An Excursion Into Exercise

I justify this posting on the grounds that exercise is almost certainly a very important factor in aging. What's really fascinating is that the research in this area seems to be absolutely polarized; those who run rats to exhaustion on treadmills generally conclude that long term exercise increases the production of reactive oxygen species (ROS, or free radicals), with the more-or-less implicit conclusion that exercise increases the rate of ageing. The more benign (or possibly just more patient) researchers who have taken elderly Homo sapiens through an exercise regime universally conclude that it improves quality of life, and there seems to be some evidence that it also contributes to increased longevity [1]. Maybe the rats should be allowed to choose not to run to exhaustion?

Anyway...

I'm an expert on getting into a running program. I'm almost as expert at that as I am at giving up alcohol. And since I'm currently back in Brisbane, where the weather is warm and the work pressures are purely internal, I've been running pretty regularly for the past month or so. There are several really obvious differences between running here and in Newcastle. The weather, of course, is the most obvious. In Brisbane I have to set my alarm for 6:30am to be on the road by 7:30, or it's just too hot to run. In Newcastle it's pitch dark at 7:30, and trying to squeeze in a run and still get to work before lunch time is a major hassle. Not to mention running in the cold. Even your ears hurt!

Then there's the setting. In Newcastle I run around Leazes Park, which is actually really pretty, and extremely Victorian, but too small to hold the interest day after day. Plus it was the pond at Leazes Park into which my motorbike was thrown a few months ago, so it still has painful memories, despite the swans. In Brisbane I have a 5K route that runs, for most of the way, past a creek, through bushland. It's cool and shady and replete with water dragons and sulphur crested cockatoos (no swans, though!) and smells of gum trees and hot grass. I swap smug smiles with the other runners and dog walkers, in tacit acknowledgement of our moral and physical superiority over the local slugabeds.

There is a hitch, however. In the past two months there have been 25 sexual attacks, of varying degrees of severity, upon women exercising on Brisbane's footpaths, including a couple in this area. The local government has offered a $50,000 reward for information leading to a conviction, and is advising women not to exercise alone. This morning I'd only gone a kilometer before encountering a very impressive motorcycle cop on my usual path. It's all a bit depressing.

But what really interested me was the way people responded. I do find myself scanning the path ahead, looking for lurkers, and trying to keep tabs on cyclists who overtake me, in case they turn round and turn evil. It does take my mind off the heat, my lungs and my legs, which I guess is some sort of silver lining. But what I really liked was the fact that it seems to have had no effect on the interactions between the early morning exercise community. We still smile and nod, and mouth "Morning", to each other. It's really encouraging to see that most people aren't letting these bastards get to them.

Lets hope they get these guys soon. A few runs to exhaustion on the treadmill will do them the world of good, and I volunteer to take any physiological measurements that might be useful, with a large syringe, as needed.

Jen

[1] Lee, I. M., Hsieh, C. C. & Paffenbarger, R. S. (1995). Excercise intensity and longevity in men. The Harvard alumni health study. Journal of the Americal Medical Association 273(15).

Ageing and Memory

First up, I have to come clean; this post is a shameless plug for a book written by a good friend and colleague of mine, Janet Wiles[1]. But in the course of writing it I had a quick look at the literature, and found lots of other interesting stuff.

My feeling, for which I have no basis except for experience, is that the major health fear of most younger people is cancer; The Big C. And that's probably fair enough; one in four women and one in three men will contract some sort of cancer in the course of their lives. And there are so many different sorts of cancer, with a multiplicity of causes ranging from DNA damage to viruses to diet. Cancer is scary because it's hard to understand and hard to control.

As we age, however, a new spectre raises its head: Alzheimer's Disease. The prospect of slowly losing our memory and cognitive abilities, the very core of what makes a human being, is not one that any of us can face with equanimity. The fact that some decline in memory and cognition appears to be an inevitable part of normal ageing doesn't help, either; most of the older adults I know (myself included) have wondered, at least in passing, if the fact that they can't find the car keys is a Bad Sign.

