Wednesday, October 18, 2006

Mitochondria and Aging

So, why are mirochondria interesting from an aging point of view? They are the site of the tricarboxylic acid cycle (TCA cycle, or Krebbs cycle, as it was known when I was an undergrad, lo these many years ago). The TCA cycle is the heart of energy generation in the cell; it produces a molecule called adenosine triphosphate (ATP) which is the energy currency of the cell. Converting ATP to ADP (adenosine diphosphate - one phosphate less!) releases energy, and lots of reactions within the cell use this fact to acquire the energy they need. So mitochondria are absolutely essential to the cell.

But there's no such thing as a free lunch. The process of generating energy also generates lots of other things, including the ominously named Reactive Oxygen Species (ROS), more widely known as free radicals. These molecules are, not surprisingly, highly reactive, and interact with lots of other molecules in the cell, causing untold havoc, some of which is believed to contribute to the aging process. So mitochondria are the embodiment of the oldest joke in the world, which is usually applied to women: can't live with them, can't live without them.

Mitochondria are essential (and really, really cool). And even apart from their role in aging, there are lots of other reasons we should be interested in them. I'll post some of them tomorrow.

Friday, October 13, 2006


Even in a multicellular organism, individual cells display a surprising amount of, well, individuality. Every cell has a distinct identity, and the majority are able to perform most, if not all, of the functions of free-living unicellular organisms . So distinct are cells that the cell doctrine of biology—the concept that all organisms are made up of cells—has been described as the fundamental paradigm of modern biology and medicine. The focus of biologists upon cell biology (there is a whole subfield of biology which goes by this name, and is perceived by its proponents as absolutely crucial to an understanding of life) has led to major breakthroughs in biology, but as we have seen, cell architecture is only fundamental to life at one particular scale . Vital interactions take place at subcellular levels, while multicellular organisms are very much more than the sum of their cells.

It is generally accepted that the cells of multicellular organisms evolved from independent single celled bacteria. Further, most biologists now believe that eukaryotic cells arose from the fusion of several different types of single celled organisms. This theory, known as endosymbiosis, was originally proposed in the nineteenth century, after the development of microscope allowed biologists to observe that cellular organelles bear a remarkable resemblance to free-living bacteria. The theory was not widely accepted amongst biologists until after it was espoused and publicized by the biologist Lynn Margulis in the 1960s. Since then, genetic analysis has confirmed that the DNA of organelles is in many ways more similar to that of bacteria than to that of the nucleus of the cell in which the organelle resides.

Basically, the theory suggests that eukaryotic cells evolved as a result of “lunch gone wrong” about 1.4 billion years ago. Bacteria prey upon smaller bacteria by engulfing them in an invagination of the cell membrane, which eventually pinches off to form a sac, or vacuole, inside the cell. Digestive enzymes then break down the contents of the vacuole and the hapless prey is consumed. It appears, however, that this process is not always foolproof. Some small bacteria, originally destined to be lunch, seem to have sidestepped the digestion process and taken up residence in the cytoplasm of the would-be diner. Whether they were originally harmful to their unwitting host is unknown; most probably the vast majority were. However, some tenants possessed abilities which were usefully complementary to those of the host—the ability to convert sunlight into useable energy via photosynthesis, for example, or to carry out other chemical reactions which were not in the host’s repertoire. The engulfed bacteria also benefited from the relationship, gaining advantages such as being part of a larger organism and therefore safer from predation, and having access to a steady supply of food. A partnership was established, and over time became not just beneficial but mutually necessary to the participants. From an uneasy admixture of predator and prey, the eukaryotic cell was born.

The specific sequence of steps that Margulis proposes to have occurred during evolution are as follows:

1. A sulfur and heat-loving archaebacterium merged with a swimming bacterium to form the first nucleated single celled organism (protist). This swimming protist eventually evolved mitosis, the process of cell division;
2. The protist merged with an aerobic bacterium (a purple bacterium or proteobacterium, whose descendants eventually evolved into mitochondria, the energy factories of the cell);
3. In some lineages, that commune engulfed photosynthetic bacteria (cyanobacteria) to form swimming green algae, the ancestors of today's plant cells.

The basic eukaryotic cell had been born, and continued to evolve and diversify into the whole spectrum of eukaryotes—single-celled and multicellular—that surround us today.
This sequence of events is now widely accepted. Eukaryotic cellular organelles still carry their own DNA, although often in a fairly rudimentary form, and the genes they carry have been demonstrated to be closer in sequence to genes from free-living single-celled organisms than to the genes in the nucleus of the cell in which they dwell. Further, there are minor differences in codon usage between organelle and nuclear DNA . The evidence appears to be clearly on the side of endosymbiosis.

Tuesday, October 10, 2006

Antagonistic Pleiotropy

The term itself is enough to warrant a blog post, but the concept underneath is just as cool, and a damn sight easier to understand. 'Pleiotropy' is simply the phenomenon of a gene affecting more than one trait. It's easy to see how this can happen; a transcription factor (such as p53) can turn on dozens of other genes, each of which has its own effect (or effects; the target genes may themsleves be pleiotropic!). And many (most?) genes produce proteins which end up in several different cellular compartments, performing multiple functional roles. Pleiotropy has been documented ever since the concept of a gene existed; Williams (1957) cites Bridges & Brehme (1944) as identifying mutations charmingly called glass and sparkling in Drosophila. They were named for the effect they have on the adult eye [1], but they also affect the colour of the malpighian tubules[2] in the larva.

