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paleoanthropology, genetics and evolution

aging

  • Gene expression in aging humans and chimpanzee brains

    Wed, 2005-08-03 14:56 -- John Hawks

    A paper by Hunter Fraser and colleagues (2005) in PLoS Biology describes a survey of gene expression in the cortex of humans and chimpanzees and the cerebellum of humans. The study investigates the relationship of gene expression with age in a series of human individuals of different ages and chimpanzees of different ages (via Gene Expression.

    The paper briefly discusses the theories describing the evolution of aging, but they have little relevance to the procedures or results. It's not clear to what extent the setup of the paper was influenced by the ultimate results, as indicated by the following:

    One promising approach to answering this question of evolutionary conservation lies at the level of gene expression: Do orthologous genes tend to undergo the same patterns of expression changes with age in diverse species, or can a common factor such as ROS lead to different gene expression patterns in different organisms? Using DNA microarrays, this question can now be addressed in a systematic, genome-wide manner. One such study found that a small but significant portion of aging-related gene expression changes are shared by the very distantly related nematode and fruit fly [14]; another study comparing aging patterns in muscle cells of two more closely related species, mouse and human, also found a great deal of divergence in aging patterns [15]. Although both of these studies are informative, neither addresses the questions of how quickly age-related gene expression patterns can evolve over short periods of time, and if humans in particular show unique patterns of aging not shared by closely related primates.

    I'm not sure that "evolutionary conservation" would be a relevant prediction of either antagonistic pleiotropy or power of selection hypotheses for aging, since there is no reason to think that the same alleles that are adaptive in one species are necessarily adaptive in its relatives. In any event, the place to look for evolutionary conservativism is not between human and chimpanzee brains! Look among macaque species if you must. There is much more interesting stuff to consider in the evolution of humans.

    That's why I say this may have followed the results rather than framed the research. Because the results show what one might expect: human and chimpanzee brains differ in their patterns of gene expression change with age.

    That's a long phrase to gulp down. The study looked at 841 genes that show changes in expression with age in the frontal pole of the brain. They found that these genes tend to change in the same way in other parts of the cortex.

    In contrast, they find that relatively fewer genes change expression with age in the cerebellum. Their results give good reasons to think that the cerebellum actually exhibits less aging-related change than the cerebral cortex. This is very interesting, especially if the majority of recent evolutionary changes have affected the cortex and not the cerebellum. If so, then we might expect many new advantageous mutations to have had suboptimal pleiotropic effects late in life. The development of a larger brain might well have led to one in which age-related changes were more detrimental. Or, conversely, the evolution of greater longevity in humans may have led to strong selection on regulator genes that had widespread effects on many cortical genes, but few effects on cerebellar genes.

    The other major result is that genes in the chimpanzee cortex do not show the same pattern of change with age as the same genes in the human cortex. The chimpanzee cortex instead has its own, different pattern of age related changes in gene expression.

    How does this difference arise?

    Given this difference in aging patterns between humans and chimpanzees, we examined the expression levels of the chimpanzee orthologs of the 841 human genes that change expression with age in frontal pole in order to see if the expression levels of the chimpanzee orthologs of these genes resemble young humans, old humans, or neither. To test this, we first reanalyzed the expression data by masking all microarray probes with sequence differences between humans and chimpanzees [19]. We then calculated, for both human and chimpanzee prefrontal cortex, the average expression level for the set of genes that increase expression with age in frontal pole, as well as the average for the genes that decrease expression with age. The result is that in chimpanzee cortex, the orthologs of both sets of human genes (up-regulated and down-regulated) are expressed at the levels of their young human counterparts (Figure 5). In other words, chimpanzee cortex expression levels strongly resemble expression levels in young but not old humans, at least among the set of genes tested here. Humans then diverge from these average expression levels as they age, whereas chimpanzee gene expression levels change in an almost entirely different set of genes.

