Running on an empty stomach.

101 Year Old Runs London Marathon.

Do you remember this sensational story breaking across news outlets internationally? In April last year Fauja Singh astonished revelers when he completed the London marathon, frankly in a better time than most of us could have achieved.

Fauja Singh was born in 1911.

That was one year before the Titanic sank. One year before the First Balkan War commenced. Three years before the First World War began. Surely he was some kind of fitness fanatic all his life? Nope. He began training for his first marathon at the age of 89.

So what is Singh's secret to such startling fitness when some of his peers got their first hip replacement 30 years prior? He said: child portions of meals.

The London Marathon  has always attracted a huge variety of ages but  Mr. Singh topped them all.  Photo accredited to Martin Addison. (This work is licensed under a Creative Commons Attribution 3.0 Unported License.)

Cue: Calorie Restriction.

Calorie Restriction, or CR, unsurprisingly means cutting out calories. But, you won't achieve it by avoiding  carbs like the plague; CR refers to a lower energy but still well balanced and nutritious diet. Basically, all the right components are there, there's just less of them.

I have decided to write this post because it ties very nicely into previous discussion on ageing and increasing lifespan yet it has also been implicated in delaying the onset of many age-related diseases. This brings us neatly back to a question posed in the previous post: should we be trying to find ways to maintain the quality of life as we age? If you dive into the scientific research behind "less food, better form" there actually turns out to be quite a lot there. CR has been linked to preventing diabetes, cancer, Alzheimer's and heart disease - much more than just expanding waistlines. 

A theory as to why dietary restriction seems to have these sought after effects in many different organisms is that the stress starvation puts our bodies under is actually a good thing. What kinds of activities might a cell undertake if it is under stress? It will stop making things, because it doesn't have the building blocks that come from our food, and has more time to repair things that are already there - our DNA for example. There are certain genes that are particularly active when we are stressed, aptly known as "stress response genes";  having the fix-it men of our cells around more often really doesn't seem like a bad thing.

WeightWatchers for scientists.

Studies centered on calorie restriction have been conducted in many different model organisms: worms, yeast, flies, rats, monkeys even. How? Well one quite obvious way is to let half your subjects gorge away to their hearts content whereas the other half are provided controlled meals. The technical term for gorging is "ad libitum"; your dieting organisms get about 60-70% of this ad libitum level. It is known that appetite decreases as we get older so an important thing to note is that whilst the gorging animals will generally choose to eat less as they approach the end of their lives, the CR intake is set from the beginning of the experiment and does not change. This means that the gap between the two calorie intakes will gradually close during the course of this experiment. This information comes from a review published in Cell Metabolism which also sets out other methods for studying dietary restriction, should you be interested the source is here.

Calorie restriction has made headlines, diet books and even TV documentaries (BBC's Eat, Fast and Live Longer), but the real question is: who has the willpower to do it?

Never too old to learn.

Ageing is unavoidable. Ageing is something we try to avoid most.

Beauty products and anti-wrinkle remedies parade their antioxidants, glycans and tocopherol (vitamin E by the way) and we accept this jumble of scientific terminology on a label next to a face glowing with youth as a promise that tomorrow we will wake with one less crease, or maybe the next day, or the next day..

What is quite ironic about these products and their exuberant claims to reverse ageing is that scientists are still unsure as to what is the source of ageing in the first place. Of course there are numerous theories and possible explanations, one of which I will address later in this post, but the fact remains that we don't know. In fact, it is quite possible that ageing may be a result of the contribution of many of the theories, or at least parts of them. This is counter-intuitive. The concept of there not being a simple definitive answer is a concept most of us struggle to accept. The lesson to be learnt here is that this ambiguity is unfortunately also a common occurrence in science.

The mitochondrial free radical theory of ageing.

Free radicals are pretty widely known.

All of our cells respire, it is how we generate oxygen and energy. Respiration takes place in small energy factories in our cells, the mitochondria. Any efficient factory has a production line, in the mitochondria it is known as the electron transport chain or ETC. As in any factory employees get tired and machinery breaks down: things can go wrong. A small blip in the production line could cause a faulty product to be attained at the end. When things go wrong in the ETC we end up with free radicals.

Our bodies are wonderfully complex designs, of course we have a system in place for when the ETC leaks free radicals: Scavengers. But if these are overrun by reactive oxygen species, or they stop working properly, that's when problems may occur.

