so what I go to speak about so I'm going to take you through some of the demographic trends I'm hoping there's some geriatricians in the audience who will be familiar with these and I'm also going to talk about variability and malleability of Aging so like Robert I also hit 60 in fact last month so I'm getting more and more interested in this process I'm going to focus then a little bit on features of immune aging so what happens to your immune system as we get older but then I'm going to really move into just how much of what we think of the aging process focusing on immune aging but I'm happy to speak about other aspects that's really a result of our modern lifestyles and then moving on to how we can do something about this what we know about immune aging and the mechanisms involved that have led us to improving immunity in old algae that I'm going to finish with a little bit of medicine life data on myself so this is why I become interested in aging and why we've got an institute of inflammation and aging at Birmingham so these are UK statistics but it's pretty well similar wherever you go in the world so if you look at the under 16s the birth rates are falling but it's the over 65s that are increasing in their number because we're living longer so in that 25-year period from 1984 to 2009 we acquired another 1.7 million over 65 year olds but the group that are in fact increasing at the fastest rate of these groupings in the dark blue these are the over 85 s their oldest old and in that 25 year period their numbers doubled to 1.4 million and the predictions are that by 2034 were almost one in four of the population will be over 65 and 5% will be over 85 but there's a lot of variability so this is data for Birmingham so longevity is also highly variable so this is our cross city line which today isn't functioning because strong dose has thrown trees all over the line but just eight stops on this line from Snow Hill out to four oaks here there's a nine-year difference in life expectancy so here we are in the 21st century and we still got big this is a life expectancy and you'll find this in most cities in the UK but our experience of old age is also highly variable and I'm going to introduce you to three European ladies all actresses and in one picture that 21 and in the other picture there's 78 and we begin with the Italian representative Sofia Lorentz so here she is 21 and 78 she's now actually 81 she's still acting she's in a film directed by a son just last year so I think a great example of aging successfully and healthily now we moved to the French representative this is brigitte bardot 21 on the right and 78 on the left and brigitte is now also 81 she's born just a couple of weeks after Sofia and she might have got a few more wrinkles but actually she's still very active she's politically active and so I think another great example of what old age can be like now we move on to the British representative this is Elizabeth Taylor 21 on the left and 78 on the right and Liz never made it to 79th birthday she passed away just a few months after this photo was taken and she spent the really the last year's of her life wheelchair-bound really not a successful old age so longevity is variable and your old age is variable and here's some of the data on life expectancy so female life expectancy increasing and it's increasing at two years per decade put another way a child born today has a life expectancy of five hours more than one born yesterday it's a very dramatic but this is why we've really started to pay attention and why the government has paid attention around 25 years ago in most part countries in the developed world healthy life expectancy that started studying off so healthspan is not keeping pace with lifespan and on average a female ism well for the 19 years of her life at the end of life and the male at 16 years with of course significant impact on our NHS and I don't have to tell you about this is all over the news continuously so we need a definition of aging aging is not just the number it's not just a lead another candle to your birthday cake each year and this is the one that I use so it's the increasing frailty of an organism with time that reduces your ability to deal with stress resulting in increased chance of disease and death and it ask you to bear that in mind as we go through the talk so how are we going to move forward if you think of the current paradigm in disease all of these diseases here or age-related so they increase with age and we currently try and tackle them one by one so if we're trying to cure cancer we do cancer research cardiovascular disease we do heart disease research but if you think if all of these are actually caused by the aging process they're age-related why not just tackle this process I hope I can persuade to this as possible so here's one example chloric restriction in this technique what you do is you take any sort of species and these here are all responsive to chloric restriction and you cut that calorie intake by 25 to 30% what happens when you do that is that the animals live longer so here's the ad libitum fed C elegans there's the code unrestricted and they live on average about 25% longer so reducing your calorie intake will get you to live longer you're probably thinking yes but that's lower species what about higher species professor Lord what happens there well it turns out it looks as though it's true there - these are studies in the US and there are two of them on going in macaque monkeys and at the moment these macaques are 33 years old so they're equivalent of about a 75 year old human so here's the ad libitum faired macaque they're on the left and you can't see from where