we become incapable of forming new memories and learning new things? Do we start losing memories, and is there any predictability to what will be lost? Could it be done selctively to allow one's life to continue while keeping the personality intact? How independent are personality traits of the environmentally driven sort from the memories of the events that produced those traits? (I recall that Heinlein's 2000+ year old man, Woodrow Wilson Smith aka Lazurus Long, faced some of these issues.)

The first people to enjoy the availability of brain rejuvenation are going to then face a nagging anxiety as to when they discover the next boundary to peretuating a conscious mind. Ultimately, it may not be sufficient to keep the brain healthy. Transferring the consciousness to a higher capacity model will be needed. Then we get into 'Godel, Escher, Bach' territory with question of identity and all that. What a fine luxury it would be to face those issues for real.

James Bowery said at August 10, 2005 10:56 PM:

The failure to pursue rigorous consciousness research is really the failure to bridge the gap between the fantastic resources of new information technologies and the seemingly insurmountable problem of identity loss due to age-related degeneration.

There are a lot of charlatans around the field of consciousness research which is almost as much of a problem as the lack of good scientists working the problem -- but this should neither surprise nor dissuade us.

Until there is such research carried out I must reiterate the most important thing is the funding of the C-Prize.

Mthson said at August 11, 2005 12:38 AM:

If differing metabolism speeds might cause different rates of aging, should we try to minimize metabolism? Breath slower? Don't think unnecessarily? Avoid sexuality? (Am I offending people yet?)

Tdean said at August 13, 2005 4:09 PM:

Given what we know about neural networks, a set of which the brain is a member, there should be little to worry about with regard to losing memories or uncontrollably changing one's consciousness during a gradual process of neuronal repair. Memories in the brain are not stored in discreet locations but are the products of patterns of enhanced connections between billions of neurons. During a process of gradual neuronal replacement or repair, those "memory networks" would be maintained or enhanced so long as the networks were excercised or activated, perhaps by intentionally stimulating memories or knowledge. And a genetically engineered repair method focusing on enhanced or modified genetic expression would not necessarily alter neuronal connections significantly.

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