Free radicals are also known as reactive oxygen species and as their name suggests, there are highly reactive. They are also not particularly fussy. Lipids, proteins and carbohydrates are all potential targets. So, could these reactions be ageing our cells? Probably.

Some research certainly says so. A study carried out in McGill University, Canada showed that when components that make up the ETC are mutated so they work less, the lifespan of worms increased. The idea here is that slowing down the manufacturing pace results in less free radicals, and as the theory states, a higher lifespan.

However, anyone who watched Sir David Attenborough's recent BBC hit Africa will have seen for themselves one of the contradictions to this theory: The naked mole rat. Whilst it does look rather irrelevant to humans don't knock them just yet, the naked mole rat has been hailed as "holding the key to the elixir of life". Why? The average rat life expectancy is two to three years. The naked mole rat can reach its flirty thirties. It also is highly resistant to cancer. So where does this all lie in the context free radicals. Well, if this theory was definitively true then surely we would expect the naked mole rat to have less reactive oxygen species than its bog-standard peers? They do not. In fact, they have more, and here's a paper to prove it.

Don't be fooled by the wrinkles, this creature is the picture of health. (This work is licensed under a Creative Commons Attribution 3.0 Unported License.)

The paper was published in Nature and the first thing to note is that this paper is not a trivial one, Nature is one of the Holy Grails of journals. The main point of this paper was that the research group who published it managed to sequence the wrinkly fountain of youth's genome. The previous post equipped you with knowledge of sequencing so I won't go into too much more detail about that, more importantly is how exactly did the researchers go about assessing the cause of the animal's incredible lifespan. The basic method was actually quite simple: they compared what genes were expressed in three different naked mole rats, each a different age - newborn, four years old and 20 years old. They were specifically looking in the brains, livers and kidneys of these animals. Something was up. Barely anything was different between the different aged rats; this is a stark contrast to humans where patterns of genes "turned on or off" change as we get older.

As well as genes that didn't change at all there were even some which did change but in the opposite way to how they would in humans. For example, one gene, that codes for a protein called SMAD3 was up-regulated in the naked mole rat brain whereas in humans there is less of it when we get older. In scientific research differences  allow conclusions to be made, tentative as they might be. For example. SMAD3 is known to help stop cells dividing. As you probably know, cancer occurs when our cells can't stop dividing - could more SMAD3 be one of the reasons naked mole rats are able to evade cancer so effectively?

So free radicals are bad. But naked mole rats have lots and live longer than normal. Doesn't quite all add up - see what I meant about disharmonious science now?

Why is ageing so hard to study in humans?


Good experiments need control groups.  What would be the control group for older than average humans? Dead humans who would've been the same age? It can't be done! Another reason is, shockingly, it takes a long time. It's not really plausible to study a human for their entire life, cost is the obvious factor but also, would you choose to be poked, prodded and examined for the entirety of your life all for the good of science? Didn't think so.

We are an ageing population.

In 2011 the World Health Organisation (WHO) estimated that between 2000 and 2050 the number of people aged over 60 will increase from 60 million to at least 2 billion. That is a huge increase and as expected will put enormous strain on existing resources, care homes for example.

Should we really be undertaking research to increase lifespan?

Should the real question be: how can we age well?

Please feel free to comment with your own views on the matter, I'd be glad to have provoked them.

Up close and personal.

Then and now.

2000 years ago there was so much room for medical advances because things simply hadn't been done before. This was back when infection was rife and what would now be a routine operation would then leave your fearing for your life. If you were unlucky enough to be born before the 1800s don't think your doctor would have thought to wash his hands before putting you under (thank Joseph Lister for this phenomenon today). There haven't been many recent leaps on the same scale as those which occurred throughout the 19th century however I can think of one: Personalized Medicine.

And it does what it says on the tin.

Joseph Lister pioneered sterilization techniques and antiseptics (This work is licensed under a Creative Commons Attribution 3.0 Unported License.)

"Your differences make you beautiful."

If anyone has ever said this to you do you think they had medical treatments in mind? It seems so simple but it is only recently, when jargon about genomes and sequencing has decorated "science" news articles, that people have realized: one-size-fits-all is never the most flattering option. We need tailored medicine.

So how is this revolutionary concept even possible? This question has a one word answer:  sequencing.

