Can We Live Forever - Edinburgh Science Festival

This is the first of two blogs written on the back of my Edinburgh Science Festival talk earlier this year. The first about ageing research generally, the second is about the drugs.

I was delighted (well one has to say that) to be invited to take part in the debate on drugs to treat ageing along with Prof Tom Kirkwood and  Lynne Cox At the Edinburgh Science Festival. Tom is, in my opinion just about as world expertly as you can even get on ageing and Lynne works directly on rapamycin so I was at first surprised to be invited along to join them. ...but then there is currently quite a lot of hysteria and nonsense published in newspapers about these drugs (rapamycin, resveratrol, metformin etc) and I suppose I am well known to be unable to help myself for ranting on about this!! So I guess that is why I was asked. That being a long winded way of saying, that whilst I would have loved to have shown up and said "its all very promising and exciting" (which it isn't), but even if I believed it, that was not my remit!

So what is the status of ageing research? In the words of the debate... "Can We Live Forever"? Now lets translate "forever" to "for a thousand years or so". Can we? Well that we can is the claims of some very famous writers on the topic.

In 2004 Aubrey de Grey famously told the BBC that the first person to live to 1000 has already reached 60. Now Aubrey de Grey is a fine writer and (read his bio on Wikipedia) has become quite famous for this, but lets face it, with a name like Aubrey de Grey and a hansom beard like that you've kind of got to be haven't you!

"The first person to live for 1000 years may already be 60 years old".  Or they might not be of course.

I frankly don't believe this for a moment. Sadly, I expect many people who were 60 in 2004 have probably died already and those that haven't now have a life expectancy, on average, of about 15 years. Sorry guys. But the claim got attention, wealthy people who are desperate to live for ever, probably plough money into the research Institute and hopefully something medically useful will come out of it. Albeit, not immortality. Some big noisy writers on the topic of living forever include Ray Kurzweil, I say "writers" deliberately. I don't see a lot of evidence that some are actually real scientists (??). Their thesis is (my interpretation) if you believe every newspaper headline about life prolonging strategies (drinking loads of red wine, avoiding salt, eating buckets of vitamins and antioxidants, avoiding calories as far as possible) it will prolong your life for the decades necessary for someone to find a total "cure" for ageing. I think that is deluded, desperate and dangerous.

Deluded? It's just scientifically without foundation. Just because a vitamin deficiency causes illness, it doesn't mean a massive excess is beneficial. Chemical balance between oxidation and reduction is a normal part of animal (including human) biochemistry and you muck it up at your peril. 

Desperate? My impression is that they are irrationally keen to live on forever. Why? To me it's like, well money is nice, but do you really need all the money in the world to be happy? The medical issue in the world is people and our pets dying early. ...and disease, chronic pain and disability in the elderly. ...but if I accept that they honestly desire to live forever (as opposed to exploiting desperate and ill people by persuading them to by the books in full knowledge its nonsense)... this methodology is rubbish anyway!! 

Dangerous? Their bottom line is that we should ignore official medical advice and do loads of extreme home remedy interventions which will probably do more harm than good.

So do I believe we can live for 1000 years?  Well I read a lot of science fiction and really this is where we are now. There is no foreseeable "cure" for ageing as such because it is not a disease.  Ageing is probably not an evolved feature involving genes which age you that can be deleted, more it is a case that EVERY gene has been geared to the survival of the young for long enough to breed. Beyond that, we are evolutionarily ignored.  Changing ALL the genes to allow infinite life is sci-fi and the one-drug-to-treat-them-all idea is ridiculous. To change breeding habits of humans is out of the question, ...but in animal models where we can work for generations of creatures I think we could double or triple life expectancy. I'm thinking pedigree dogs.  Take the poor Bernese with a life expectancy of 6 years.  If you only bred from long lived animal lines (looking back at the Dam and Sir's ancestry) I think you would pretty soon (dozens of years) be able to get these creatures to live MUCH longer ...and of course bringing some longer-lived breed blood lines into the pure breed would potentially change the breed characteristics little, but speed the process up a lot. So why does nobody do this? Go Figure.