Janet's book arose from a survey which she and her co-author (and mum!) carried out, about memory function and concerns about memory in older adults. They used the survey to identify the issues which most concerned older people, and then went back to the literature[2] to identify which phenomena are aspects of normal aging, what might indicate some sort of pathology, and what strategies can help with memory problems [3].

I've always assumed that worries about memory are probably unnecessary; surely cancer is much more prevalent than Alzheimer's? [4]. It turns out that this is not, in fact, the case. There have been several large-scale investigations into the incidence of Alzheimer's. Generally, the incidence seems to be aroun 1% of the population at age 65, rising to around 8% once you're over 85. Interestingly, the incidence at age 80 - 84 is around 3%; there's a big jump once the magic 85th birthday hits. Even so, the incidence is pretty low. However, that translates to a lifetime risk of getting Alzheimer's pretty similar to that of getting cancer; around 25%. The good news is that the relationship between brain changes and disease symptoms is not straightforward; most people age 90 have Alzheimer's-like changes in the brain, despite not having dementia. And some factors, like education, appear to be neuroprotective. So, get educated...

...buy the book!

Jen

[1] Wiles, J. & Wiles, J. (2007). The Memory Book: Everyday Habits for a Healthy Memory. Apple Press. Available from Amazon UK.
[2] Janet is a cognitive scientist, and has in the past spent an unhealthy amount of time with psychologists. Nowadays we've lured her back into the relative sanity of the computer science department.
[3] When the local news in Brisbane did a segment on the book, I got to be interviewed confessing to the world that I can't remember a thing unless I write it down. Thanks, Janet!
[4] And, of course, heart disease or road accidents are far more likely than either.

Ageing Genes Back in the News

There's an interesting report in yesterday's (26 December) issue of Neurology: researchers in the US have identified a gene which is reponsible both for longevity and for the retention of mental sharpness. "Wow!", thinks I, "my work has been done for me, we can all go home." So I downloaded the paper[1]. Now, I think this is a very nice piece of work, and has some intriguing implications. I have issues, not with the paper itself, but with the way it's being reported.

Looking on Google News[2] yields the following headlines:

"Longevity Gene Also Keeps the Mind Sharp"
"Gene Tied to Longevity Also Preserves Ability to Think Clearly"
"Longevity Gene Also Protects Memory, Cognitive Function"
"'Supergene' Gives Long Life, Clear Mind (I love this one! Does it also enable you to leap tall buildings at a single bound?)
"Study: Gene Tied to Long Life Wards Off Dementia"
...and on, and on.

The most moderate is probably "Gene Tied to Longevity May Protect Brain", but who can really resist "Gene Aids the Elderly"? Or even "Single Gene Could Lead to Longer Life, Better Mental Function"?[3]

OK, so what did they really find?

The study took 158 people aged 99, and looked for the presence of a gene variant previously associated with longevity (CETP VV, a gene whose protein is involved in lipoprotein metabolism). They also gave their subjects a test known as the Mini-Mental State Examination (MMSE), and looked for correlations between MMSE scores and the presence of CETP VV. They did, indeed, find a statistically significant association between the presence of the allele and high test scores; hence the media hysteria. But, of course, the picture is not that simple.

The authors state that "Subjects with good cognitive function had a higher frequency of the CETP VV genotype than those with poor cognitive function (29% vs 14%, p = 0.02)". Further, "those with the CETP VV genotype were twice as likely (61% vs 30%, p = 0.02) to have good cognitive function than those witht the II genotype." OK, those numbers look reasonably interesting, but when you consider that only 43.5% of the group had "good" cognitive function, and only 24% had the "good" allele, it's clear that the gene is not the only factor at work here, by a long shot. In fact, if you translate the percentages into absolute numbers, there were 20 people with good cognition and the good allele, compared with 12 with poor cognition and the good allele. If the traits are independant, you would expect 16 (24% of 43.5% of 158 people) people to have both the good varieties, just by chance. It may be a significant difference, but it's a hardly a "supergene".

In addition, the mechanism of action of the good allele isn't known. The researchers suggest that it may be related to the previously-identified link between CETP VV and low incidences of heart disease, or it may be a completely new pathway. If it's something as simple as increasing blood flow to the brain, then maybe its beneficial effects can be achieved by something as simple as increased aerobic exercise, rather than tinkering with the mode of action of a crucial metabolic pathway.