you are but probably but he's got cataracts he's lost most of his teeth the poor guy's lost most of his hair curvature of the spine here this is an aged monkey look at the guy on the right this is the calorically restricted monkey no cataracts he's got most of his teeth this guy will give you a really good bite if you get anywhere near him lovely straight spine there kept all of his beautiful ginger fur this is a really spunky monkey you know this guy's up for everything but are we until we don't know yet when they're going to live longer they probably are but look this is what's the really interesting thing when you look at the instance of all of the age-related diseases so cancer cardiovascular disease diabetes neuro degeneration in the ad libitum group you've got only about 20% that are disease free and the calorically restricted group you've got 70% a disease-free so it looks like they're going to live longer and they're certainly going to live healthier but you're probably thinking about those are my cats professor lord this can't possibly between humans because the answer is we don't know yet the longest caloric restriction study in humans is only eight years old but if we look in the world of Epidemiology we get some clues that it may be true for humans too so these are data from Okinawa and island off the southern tip of Japan and Okinawa has the highest fraction of centenarians in the world they have 18.5 400,000 the nearest to them is mainland Japan that has 4.5 400,000 so they really have a huge number of centenarians but observations in the Okinawans are shown that part of their social behavior is they say that you should leave the tables slightly hungry so they naturally calorically restrict and when you look at the intake of children they're actually only taking in 60% of the recommended calories that we state here in the UK and adults it's about 80 percent so they're living longer but do they live healthier well yes they do if you compare Okinawans with Americans they're 75 percent more likely to retain cognitive ability they have 80% fewer breast and prostate cancers fewer ovarian colon cancers fewer hip fractures if they fall and 80% fewer heart attacks so there's a hint now the claw restriction will probably work in humans too okay so hopefully I've persuaded you that longevity and aging itself are both malleable what about the immune system is so I'm going to lead into now this is what I spend most of my time working so if you think about the role of the immune system it has to detect and kill pathogens it should be able to remove damage senescent or transformed cells it should react better on the second exposures that's the basis of immune memory and vaccinations and it should do all of this without damaging itself so what's the evidence that your immune system ages well if we look at bacterial infections so these are just data for c difficile and mrs a and i looked at the data from 2007 to 2010 and you can see particularly for c difficile really age-related increase in cases of c difficile not quite so marked for mrs a but still about a doubling of your chance of getting one of these hospital-acquired infections the older you are what about vaccinations these are some nice data from Birgit scuba club and stein in austria but it's it's true it's here is tetanus but it's pretty well true of all vaccinations so above this red line you've made enough tetanus antibody to protect you should you be exposed to tetanus and below it too you're less likely to be protected you can see immediately after the vaccination if you're 70 and younger then the chances are you'll make a protective response 70 and older chances are you won't but look here six to ten years later now it declines to 50 and younger you've still got enough antibody to be protected but 50 and older then you're less likely to be protected and in Austria they now recommend that tetanus should be boosted every 5 years and not every ten other evidence of immune memory declining of course is shingles so you're exposed to varicella-zoster when you're young is to have your chickenpox you develop immunity to it but it's not lifelong the older you get you lose your immunity and it Ria's a shingles so your immune memory also fades with age again I won't have to tell the audience that cancer if you think this clear as this immune surveillance role also compromised by age so most cancers profoundly age-related this is acute myeloid leukemia with strong age relationship but it's true of most cancers so that immune surveillance row immune system also declines what about this idea that you shouldn't harm yourself well this is rheumatoid arthritis and again incidents increases with age and several autoimmune diseases increase with age so that aspect of the immune system also compromised lastly is the aged immune system frail so is it just susceptibility to infection or is it more than that so hopefully they'll these data will precise way to do that it is frail so the vertical bars here are flu epidemics the Green Line is patients going to their GPS or the respiratory infection the blue line is hospitalization and the yellow line is death so if you're 45 to 64 years old the incidence is around 900 100,000 and the peaks of the flu epidemic but in this age group you're highly unlikely to end up hospitalized and you're certainly not going to die in that age group if you get the flu 65 to 74 years old now we've got an incidence of 1,100 100,000 so increased susceptibility as you get older now you might end up in hospital about 10 to 15 percent chance you'll end up in hospital but still a fairly low chance of you passing away from infection over 75 years old now we see a big difference oh