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The Physiological Society Benevolent (Financial Hardship) Fund

This not a blog... just a plug for the Physiological Society's hardship fund called the Benevolent Fund (or BenFund for short).  If you have an extreme financial crisis and work or study in a Physiology type of discipline, it might be worth checking it out.  I am now the Chair.
The link is here

Teaching Old Drugs New Tricks

My blog on drugs to treat ageing dogs: Copied from the University Liverpool Website: 

“Rapamycin is an old immunosuppressant drug that is now being re-investigated for its so-called ‘anti-ageing’ properties, not only for us but also, as reported recently in all the newspapers, for our canine companions (see Nature report on University of Washington in Seattle study).

So I ask myself; will a pill to increase lifespan really help us and will it help our dogs?

On the face of it, stopping the ravages of time seems a good idea. There are, as a consequence, lots of putative anti-ageing compounds under investigation at the moment. “Anti-oxidants”, curcumin (the chief component of the spice turmeric), green tea extracts, and my personal favourite resveratrol (found in red wine) are all under investigation, but my excitement is in our increasing understanding of how and why we grow old, rather than any marginal longevity gain with some “nutraceutical” or another.

Mechanisms of deterioration

The objective should surely be to increase our understanding of the mechanisms of deterioration rather than to just pump ourselves (and now our pets) with herbal remedies or other chemicals and play “Last Man Standing”.

A question that many ask is; is it even a good idea for us to interfere with such a fundamentally natural process as human ageing?  My answer is ‘yes’, obviously, because whilst there are occasional scare stories suggesting people will live for 1000 years and the planet will be completely coated by humanity several layers thick… most people researching ageing are actually researching disordersassociated with ageing such as frailty, osteoarthritis, Alzheimer’s Disease, for example.

The aim is to deliver a better quality of life rather than some miserable immortality.

Trialling these drugs in dogs first is a sensible idea though. They are reasonably safe, although nothing is entirely without risk and mechanisms of ageing are similar between animal species, but are essentially sped up in mice and canines.The study should therefore return data far quicker than it would come back from a human study and it negates the need for some laboratory animal experiments.

”Most people researching ageing are actually researching disordersassociated with ageing such as frailty, osteoarthritis and Alzheimer’s, for example. The aim is to deliver a better quality of life rather than some miserable immortality”

Generally, with notable exceptions, animal life is proportional to size, with tiny mammals surviving only a couple of years and us larger animals lasting for decades.  With dogs themselves, it’s generally the other way around though.

The 1999 multi-breed study by the Animal Health Trust found that, again with exceptions, smaller dogs tend to significantly outlast larger breeds.  In fact the short-life expectancy of many breeds is shocking to many people.

The Kennel Club is inching in the right direction, but one might hypothesise this is largely under continuing pressure from the paradigm shifting BBC docuxposé “Pedigree Dogs Exposed” aired in 2008.

For us dog fanciers, dogs contribute so much to society already; from companionship to finding people in avalanches or earthquake building collapses.  From assisting people with disabilities to protecting us at airports by sniffing out people with explosives and other bad guys.

Most recently, it has become evident that dogs can help with human health too. Dogs can most assuredly detect certain diseases with their exquisite sense of smell and, ironically, they encourage exercise and activity in people; activity being the anti-ageing therapy with the very strongest evidence base of all!

A small increase

So now, they are helping us to develop drugs to increase our own longevity and for this, their reward will be, potentially, a small increase in their own life spans.

Let’s not kid ourselves this will be some sort of advance for canine health though.  In mouse studies, really large doses of rapamycin increased longevity by about 9% for male mice.  Perhaps we can hope for an increase of 5% or more in dogs?

