The surprising truth about exercise (and ageing)

Professor James A Timmons PhD CSO, XRGenomics LTD Chair Systems Biology, Lougborough

© Thomas Jensen

Disclosures & conflicts of interest

My research has been funded by: Public: MRC & BBSRC (UK), EU (Metapredict) & NIH (USA) Private: Gatorade (GSSI), Wyeth Inc I have consulted for Pepsico Inc on personalizing nutrition in sport (During 2012-2013) I am a Director at XRgenomics LTD, a personalized medicine company

What does exercise do for you?

The surprising truth about exercise (& ageing) "Our understanding of the relationship between exercise and human health is evolving rapidly.

There have been many surprises in recent years and our current public health recommendations are outdated.

I will explore the striking revelation that following these exercise guidelines can produce adverse health responses.

I will conclude that the only way forward is to personalise life-style advice and discuss how far we have progressed towards that goal .”

What is a Healthy Life-style?

    

Don’t smoke Maintenance of body mass appropriate for height - BMI 23-27 ?

Regular ‘ exercise ’ (150 min aerobic/wk) ?

Eat a low fat diet, high in plant foods ?

Moderate alcohol intake ?

Where does our public health evidence come from, and what behavior-change will YOU benefit most from ?

The SMALL print: These conclusions are statistical estimates from EPIC, NHANES, CaPS ….

Epidemiology & the misuse of the term prediction

  

Exercise capacity correlates with health outcomes People who report being more active, have better health You adjust the correlation for factors you know about….

These are not ‘predictions’ – they are correlations and this is the weakest form of ‘evidence based medicine’

Epidemiological evidence is the start of research not the end No-matter how large the study is, or how often an association is reproduced, the correlative data does not prove that if you take an individual, intervene to change the behaviour (biomarker) that this will benefit them Eating chocolate makes it more likely that you, as a nation, will win a Nobel prize

Over-view of talk



The long-term impact of 150min of exercise/wk on human health



Impact of exercise on risk factors modification



What format of exercise works?



Life-style modification for:



Type II Diabetes



Cardiovascular disease



Personalized approaches to exercise and ageing

What the ‘experts’ tell the public about exercise

“For aerobic exercise to be beneficial it must raise your heart-beat and make you sweat ” “Do a minimum of 150 min/week of moderate-intensity aerobic exercise + strength training” “If you can go beyond 150 minutes, you’ll gain even more health benefits”

Is this advice based on solid science ?

Does this advice actually work ?

http://www.nhs.uk/Livewell/fitness/Pages/physical-activity-guidelines-for adults.aspx

The surprising truth about exercise (& ageing)

There are NO long-term (10yr+)

exercise-only

intervention studies in humans

6kw 1yr of exercise modifies “risk factors”

Risk-factor Increase aerobic capacity (80% of people) Proposed benefit



All-cause mortality?



Type II diabetes Improve insulin action (65% of people) Reduce blood pressure (50% of people) Increase good cholesterol (70% of people)



Stroke



Vascular disease Promote muscle/bone mass (70% of people)



‘Ageing’, fractures How do these factors respond after 150min/wk exercise for 12-20wks ?

12-20 weeks of 150 min exercise training per week Each person responds to exercise in a unique way Systolic BP Insulin SENSITIVITY AEROBIC MUSCLE MASS In multiple supervised intervention trials, between 5-20% of subjects had a substantial increase in resting blood pressure – i.e. an adverse response Kraus et al plos one 2012; Timmons et al JAP 2010; Philips et al PLoS Genetics 2013

Our survey says: You need to do 150min…..

Question:

Have epidemiologists confused the poor sensitivity of their methods, with the real requirements for exercise to change health biomarkers?

Can we achieve the same responses in 1/50 th of the time?

http://www.nhs.uk/Livewell/fitness/Pages/physical-activity-guidelines-for adults.aspx

HIT: Roll up & behold the magic exercise regimes… Intensity Equipment cost Year Protocol 2007 2012 <3 min <9 min <15 min 2014 6x 30sec @MAX 2 x 20sec @MAX 4x 1min @ 110% of VO2-max work-load

$$$$$ $$$$$ $$

Gibala et al 2007, Timmons et al 2009, Vollaard et al 2011; Metapredict consortium 2014

Impact of MAX HIT on INSULIN in sedentary younger people 15 min/wk 100 75 50 25 0 0 Pre Post 30 60 90 120 3 min/wk In sedentary young people ‘15min’ or ‘3min’ HIT is MORE effective than ‘150min’ training for improving insulin action Timmons/Vollaard et al 2009, Vollaard 2012

10x1min @vo2max HIT – Sedentary or Diabetic subjects ‘2009’ HIT is MORE effective than classic training for improving HOMA index in sedentary overweight or diabetic middle-aged people Little et al 2011 and Earnest et al 2012