but the instances now put 1,400 400,000 in the peaks of the infectious periods and this now is about a 30% chance you'll end up in hospital or passing away so your frail and your immune system is frail you're more susceptible to infections does a result of the infection got an increased chance of dying so why is this what are some of the mechanisms involved and I'll take you briefly through these so we look at immune memory what's going on there so to remind you the naive T cell is produced in the thymus when it meets its antigen sting proliferate like crazy then controls the infection either through cytolytic t-cells killing the virus infected cell or the production of antibody through b-cell helped majority of the cells then die by apoptosis but you retain some memory t-cells so that you've got then immune memory what happens with aging is that your famous atrophy is so this happens in humans from Burtie al happens about 3% per year so by the time you get to 70 years old you've only got about between 1 and 5 percent of the thymic output that you had as a 20 year old so you've got less naive T cells produced but your immune system keeps its lymphocyte numbers level so you undergo homeostatic proliferation so you increase the number of your memory T cells you also increase the naive T cells that are in the circulation as well but overall you get a change in your naive to memory ratio so you got more memory than naive T cells and if you think of this in evolutionary terms this makes perfect sense because what you've done is you have created a cassette a memory cassette to the pathogens that you will meet on a regular basis and as long as you live long enough to pass your genes on hey who cares what happens after that so it makes a lot of sense and you think well this is great then you know what's the problem but of course I probably don't have to tell you that your lymphocytes can't proliferate forever like most cells in the body they have telomeres and every time your cell replicates you lose 4 to 12 sorry 50 bases of your telomere and eventually the telomere is so short that you get then cell senescence lymphocytes are unusual they've actually got telomere so they can extend to telomeres but this doesn't last forever and this is shown here in data from our knee up bar at UCL so he looked at cd8 telomere length in young and old healthy subjects and you can see in the older patients subjects they had much shorter telomeres and when he looked at lymphoproliferative syndrome in younger patients they also had shorter telomeres so the more your T cells proliferate the longer your the shorter your telomeres are and this then affects the ability of the T cells to proliferate when it's exposed to the antigen that it was previously adapted to so to summarize that you've got less new T cells being generated you're acquiring senescent T cells which don't proliferate well at all and you're to homeostatic proliferation increasing you're naive and memory pool it gets even worse than that so you've got your memory t-cells they're not great at proliferating but these highly differentiated cells also lose a co-stimulatory molecules cd28 and you may remember that what normally happens in your immune system that you have to have two signals so you have peptide presented on MHC and then you need this co stimulatory signal and the antigen presenting cell is primed by a danger signal by exposure to a tissue injury marker or a pathogen and normally if that's missing then you get energy what happens in these highly differentiated T cells is that they begin to express natural killer cell receptors so things like KLR G 1 and K G 2d this allows them then to get the second signal from self cells from tissue damage markers so this means that you're more prone to autoimmune disease and we showed this in a study a few years ago so if you look and compare young and elderly healthy subjects and just look for rheumatoid factor so this is your ante IgG antibodies and these are increased in even in the healthy elderly and you find a whole range of Auto antibodies present in healthy elders and one of the reasons involved we looked at these regulatory cells that be regulatory cells and we find that their induction is much reduced with age and when you stimulate them either directly through ligating cd4 T with cd40 ligand then this is affected with age and when we looked into the reason behind it we find the defect there is largely there in the B Strep b-cell itself so the signaling through this molecule stat 3 is profoundly reduced in the older person's t-cells so your neutrophils so you're more prone to bacterial infections your immune memory phase and you're more prone to autoimmunity as we get older but what about this aspect what about the frailty so if I explained why you might be more susceptible to factions but why is the older patient more frail when they do get an infection so for this we really began to think about the innate immune system and we've focused a lot of our work on the neutrophils but I can talk about monocytes as well so to remind you these are the most abundant white cell to carry out their function they have to leave the the circulation Keamy taxed or the site of infection there they fight phagocytose the target and then they have a range of bacterial killing mechanisms they can generate reactive oxygen species intracellularly and kill intracellularly and we now know that they can also kill extracellular lee so they can release their nuclear DNA extracellularly this is then peppered with proteases and histones that help to immobilize the bacteria and may even in some cases kill the bacteria so what happens with age so this is my earliest foray into the