In life science research there is an area called Bioinformatics. It is where biology and computers collide harmoniously together (most of the time) and is a direct result of the techy-era we are all living through. Sequencing itself simply refers to unravelling each and every one of our "codes" and this is a huge part of bioinformatics research. A DNA code is the making of every living thing on this planet and each one of us has a slightly different version of the human code, otherwise known as the human genome. You therefore won't be surprised to hear, if you haven't already, that the Human Genome Project describes a huge amount of work undertaken by scientists across the globe with the sole aim of finding out the exact human DNA code. When this was first done it took years and approximately £100 million. Now it costs about £800. See where I'm going with this yet? If it is possible to sequence human genomes at this price it is not ridiculous to envision a "sci-fi future" where your genome will be sequenced in 10 minutes at the doctors to see what is wrong with you. Once this is known, treatments can be designed specifically to treat your "abnormality" or, more technically, mutation, rather than by assessing symptoms.

The cancer conundrum.

Okay, so this might be a slight exaggeration, if you go in with symptoms of the common cold I doubt you will be subjected to full genome sequencing, but think about it on a bigger level. Cancer for example. Cancer is crippling every country, even more so now we are an ageing population. Everyone can relate to it. And everyone wants to stop it. The honest truth is we can't completely. But, we are getting better, partly due to personalized medicine.

Cancer is a heterogenous disease: every case is so different from another. Even two patients both with breast cancer may have completely different sets of mutations which have caused it. Even within one tumour the mutations could be different, depending on the position of the cell. Starting to see the difficulties? That is why learning the exact pathology and genetic make up of a cancer helps enormously when trying to treat it.

And it's not just a distant hope: at the end of last year newspapers reported that the government intended to sequence 100,000 genomes as part of a new public health initiative. In case you don't remember and so you don't think I'm making this up here are some articles which were published in December 2012:

Both the Guardian and the BBC particularly emphasize the promise it holds for cancer patients.

My only criticism of this plan however is the realism (or lack thereof) of being able to detect rare cancers with just 100,000 people. You don't have to have much statistical prowess to see the problem I'm pointing to. Rare cancers are, well, rare. If 1 out of the 100,000 shows a genetic "mark" is it reasonable to say that mark is the reason for their rare cancer? You would want to check in more people who have this rare cancer whether they have the same mutation before concluding there is a cause/effect relationship between the abnormality and the disease. Statistics are crucial for scientific research.

BUT that was just a sideline and so I stop pretending to know anything about statistics I will swiftly move on. So hopefully if you have read the post up until this point (I am aware you may be in the minority) then I will have sparked an interest in this topic in you. And, as curious people generally do, you will want to know a bit more detail. You may even be screaming at your computer screen in frustration already that I haven't once mentioned an example of personalised therapy. Guess what I'm going to do now.

The example I have chosen to illustrate the phenomena that is personalised medicine is a review article published in the journal Cancer Treatment Reviews. A journal is a collection of articles which demonstrate new scientific research. A review is when someone doesn't actually do research themselves but goes about hunting for different published articles on a topic and draws them together under a certain theme. The theme of the example I'm going to give..

Targeted therapy in metastatic colorectal cancer - An example of personalised medicine in action

Sounds relevant.

Just in the abstract, a short summary of the paper before it all gets a bit hefty, two phrases jumped out at me: "tailored treatment regimens" and "optimised outcomes".  These phrases in the same sentence already flourishes the promise of personalised medicine.

Now, tackling the hefty bit.

I am going to make an executive decision to not describe the whole scientific paper and its findings to you. Instead, only the most relevant finding to what we have already talked about will be explained. Executive decision number 2: I've done enough talking so watch this (amateur) video I made to find out more.

So what can we conclude? If your genome is sequenced and a mutation in KRAS is found, there would be no point using antibodies against the EGF receptor to try and treat the disease. In this way personalised medicine saves money, time and unnecessary discomfort and false hope for patients.

A bit of detective work.

One last thing about the above review and another little insight into how scientific research is conducted and shared with others. At the back you will find a "Conflicts of interest statement". This fleeting section actually holds unequivocal importance. It  is where we can assess if  there any ulterior motives for the conductance and publication of any research. It may shock but scientists aren't always working towards a greater good. For example, are they going to receive a big fat cheque (otherwise unheard of in the slog that is science) if they reveal a certain drug is in fact miraculous? In any industry there is always room for skepticism. In this review we learn that all the authors have connections and have received money from various drug companies. My conclusion is still that this review is legitimate but yours may be different and at least if these issues are stated people can make their own judgments. It's when they aren't revealed that alarm bells really start ringing. If a paper is submitted without having expressed any conflicts of interest and some are later discovered papers will be forever "black-marked" with this error, sort of like a blemish on your criminal record within the science community. And, as with anything, the more you try to hide something, the guiltier you look.