So, to summarize:

It's a nice paper, and the results are interesting and may direct research into useful areas.
But:
1. It's a small study (158 people)[4];
2. The results are only just statistically significant;
3. Other factors (other genes, environment, nutrition, exercise...) appear to be more important in influencing the phenotype than the gene itself;
4. "Cognitive function" was measured with a single test.

Neither the general public, nor the researchers, nor science itself is done any good by hyping results such as these into news of supergenes which are going to turn us all into centenarian geniuses. It's never that simple.


[1]Barzilai, N., Atzmon, G., Derby, C. A., Baumann, J. M. & Lipton, R. B. (2006). A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology 67: 2170 - 2175.
[2] http://news.google.com/news?hl=en&ned=us&ie=UTF-8&ncl=1112251435
[3] Scientific American, how could you?
[4] The results were validated with a larger sample, but it's still a small, preliminary study.

Integrated Functional Networks

Well, I finally made it Australia, after a flight which I prefer not to remember in too much detail[1]. Today I gave a seminar at the School of Information Technology and Electrical Engineering at the University of Queensland, my old stomping ground.

I haven't been back to Aus for a year, but it feels as if I've never been away, despite the fact that I've done a lot of work in the past year. The seminar was about what I've been doing in Newcastle; integrated functional networks as per the title of this post. I've only been working on this for a year, but I think we're now in a position to identify both the promise and the challenges of this approach.

What's an integrated functional network? It's a network of interactions between proteins within a cell. The interactions are identified by scanning as many as possible of the large data sets that are currently available, generated by lots of different technologies. Different types of interactions are combined using a statistical approach, and the result is a network in which links between genes mean that there is some sort of relationship between those genes. Each link has a weight which reflects the probability that it really exists, given the evidence we have.

These networks are a hot topic of research at the moment, because they take data that is tucked away in big databases and makes them available to biologists with specific research questions. Many of the big pharmaceutical companies are using them to identify potential drug targets, for example. We're hoping to use them to guide research into the genetics of ageing.

So I gave the talk, and got some valuable feedback, and then we went to lunch, which was great, since the people there were all old friends and colleagues. The slides are going to be online somewhere at some stage; I'll post an update when they go up.

From the sublime to the ridiculous: tonight's the University Staff Club Trivia Night finals, and my (ex) team is competing. I'll be there to cheer them on (and maybe drink a champagne or two!).

[1] Why do the nutters always want to talk to you at 2am when you're trying to watch "Finding Nemo"?

Dubai, or not Dubai?

I'm officially in transit to Australia, to spend Christmas with my family. I'm actually in Dubai, which has its pluses as well as its minuses.

I left home at 8:00am Friday, to catch an 8:30 train to London. Arrived 12:00; another hour on the train to Heathrow and then 45 minutes in the Emirates check-in line. When I actually got to the desk it was a little galling to find that I'd actually been in the wrong line; my first leg was with Virgin Atlantic. Still, these things can happen to anyone! I moved to the Virgin line, and finally managed to check in. Seven hours from leaving my front door to walking through security, and I haven't even boarded the plane.

We did board - eventually. Only about an hour late, but enough to make us miss the connection to Brisbane. So I'm spending the night in Dubai. An interesting city.

At first they were proposing to put us up at the Marriott, but it turned out that all they had were executive rooms, at an equivalent of $500US per night. "Oh, yes!" I was thinking. "At last, the life I should be living!" Alas, it was not to be. We're at the Arabian Park, a perfectly adequate hotel, but not exactly the high life.

They think big in Dubai. The buildings are big (although some are cool and curly, but not many). The roads are big, and the traffic is appalling. I went to a (big) shopping mall to get some money from an ATM, only to come face to face with a dilemma. I have no idea what the currency is, or how it translates to dollars (Australian or American) or pounds. So I'm looking at the ATM, and it's teling me that I can withdraw up to 3,000 somethings. The minimum is 200; I choose to go with 600, which is the second lowest option. I may just have cleaned out my bank account, and made it impossible to pay the rent this month; or I may have about two pounds in my purse, and will be totally humiliated when I have to pay my internet access bill in the morning. It's these little nuances that make international finance so interesting.