world of immune aging so we showed early on that in response to e.coli even in healthy elders that the ability of the Faga site to uptake bacteria is reduced by about 50 percent so all of the neutrophils of the oldest subject can uptake ecoli they just eat about 50 percent less which is not great if you've got a bacteria reproducing every 20 minutes when we look at killing mechanisms so this is Net Generation so on the right - you see this is staining for DNA so the the bright rings here these are the neutrophils that haven't released their nets and the more diffuse staining is where they've released their nets and whether you stimulate with an artificial stimulus like PMA or CXC l8 their elderly donor neutrophils release less nests so their extracellular killing mechanism is also reduced why is this well this net generation requires reactive optional species to stimulate to trigger the whole process and so reactive oxygen species this intracellular mechanism is also reduced in the older adult so that helps to explain why perhaps the adult is more susceptible to infections as you get older but again what about this loyalty aspect so to remind you when your leukocytes move towards the site of infection what they do is they actually release proteases into the matrix and literally I think of them as burrowing through the tissue so we decided to analyze chemotaxis we to use this we do this thing called an insult chamber so you can place the neutrophils in one side of the chamber and the chemoattractant in the other and then using time-lapse video microscopy look at their migratory tracks and you can look at the overall speed chemo Kinesis the directional speed velocity persistence or how often they change direction and from that given overall chemotactic index and this is what it looks like for a young healthy subject so it starts here and ends here beautiful straight line the CXC l8 is at the top in your viewing here this is an older subject I don't think you have to be an expert immunologist to see that there's a problem here the targets at the top look this one's going backwards sideways they're changing they've lost their Sat Navs so this is a healthy elderly person so this is problematic and it's not just a chemokines when we expose the neutrophils to sputum from a patient in fact in pneumonia we see the same age related defect so when you've got quite a complex chemoattractant mixture the neutrophils still can't migrate really well from the older adults when does it start one sorry Robert Lee kicks in quite early so it begins actually a midlife but it's statistically significant by the time you get to your 60s and 70s so a true age-related effect and as I said while we think this is important it's because of this this is the vascular endothelial cell with the neutrophil there and they create this area of damage as they migrate through tissue through this release of neutrophil elastase and so we worked with some mathematicians to model what might happen and these models predicted that the rather rambling movements of the older person's neutrophils would cause about 40% more as they move through the tissues this would then be 40% more inflammation so we had to test this out so we worked with respiratory physiologist to figure this one out and they developed this assay for a peptide that's released when neutral elastase breaks down fibrinogen in the matrix and this peptide accumulates his serum so you can measure it quite easily and when we looked at our healthy old versus healthy young subjects it wasn't 40% higher but it's actually double so these neutrophils have causing the damage the whole whole time and this correlated very nicely with higher levels of systemic inflammation this is well recorded and old age even in healthy elders they have a higher level of systemic inflammation it's termed inflammation but you're probably thinking but yes but when they got pneumonia the neutrophil will be primed and they'll behave wonderfully no it actually gets even worse so my colleague Liz safety when we this is a comparison of the healthy young healthy young and the healthy old the chemotaxis but when you look at lower respiratory tract infections community-acquired pneumonia and sepsis with pneumonia actually it gets even worse in the older subjects and when you get an extreme situation like sepsis even the younger person's neutrals don't cope very well so at times infections the neutrophils have even lower chemotaxis and when you look at this this is data so now this is the data flap a little peptide that's released in a young patient with pneumonia versus an elderly patient it's now five times higher with much higher inflammation so we think this is the reason behind some of this frailty with old age okay so that's a little bit of what happens to immunity in old age what about this idea of how much of it might be related more to our lifestyles this is just to remind you that this increased longevity is a relatively recent phenomenon so until around 150 years ago the average life expectancy unless you were royalty was 30 to 40 years old the increase for royalty actually began around 1750 it's around 1850 that the rest of us started to live longer so relatively recent so if you think about this again in evolutionary terms how we really had chance to adapt to changes in lifestyle so how much of what we think of as aging is actually lifestyle food is much more readily available than when we were hunter-gatherers and we're a largely sedentary society so if you look at some of the data for the UK these are data for the males on the left and females on the right so these are the guys that are pretty sedentary these are the guys doing moderate activity