To us humans, a 5% increase could be a really big deal, a few years of (hopefully) happy healthy life. …but to dogs? Well consider the poor old Irish Wolfhound.  Median life expectancy 6.2 years. Increasing this by 5% equates to just a few months.

Placebo; something about nothing!

I am sorry to dissent from the general chorus of both lay and scientific praise for the Horizon placebo program (Medicine's of the Mind "Power of the Placebo"). Many people seem to have found it fascinating, I'm not one of them. I thought it was all nonsense (if you are quick you can still watch it here)!

One of the disappointing things science can do is take a really simple phenomenon and make it more complex. Science should attempt to do the opposite.  So to clarify; most lay people have never (IMHO) had a problem understanding any of the following cliches:

• If something excites you (not like THAT) your heart to beats faster.
• You get a performance boost from confidence and/or positive mental attitude.
• Under-performance can result from under confidence.
• Fear can turn your stomach.
• Fear can make you go weak at the knees.
• In a fight situation, humans and other animals can suppress pain and don't really hurt until they are out of the danger zone....

There are so many of these its crazy. Placebo is just another one of these; if you truly believe you will feel better, you will feel at least a little better.

In teaching its a critical factor.  Telling students they will all do well WILL improve their performance.  And if you are my students worry not, it's no trick, I don't mind if you read this because I am absolutely sure you WILL do well.  There is nothing like confidence for optimum performance.  I have seen students in the past so nervous they couldn't even write their own name on the front of the papers.  Guess what?  They do terribly in the rest of the exam too.  Listen to my voice my students:  you WILL do well, really you will!

Now the program went to great lengths to show that there were real chemical changes in the body whilst this was happening (after people took placebo). But HELLO!! we are little more than a collection of chemicals. Everything you sense, think or do involves changes of chemicals. If you see something, glutamate is released in the eye and various neurotransmitters are released throughout the brain. If you think or imagine something, chemical changes take place in the brain. If you believe you will feel better, of course chemicals will change. If you lift your own leg... chemical changes take place in the process.
A couple of specific points about the program; the cyclists performing better and/or feeling they performed better?  Well people are absolutely hopeless at assessing their own feelings to start with (as I discussed here), and any good coach would know a bit of appropriate inspiration at the right moment will improve performance.  Why do people break so many world records at the Olympics?  This is exactly the same as the benefit of a so called "pep talk".  The the "mystery" of the placebo was further illustrated with a patient who's symptoms improved even though she was told she was going to get placebo.  All that matters is whether you feel you will feel better.  ...and typically of course the disease they chose was IBS "irritable bowl syndrome".  This is notorious for being a "there's nothing wrong with you get out of my surgery" type of disease.  Frequently people can be really ill with it too of course, and disturbingly, my guess would be that people "diagnosed" with IBS are frequently suffering from undiagnosed Crohn's or coeliac disease. Nonetheless, in many cases it the GPs way of saying, "I don't deny there is something wrong with you, but I can find anything to account for the symptoms you are reporting".  Bottom line (pun intended).. its not a great vehicle for demonstrating the magic of placebos.  

So giving people placebo, results in them thinking differently to non-placebo people and this change in thinking results in change of chemicals. To me, it is no big deal.

So why am I so evidently wound up by this? For two reasons.

(1) The idea that we are anything other than a collection of swirling chemicals and electricity is patent nonsense.  I feel there is no place for such arcane pre-science gobbledygook.  If you are surprised that chemicals change in the body when people "think positive" where have you been!? ...and if you thought that and you are even a biological scientist... Wow.

(2) Throwing your hands up in the air with amazement when someone shows that thinking changes chemicals in the brain is opening the door for woo. Why do I say that? ...because the next thing will be TV showing how people feel better after taking homeopathic remedies (aka water) and correlating this to chemical changes in the brain. Look they will say, homeopathy changes chemicals in the brain... So it was true all along. Well no it wasn't. Homeopathy is nonsense and just try and remember chemicals are constantly changing within the body. And will do so until well after we all die.