I'm currently in bed, with a wake up call booked for 4am. With any luck I'll be home in another 12 hours, but I have Singapore to negotiate yet. The way my recent trips have gone, I'm not optimistic, although I gather you can make a good living as a street theatre artist at Singapore airport, so all is not necessarily lost. One of these days I'll get back to doing science...

Cheap wine and a 21-day growth

Yes, it's red wine revisited. I've previously mentioned the depressing finding that you need to drink 300 glasses of red wine a day in order to get mouse-verified levels of life-extending resveratrol. Tempting, but impractical, not to mention expensive, even if you go for one of the co-op's cheaper options. But this week's Nature carries a report that it might not just be resveratrol that is the essential longevity-promoting ingredient in red wine. Apparently there's another set of chemicals, irresistably named "oligomeric procyanidins", abundant in wines from Nuoro province, Sardinia, and southwest France, which appears to act against blood vessel constriction. And people from these regions apparently have "higher than normal average longevity". As a loyal Aussie, and a long-term devotee of Australian reds, this news disturbs me.

So should we move from the Brown Brothers Merlot to one of those French wines with the unpronounceable names? Maybe. There seems to be some evidence that the Tannat grape, which is grown in these areas, is particularly rich in procyanidins. But another factor seems to be the fermentation process; apparently traditional wines in these regions undergo a 21-day fermentation process, in which the juice remains in contact with the skins and seeds (and seeds are where the procyanidins lurk). Most wine has a shorter fermentation process, and so the wine ends up absorbing less of the active ingredients.

I have to admit I've never tried wines from Sardinia. Maybe it's time to give them a go. Any recommendations?

Creating Life

The reason I haven't been posting much lately (well, the excuse I'm giving, anyway) is that I've been doing the writing for which I'm paid: a conference paper on integrated functional networks and two book chapters, one on gene networks and evolutionary computation, and one on synthetic biology. They are all, of course, little masterpieces, carefully crafted and polished [1], but I was particularly inspired by the last-mentioned.

I volunteered to write the chapter because I'm interested in synthetic biology, didn't know a huge amount about it, and wanted an excuse to learn. The ultimate aim is simple, if ambitious: to create life from scratch. The intermediate aims are to engineer the genomes of existing organisms to produce specific, predictable behaviour. We already have a field of genetic engineering, of course, but it tends to be pretty restrained. Dropping a cold-resistance gene from a deep-sea fish into a banana genome so Inuit can grow their own banana sundaes[2] is one thing; producing a lawn of bacteria which acts as a photographic film[3] is quite another. I started out quite skeptical about whether it was possible to do anything large-scale and significant, but ended up pretty impressed with the possibilities.

We're nowhere near creating life from scratch, of course. Although a virus (polio) has been created by simply building a chromosome from its published sequence[4], it did need the cytoplasm from an existing cell in order to reproduce. And viruses are as simple as you get, to the point where some people deny they're alive (although I think that's ridiculous - they have obviously evolved from more complex creatures; can you evolve from being alive to not being alive?). But it's a very impressive start.

I think there's huge scope for computational intelligence and machine learning approaches in this field, and I'd love to work on it. Manybe once I've cured cancer and ended ageing...

[1] And thankfully now the problems of their respective editors, instead of me.
[2] Sadly, to the best of my knowledge, not yet done. My next grant, perhaps?
[3] Levskaya, A., Chevalier, A. A., Tabor, J. J., Simpson, Z. B., Lavery, L. A., Levy, M., Davidson, E. A., Scouras, A., Ellington, A. D., Marcotte, E. M. & Voigt, C. A. (2005). Engineering Escherischia coli to see light. Nature 438: 441 - 442.
[4] Cello, J., Paul, A. V. & Wimmer, E. (2002). Chemical synthesis of Poliovirus cDNA: Generation of infectious virus in the absence of natural template. Science 297: 1016 - 1018. And they just ordered the DNA from commercial producers. Very cool.