and the dark blue are those meeting the chief medical officers recommendations for physical activity which is 150 minutes of aerobic exercise a week so in males it's around 55 percent of the over 65s am eating it so very low and ladies were even worse it's one to two percent so we get more inactive as we get older so how much of this might be driving some of the aging phenomenon well again a lot of epidemiological data suggests this might be the case so this is some beautiful data from Katy cause analysis of the epic cohorts so you can have a little tot up on your hands in the audience so you get one point if you're a nonce if you're a nonsmoker another point if you have moderate alcohol intake so one to 14 units a week another point if you meet the physical activity guidelines 150 exercise per week and another point if you have five portions of fruit and veggie day you can score all four we've got 14 years longer life expectancy so if you only score to try to get three when you got three try to get four okay so we want to test this out a little bit further so we want to address this idea of how much aging might be lifestyle related we decided to look in people who'd kept to what we would consider to be a good lifestyle highly active adults and we picked cyclists with cyclists because we reason that it's a good Arabic exercise they would also have good Bala so otherwise they'd be falling off the bike so you can't have runners like myself because we might have rubbish joints by the time we get to 50 years old so we thought they were pretty good to group to work with and like most people are keen on their exercise they're actually quite nerdy so they keep records of what they do so we could actually verify that these guys had been as active as they they say they claim to be because they all had cycling logs and so we had 125 cyclists 84 males and fortuyn females and we picked them at 55 to 79 years old so that the ladies are going through the menopause we were going to look at aging and to be in the study they had to have been able to cycle 100 kilometers in 6.5 hours for the males 60 kilometers in 5.5 for the females they have done that twice in the last three weeks so they were maintaining this activity so these are not Olympians but they're the guys out in lycra at the weekend that you'll see around the village lanes etc we got them into the lab so this we did this work in collaboration with kings steve heretick Kings I've had a full physiological phenotype and we took blood and muscle biopsy samples so it's just cross-section at the moment but we're going to do the five-year sampling next year what did we find so if you look they've got males here and females and we split them into five year breaks so if you look at things like body mass doesn't really change so we always think that when we get older we put weight on it didn't happen in these guys that won't surprise you percentage fat didn't increase again we all often say as you get old you increase your adiposity and your fat free mass the amount of muscle they had didn't decline with age and again probably won't surprise you these are active people but this idea that we lose muscles sarcopenia we put fat on I would argue that's a lifestyle related what about other things getting will often say that you increase your insulin resistance with age no the home I our value didn't change with these people at all so they maintain good metabolic health but it doesn't protect you against everything so vo2 max declined across the group's fev1 lung function decline and maximum heart rate declined so it can't protect you totally some things are intrinsic aging processes but what about immune aging so what I've told you so far might not surprise you but this certainly surprised us so find me count but I told you that thymic shrinks from puberty so we've got a measure here of thymic output this this PT k7 Marco is a marker on recent family Kemah grits and here's our healthy young these are some healthy old lisa that older people I've got no comorbidities but they're largely sedentary they're not meeting the physical activity guidelines are they're not involved in regular exercise and then our master cyclists it looks like they haven't undergone phonemic atrophy they've maintained their good farming output we look another marker trek copy when we're trying to figure out why this might happen we know that in humans they what happens the farmers act becomes infiltrated with fad and this certainly was an association with the amount of body fat that the cyclists had but not an association with the amount of cycling they did so they might maintain it because they're not getting this fatty infiltration but we think the much strongest signal is probably coming from cytokines so similar cytokines driving thermic atrophy are TNF and a lack of il7 so if you look in healthy young and healthy old we have this decline in Aisle seven with age and we get an increase in TNF this inflammation and what we find in our cyclists is they're maintained that you interleukin 7 levels and they don't increase their TNF so two of the signals that we affect farming atrophy are not seen in the cyclist this other one kgf is another marker that affects stomach atrophy but that didn't change anything else happening on so when we looked at regulatory b-cells again healthy young sedentary old and our master cyclists they also don't seem to have this drop in regulatory b-cells with age you also see an increase in th 17 ploy inflammatory t-cells and that didn't happen in our cyclist either so we think they've got probably a reduced propensity to have this inflammatory response and reduced of autoimmune disease as well but again it