Antagonistic pleiotropy, as the name suggests, occurs when a gene affects multiple traits in opposite directions. As early as 1957, George Williams suggested that antagonistic pleiotropy might be the root cause of ageing [3]. He proposed that genes that confer a selective advantage to young creatures will be selected for even if they are disadvantageous in later life, since damage to the organism post-reproduction is invisible to natural selection. It's a neat idea, and in my opinion part, but not all, of the story.

So, is there any evidence for genes which act in this manner? There are lots of papers on the subject, and quite a scattering of potential candidates (I haven't done a proper review - I have too many other reviews on my plate at the moment!), but a recent paper that caught my eye was about differential ageing of males and females in Drosophila[4]. The author suggests that since mitochondria and X chromosomes spend more of their time in females than in males, they will tend to undergo selection which is beneficial for females, even if the adaptations are not so good for males. Mitochondria are well known to be important in ageing, so this sort of effect might explain why females tend to live longer than males[5]. I always liked mitochondria; they are truly fascinating [6]. And I like them even more now that I know they're on my side!

[1] I don't know about you, but when I think about "a pair of sparkling eyes", I rarely have fruit flies in mind.
[2] A sort of invertebrate kidney system.
[3] Williams, G. (1957). Pleiotropy, natural selection and the evolution of senescence.Evolution 11:398 - 411. Available online at
[4] Tower, J. (2006). Sex-specific regulation of aging and apoptosis. Mechanisms of Ageing and Development 127(9): 705 - 718.
[5] I hadn't realised that fruit flies showed the same pattern of survival as humans; I wonder what other organisms do?
[6] I went to add a link to my previous post on mitochondria, only to find I haven't made one. So the next topic will be...

Saturday, October 07, 2006


A new Supercentenarian Research Centre has just been established in Pittsburgh[1]. A supercentenarian is not, apparently, a 100-year-old with their underpants on the outside, but a person of at least 110. According to the article from the Washington Post, although the number of centenarians is increasing, the number reaching 110 is not, a statistic which I find somewhat odd. Obviously, your chance of dying increases with every year after young adulthood, but if increased longevity is due to environmental factors, you'd expect it to apply to all age groups. They're looking for donations, and hope to eventually become a funding body, making grants to projects which look very much like the IL's 85+ study.

For the record, there are currently 76 people in the world who are verified to be 110 or older. The Washington Post made no mention on their choice of costume.

[1] I don't know why all the articles I read mention the location; it's like the way newspapers always give people's ages when mentioning them. Completely irrelevant, most of the time. Mind you, I just did it, too.

Friday, October 06, 2006

Telomeres in the News

There's an interesting article in Monday's Life Style Extra about a link between osteoarthiritis and ageing. The link is, apparently, via the telomeres, which are the bits at the ends of chromosomes. Over time the telomeres get shorter, so telomere length can, according to some, be used as a measure of biological age. In the study being reported, people with arthritis had telomeres siignificantly shorter than their less-afflicted peers. The suggestion is that osteoarthritis leads to increased oxidative stress within the cells, as does ageing.

It's an intriguing idea, and not, on the face of it, improbable. I do have a problem with people using "ageing" as a synonym for "telomere shortening"; they are clearly related, but not the same thing. Just about everything[1] ages, but not all organisms have associated telomere shortening.So they are related, but not identical, concepts. To be fair, the article does make this clear; it's just the headline that is a tad dramatic. "Osteoarthritis causes oxidative stress which shortens your telomeres by an amount equivalent to 11 years worth of normal levels of oxidative stress" isn't as catchy as "Arthritis ages you by 11 years"!

There's no hint as to what the mechanism aould be, and I couldn't find the original report, because the links on the researcher's web page are all broken. Interesting observation, though.

[1] There are a couple of organisms which are not supposed to age, but I think the jury's still out, really.

Monday, October 02, 2006

Bio M&S Day, Guelph

I have to say, "Guelph" is just the coolest name for a city. Given that I've lived in (and, in fact, given birth in) Wagga Wagga, this is high praise!

So, last Saturday was the Bio M&S day in Guelph. Half a dozen speakers addressing various aspects of computational intelligence in bioinformatics, and an audience of maybe 10 - 15 [1] people from a wide range of backgrounds. I hope the audience got something out of it - I had a fantastic time, and found the whole day very enjoyable, even though I was jetlagged out of my mind.

Most of the speakers (including me) had presented at CIBCB in the previous couple of days, so I was familiar with the work, but it was really nice to have full hour-long talks instead of the 15 minutes you get at a conference. I'm starting to understand what Gwenn Volkert is doing with Hidden Markov Models and Kay Weise on modelling RNA secondary structure. Paul Higgs also gave a really interesting talk on the evolution of biased codon usage in mitochondrial genomes. Mitochondria are amazingly cool: important in ageing, which is fortunate for me, but just downright cool in their own right. I posted a long rant about mitochondria in the blog I kept for my last job, which is now offline. I'll repost it here at some stage. Everyone should know and love their mitochondria[2]!

My talk was on gene networks (surprise, surprise!) and seemed to go down ok. I enjoyed it, anyway, so there was at least one person in the room who was awake! That didn't last, of was a long, but thankfully uneventful, trip home. I slept most of the afternoon, which is a bad idea; heaven knows if I'll sleep tonight. Back to work tomorrow.

[1] I didn't count!
[2] I can feel a tshirt coming on...