    In their discussion, Fraser et al. focus on the possibility that radical oxygen species (ROS) related damage may differ between humans and chimpanzees. Perhaps so, but it may be pointless to look for a functional explanation for the difference. A non-functional explanation is that human genes active in the brain have undergone many rounds of natural selection, each leaving the possibility of slightly deleterious or neutral age-related effects. Added up over six million years, that leaves a lot of age-related changes in expression that just haven't been selected out. A few may be important causes of neurodegenerative disease, others may be barely noticeable.

    It's a wide-open frontier for evolutionary explanation.

    References:

    Fraser HB, Khaitovich P, Plotkin JB, Paabo S, Eisen MB. 2005. Aging and gene expression in the primate brain. PLoS Biol 3:e374. Full text online

    Tags: 
    brain
    aging

  • Prove Aubrey de Grey is a nut, win $20,000

    Mon, 2005-08-01 00:42 -- John Hawks

    MIT Technology Review is offering a prize to any researcher in biogerontology who can write an essay demonstrating why Aubrey de Grey's SENS project is unworthy of serious scientific consideration.

    Aubrey de Grey is a well-known futurist, with a twist. A few months ago, Technology Review had a profile of de Grey, that starts like this:

    Aubrey David Nicholas Jasper de Grey is convinced that he has formulated the theoretical means by which human beings might live thousands of years -- indefinitely, in fact.

    Perhaps theoretical is too small a word. De Grey has mapped out his proposed course in such detail that he believes it may be possible for his objective to be achieved within as short a period as 25 years, in time for many readers of Technology Review to avail themselves of its formulations -- and, not incidentally, in time for his 41-year-old self as well. Like Bacon, de Grey has never stationed himself at a laboratory bench to attempt a single hands-on experiment, at least not in human biology. He is without qualifications for that, and makes no pretensions to being anything other than what he is, a computer scientist who has taught himself natural science. Aubrey de Grey is a man of ideas, and he has set himself toward the goal of transforming the basis of what it means to be human.

    De Grey has set himself up as just the gadfly to prod biologists to make it happen. Consider this essay, where he describes researchers on aging as "catatonic" for standing mute before his agenda.

    And an agenda is what SENS is. The central idea is that the causes of aging are finite. De Grey lists seven basic causes, and argues that there likely aren't any more to be found, since no new ones have emerged in over twenty years. The seven range from an accumulation of mitochondrial mutations to programmed cell death and the breakdown of extracellular support structures. SENS seeks to find ways to nullify these seven causes of aging.

    Not bad for a start. De Grey and others have identified in principle some ways that each of the seven causes could be stopped. It's when you read into these details that you begin to comprehend the breathtaking ambition behind the agenda. How to solve the problem of mtDNA mutations? No problem --- just replace the body's stem cells with others that have the 13 mtDNA genes present in the nucleus. And find ways to make them active in the right amounts. And work out a way to get them across the mitochondrial membrane. The thing is, they have ideas about how all these things might be done. The only barrier is, of course, is finding out whether all these steps will work.

    The main focus is cellular aging, but to the extent that stem cells might be able to replace tissues with younger, more functional versions, the focus is probably what is needed. But there are plenty of stumbling blocks. Cells are Rube Goldberg devices, with complex sequences of protein interactions necessary to make them work. Aging happens because these sequences have only been tuned by evolution over a short lifespan. It just doesn't matter that much to most organisms' reproduction if their cells break down and stop working after a certain period of time. It can even be a good thing to have them die on purpose -- when cells just refuse to follow their molecular controls, we call it cancer.

    Many of de Grey's proposed solutions would have us sweep aside these complex mechanisms, starting from scratch with new genetically customized replacement stem cells. That idea would limit to some extent what you would need to know about gene interactions -- it's like those custom kits that let you make a Ford Pinto look like a '26 Packard.

    Perhaps the way to go, but is there some critical flaw? There are lots of interesting evolutionary reasons why aging should be an intractable problem, but it looks to me like many problems are swept away by the assumption that stem cells can be engineered to possess or lack any feature de Grey would require. The challenge may flush out somebody with a better idea of why it wouldn't work.

    It will be interesting to see if anyone takes up the challenge. Personally, I wish somebody would offer a prize to show some anthropological research project is not worth serious consideration. Of course, with my luck it would be one of mine....

    Tags: 
    aging

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