didn't protect against everything so markers of senescent t-cells still increased in our cyclists so it protects against some things but not others okay but can we turn the clock back what can we do about this how is all this knowledge going to take us forward and this is where I've done a lot of work with my clinical colleagues so I'm a basic scientist I'm not a clinician and to do a lot of the work that I'm now going to tell you about I've worked very closely with with clinicians so this is not our data but to show you that exercise might also be able to be an adjuvant in vaccination this is some data from the u.s. from Marion cahoots lab and what they did was they got older adults to go to air robux classes for three months before they had their vaccinations response and you can see that in the ones that did regular exercise they got a better vaccination response what about that caloric restriction it's probably never going to catch on as a lifestyle in any big way if you think of the current obesity crisis trying to get people to reduce their calorie intake by 25% is a big ask but a lot of the drug companies now are trying to make caloric restriction memetics we know how caloric restriction works the pathways that it hits so here's one of them rapamycin that you may recognize as an immune suppressant used a lot in transplantation and what you do with rapamycin it's one of these agents that can extend lifespan in several species including mice and what Novartis have done they've done a six-week trial giving rapamycin for six weeks to patients at different doses and they looked at their vaccine response and they get anything from a 20 to 30 percent increase at even low doses of rapamycin and this works by hitting the ant or pathway which is also an aging pathway probably again not going to catch on there are lots of side effects as you can imagine here but they are now working on rapper logs so analogs rapamycin that won't have the side effects also think about flagellants we know from the immune system when you analyze analyzed monocytes that one of the toll light receptors that detect pathogens and danger signals many of them are affected they're reduced in either their expression or their signaling but the one that isn't is toll receptor five tlr5 which recognizes flagellin and so this is a nice study published in vaccine where they've conjugated flagella into the h and one in then influenza vaccine and got a much better response if they include flagellin in the ancho vent which took a different approach again to this so again you're probably very familiar with that circadian biology is is one of the sexy topics at the moment and we know that your body works better at different times of the day and this includes your immune system we've done some studies looking at things like fire me count but with the time of day and knew that there were more naive t-cells in the morning so we did a very simple study vaccinating people either at the morning GP surgery or the afternoon GP surgery and then looking at the response and what we found is a very significant difference between the morning and the afternoon vaccination and what we're now doing funded by the MRC is seeing if this also works in Pneumovax so this is a T dependent vaccine but we're also seeing if it work in a t independent vaccine and we'll be starting that study in the autumn ok last little bit wonky neutrophils what can we do about those if they're so important we've got to get to the basis of this and again this is study work we've done with lists ap who is a respiratory physiologist we had to understand why they were wonky so neutrophil migration is very complex but one of these signaling pathways that's important for directional control is pi3 kinase so we wondered if the pi3 kinase signaling was defective in Beautiful's from older donors and so we did the study and at the top here is the phosphorylation of the p85 subunit of pi3 kinase which could be a marker it's activation control here and then exposed to different chemokines see a very this is within five minutes a very rapid activation of this pathway if you see in the old we see no activation of the pathway but for the alert people in the audience what you should spot is the differences that the control so the unstimulated neutrophils the pi3 kinase was already phosphorylated so we wondered well if we inhibit this kinase will we then correct the migration defect and sure enough that's what happened so neutrophils have four iceland's ands of pi3 kinase and if we took either a pi3 kinase delta or gamma inhibitor we could increase the chemotaxis response and the gate great thing is there are now pi3 kinase Delta inhibitors in clinical trial we're not actually following this we're using a differentially repurposing a drug that hits the same pathway to get the same effect okay so in summary so far for the sine side I hopefully I persuaded you that innate and adaptive immunity decline with age that lifelong physical activity protects against some of the aspects of aging but not all of them and the exercise of pharmacological approaches are being developed to improved immunity in old old age and in fact general health in old age so about some of the other stuff I was asked to talk about some of my career to date some of the things I thought I might have done differently so I like this definition of career that you can find a headlong progression usually downhill and usually out of control and that certainly describes the early phases of my career so I'd be honest you know what I loved in the early stage of my career I just loved being in the lab you know that was I didn't think about much else so the early stages I did my PhD had