Trials, tribulations and mind over matter.

Lets play the word association game.

Health.

Disease.

Drugs.

In our society pharmaceutical products are the first port of call when we feel unwell. The existence of a pill-popping culture is something that science writer Ben Goldacre makes a particularly good case for in his bestseller, Bad Science. The BBC Horizon programme "Defeating the Superbugs" revealed that in India it is possible to buy antibiotics from what is the equivalent of corner shops. As you may have done with your penny sweets people can buy as much treatment as they can afford or want rather than a prescribed course. Whether it is a culmination of misinformation and lack of education about antibiotics or purely sheer idiocy, this throws into question the responsibility we all have when it comes to drugs. This story is particularly relevant in light of recent news that the Chief Medical Officer for England is drawing parallels between antibiotic resistance and terrorism in terms of the threats they pose. Here is a link to the BBC article in case you missed it.

Pick N Mix antibiotics anyone? (This work is licensed under a Creative Commons Attribution 3.0 Unported License.)

You probably take various drugs every year; whether it is aspirin after a long night or something more serious, pharmaceutical compounds are something everyone has experience of. But how many people know the process by which they are approved?

How much do you know about: Clinical Trials.

A lot has changed.

Drug development has been around in some shape or form for hundreds of years but, as you can probably imagine, a lot has changed. Most noticeably the scale of development has grown enormously; 200 years ago most drugs would be prepared by individuals using natural resources and there were very limited amounts, now the World Heath Organisation (WHO) estimates the global pharmaceutical industry to be worth $300 billion a year. Obviously with such presence a comes lots of control and standardization - particularly when it comes to the discovery and eventually approval of use for a new drug.

So, how is the medical research carried out in humans?

Each phase has its own unique aim.

Phase 1. - find the maximum tolerated dose and schedule of administration. The new drug is first tried at a very low dose in three people and gradually increased, each time administered to another three people, until side effects emerge in two out of three of the subjects - it is at that point the maximum dose is defined.

Phase 2. - assess the effectiveness. Characteristic of clinical trials is the increase in the number of patients at each phase - during the second phase the number increases from around 20 to over 100.

Phase 3. -  compare it against the current best treatment. If it isn't any better then there is no point in continuing. But, better doesn't just have to mean it is a more effective than the current drug, it could be the same effectiveness but with fewer side-effects - the drug will still have a big impact on a patient's quality of life. The number of patients in this phase reaches the thousands.

If a drug makes it past this phase it gets licensed which may seem odd as the trial hasn't officially ended. But, it has been deemed safe enough and its effects impressive enough to be tried on the general population.

Phase 4. - watch how it is getting on.


So those were the basics of a the human part of clinical research, as I was taught them in my biochemistry degree! But - there was something even more interesting I hit upon when reading around about clinical trials..

The Placebo Effect.

This is a widely studied phenomenon but one man I particularly started reading about was Ted Kaptchuk. According to the biography on his website Ted originally studied Chinese medicine and is now a prominent figure in the "Placebo community" having had numerous scientific publications.

One publication in the British Medical Journal (BMJ), a highly esteemed journal where researchers and professionals can specifically find information and studies about health, caught my eye - a summary can be found here. It caught my eye because it showed how the scientists view on placebos is changing. If you Google "clinical trials with placebo" a whole host of articles boasting of "placebo-controlled studies" will appear - placebo's often form an integral part of a trial. But, what Kaptchuk's 2012 study showed was that in the 19th Century placebos were not regarded with as much significance.

How was the study conducted? The researchers simply searched a computer database for any papers containing the word "placebo" in the archives of the BMJ between 1840 and 1899. Bit like pressing Ctrl "F" when looking something up on your laptop really. But this has a more technical name than the Ctrl "F" trick, this study is a Meta-Analysis. It may seem surprising but meta-analyses are one of the highest regarded forms of scientific research: you combine all the previous research that match the criteria you set, in this case containing "placebo", and draw conclusions from looking at all of the results. What they found was that nearly a third of all papers published at this time described placebos in a derogatory way, or used the term interchangeably with "no effect". Only one paper out of the 71 assessed suggested the placebo had "a clinical effect".

Debate about the "Placebo Effect" is now much more prominent than this study suggests it was in the 1800s.

If you are interested you might enjoy this video on the NHS website where Ben Goldacre discusses the placebo effect, he also brings in the ethical issues surrounding "lying" to patients who are actually receiving placebos.