And on that cheerie note, I think I shall go and buy a high fat pizza and bring my own demise a little closer!!

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Bad Pharma and Negative Data

Negative clinical data.

This is a topic getting a lot of airplay and a lot of words! Here are a lot more (sorry). There is a huge issue with clinical trials failing to report the failure of a drug. There are also a number of quack remedies which have been tested frequently and usually deliver negative results that are never published. If ever, by the effect of pure chance, they do appear provide some marginal benefit, this is shouted from the rooftops. So how how are your sports team doing? There are two ways you could assess that, you could say they are 100% winners. To get this value you simply report the results where they won. However, a fairer assessment would be to report all the results and then you would see that if it were baseball, most likely, they loose half the time and win half the time. More-or-less. The withholding of negative clinical trials data is thus wicked, but I think outside of the people who do it, it is already universally condemned! This was discussed at great length by Ben Goldacre in his book Bad Pharma. It is indeed an excellent book and very important. Although I feel I can make four criticisms since I am pretty certain he would never follow me on Twitter!!! ...

"Reps may do bad things I suppose, unlike me. I do good things, but I just do them badly!"

(1) Bad Pharma was painfully long and I was quite frankly on my knees by the time I approached the end. (2) Ben is really horrid about drug reps. Ben seems to think they are evil, but I have known people go into drug repping and from my experience they were just ordinary people searching for a job. They may not love their job like the rest of us do, but they have to do it because it is their livelihood! I would blame the system that allows Vets and Medics to be ill equipped to handle the high pressure sales and gobbledygook "science talk". I feel sorry for drug reps trying to sell their wares to hospitals/GPs/Vets. (3) There were not many laughs in there, given how long the book is! (4) I don't think he quite gets the situation with negative preclinical data. So here's my bit on that.

"The Bad Pharma book by Ben Goldacre highlighted problems with negative data, but it treated clinical sciences and basic research just the same."

Negative Preclinical Data

It is not the same. I know the Journal Editors (I also Edit!), will all say negative data is perfectly acceptable, but the reality is; it is just not as hot.

"List all the Nobel Prize Winners you can think of that got the Prize by showing that their own theory was untrue"

Firstly, even I accept that negative data is less exciting; we knock about ideas in my lab... we wonder if this works like that. We do an experiment and we find.... it doesn't. No one can really pretend that is going to be a widely exciting read for others. RBJ had this great idea: His group spent months testing it and turn out to be wrong. Sure if there is some huge piece of dogma you can debunk you could probably publish this IF you also included an alternative positive set of data. Not true? OK lets have a competition, you list all the Nobel Prize winners who got their Nobel Prizes for the failure to discover something? OK I'll even allow you to throw in the discovery that something they thought might work.. doesn't work. Meanwhile, I will start to list Prize winners who were elected on the basis of positive data. Its all nonsense. A hypothesis constructed, tested and verified (positive data) is nearly always going to be easier to publish in a mainstream journal than "we tried this... it didn't work".

Am I complaining? Not about the fact that negative scientific data is tricky to publish, it has always been like that. My gripe is that (a) Ben and others seem to think this is in someway scientific corruption. (b) Editors need to have the courage to say, generally positive PRE-clinical data is more interesting and publishable than negative. I can have 10 new theories before breakfast, when tested, most of them will prove untrue I am sure, we can't fill the literature with disproving of all our own theories!

"None of us want to spend our days reading about how Jo Blogs tested his own private theory and found it to be untrue!"

The last point, wouldn't it be useful to have access to negative data to stop scientists around the world keep trying the same things and getting the same negative results? Oh yes indeed. Little journals or peer-review repositories which specialise in negative data are the way to go. They exist already, so lets just use them (if you are a scientist) and stop confusing the shocking hiding of negative clinical data, with the quite legitimate low profile publishing of negative data and broken hypotheses.

There feel better now.

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