asked and I then returned to Oxford for my postdoc and actually worked in diabetes in the early and the early days there's no pressure you know you just went home at night you could think about the science but you were just a data generator you know the lab had got the money in for you he wrote the papers up together it was a great life and then reality struck I was 31 I'd done two postdocs I had a temporary lectureship at Birmingham I've been in three different De Palma's two different University side ping-ponged backwards between Oxford and Birmingham for several years I got a mortgage I was on a new yet another short-term contract I got a young child and no cunning plan so what did I do first thing it's actually the last thing I actually got a mentor or actually say my head of Department imposed himself upon me says Ian McLennan so Robert will know him and he was super and he gave me a real reality check he said Janet where's your five-year plan where are you heading I had to think did I want to stay in academia yes I did I decide I pretty well knew that but what did I have to do to achieve that how to make sure I was publishing good papers and luckily you know that wasn't the problem at the time I wasn't publishing okay I'd gained some teaching experience through that one year lectureship but I needed to up my national and international visibility so Ian really said any opportunity if you get a chance to review grants review papers be on a grants panel take it and that was really good advice so even quite early in my career I was actually asked by the BBSRC to be on one of their grants panels he said you've got to get a personal fellowship Janet you've got to search show that you can do it by yourself and survive and again I was fortunate I got a Royal Society fellowship that allowed me to set up my lab and they were great they really let you get on with things didn't pester you too much and it was a great experience working abroad is the one thing I didn't do that's my one regret and I think thing about you know life balance I should have done that earlier on because you know with the family it was then much harder so that's my one regret and the other than little months here and there I haven't had an extended period abroad I think getting the right location so when I returned to Birmingham from Oxford I'd originally only intended to be there for a year and that was 30 years ago and what's kept me there is that my research is is really what is now called translational research and I knew early on that's what I wanted to do as a basic scientist I wanted to be doing things that were close as I close I could get to patients and this is where I'm located now I'm in the new Queen Elizabeth Hospital which sees a million patients a year it's the largest hospital in Europe and we've actually got we're actually integrated into the hospital we've got basic labs here we've got our own clinical research facility so that we can literally translate from bench to bedside very quickly and the Institute is about half clinicians half basic scientists so we're interacting constantly and I think that's that's an important thing as well what about the other stuff what about my meds I live well hopefully you're all decided you're going to be academic clinicians anyway but it is a great life's lots of stresses there but some fun things too so you get to meet some famous people so the older members of the audience will recognize the Cliff Richard so he came and helped us with a lot of our fundraising so he's been great you get to be on the telly so I was on the telly last year with Angela Rippon in a program called how to stay young doing the thing called the sick to rise test and our head of college Dave Adams routinely comes up to me and just says 10 because that was the maximum score you could get he's very pleased that he got the maximum score but try to keep it balanced so keep your hobbies so I'm a keen runner I don't run as much as I used to so I haven't ruined marathon since 2010 but I still try and get old out as frequently as I can I live on the Trent Mersey canal so I try and get out in my boat where as often as I can as well keep other hobbies as well so these scouting so until two years ago I was are Cayla and had been on r-calif for almost 40 years so I'd done this since I was doing my GCSEs so I think it's good to keep that balance the only thing that stopped me was needing to get to the scout hooked every Wednesday at 8:30 so I could no longer do that but I still go out and help on the camps and things like that so try and keep a balance keep with fun in your life don't make it all work I think that is important and you can get involved in political campaigns even if they don't succeed so this is our effort to try to show that science really is something that flourishes when we work together and we don't have national and international boundaries imposed upon us so hopefully we'll try and keep that going and I think that might be it this is my wonderful team at John hazel Dean's wedding it really is teamwork and I think you'll all probably develop and be members of teams and I've enjoyed very much being involved in teams that are a real mixture of basic scientists and clinicians so Liz safety I couldn't have done any of my neutral work without her Marc Foster's who is a trauma surgeon he's actually a military trauma surgeon because permeance also they role Center for defense mode and so I do my trauma work with him Chris is a burn surgeon Daisy's a trainee at the moment she's doing a PhD with us Thomas Jackson is a geriatrician and the three people in yellow are the basic scientists who did the work so thank you for your attention [Applause]