EU FP7 Metapredict trial – aerobic fitness in middle-aged over-weight sedentary subjects

100 min 9 min Kettle+Cycle+Coffee Change+Cycle+Shower+Eat 6 weeks 4x1min @110% Vo2max load 1400 1200 1000 800 600 400 200 0 -200 -400 N=130 Mean response: +259 mL O 2 , SD=244 Baseline with response: R 2 =0.014

10% gains p<0.001

Test-retest <4%

20 weeks 3x50min @75% Vo2max ~HIT 10x more time-efficient but still we get non-responders

The surprising truth about exercise (& ageing) Exercise intervention studies in humans can change risk biomarkers and this can be achieved with as little as 3min of max exercise a week (no sweat) HIT is self-adapting to each individuals change in maximum capacity but 20% of people are still non responders

Over-view of talk



The long-term impact of 150min of exercise/wk on human health



Impact of exercise on risk factors modification



What format of exercise works?



Life-style modification for:



Type II Diabetes



Cardiovascular disease



Personalized approaches to exercise and ageing

Careful you might catch diabetes Diabetes UK provide patient and public literature “Once you have diabetes, you have it for life” !! “You get a free pedometer” !!

Life-style interventions reduce Type II diabetes DPP Improved life-style is better than drugs for reducing risk of developing diabetes 10yr Finnish DPS reduced appearance of diabetes by ~50% 10yr LookAhead improved risk factors and increased remission from Type II diabetes

Life-style interventions do not reduce CV disease 522 people, 4yrs life-style intervention that reduced diabetes – 10yrs later NO NUMERICAL benefit for CVD risk 5,145 people, NO NUMERICAL improvement in heart-attack, angina or stroke by 11yrs FUNDING STOPPED https://www.lookaheadtrial.org/public/home.cfm

The surprising truth about exercise (& ageing) Life-style modification in middle-aged people does not reduce cardio-macrovascular disease (but for many, it reduces risk of “catching” Type II Diabetes) Is this failure due to the one-size-fits-all approach to life-style modification or epidemiological ‘predictions’ ?

Over-view of talk



The long-term impact of 150min of exercise/wk on human health



Impact of exercise on risk factors modification



What format of exercise works?



Life-style modification for:



Type II Diabetes



Cardiovascular disease



Predicting response to exercise and ageing

Personalize advice to get better outcomes?

Performance (variance+ sensitivity+ specificity) 30-200 RNA*

FDA/EMA approved technology platforms for RNA/DNA chips

20-200 DNA SNP assay 1 SNP Blood Metabolites

* Note that multi-RNA models are developed as single units (with high explanatory power and thus low sample size requirements)

Affymetrix RNA chips: measuring the ‘activity’ of the genome

* * * *

11 µm 11 µm

Millions of identical probes / feature

A typical study: Predicting fitness changes in humans 6-week traditional training (100% supervised, 100% compliance) Single small muscle biopsy and blood sample Baseline determinations of fitness (VO2max) – test-retest <5% 20-200 subjects cycled 4 days/week (45min@ 72% of aerobic capacity) Genomic, biochemical and physiology sub-max and max measures >1200 subjects complete with various interventions Predict the ‘low’ responders from pre-intervention RNA Timmons et al 2005 FASEB J and Keller et al 2011 JAP

Linear classifier predicts gains in aerobic fitness to traditional training Muscle RNA signature (n=24, r2=0.76, p<0.00001) Group 2 (young, athletic) R2=0.6, p<0.0001

Group 3 (diabetics) R2=0.54, p=0.009

% increase in aerobic fitness

   

Baseline fitness does not correlate with gains (r2=0.04) Diagnostic baseline RNA profile correlates with gains (r2=0.76) Model further improved by adjusting for gender/age Apply to independent prospective trials – predictions!

Timmons et al US09/56057 2009

$20M exercise interventions project 2011-2016 DUKE N=334 DERBY/MAC N=200 mRNA/DNA profile MAAST N=180

www.metapredict.eu

and www.xrgenomics.co.uk

Prediction of fitness response – why bother ?



HF ACTION - randomised multi-center trial (n=2331)



NYHA II-IV Heart failure with optimal pharmacological therapy



Exercise rehabilitation + usual care? – NOT WORTH IT; VERY EXPENSIVE



Patients at DUKE training response was established (n=1620)e.g. 1/3 rd >6% gain



Does exercise rehabilitation + usual care help? – YES, FOR SOME PATIENTS WORSE BETTER

Over-view of talk



The long-term impact of 150min of exercise/wk on human health



Impact of exercise on risk factors modification



What format of exercise works?



Life-style modification for:



Type II Diabetes



Cardiovascular disease



Predicting response to exercise and ageing

Choices for a long and healthy life?

Common sense?

Non-sense?

Discovery of molecular diagnostic of human ageing



We all appear to “age” at different rates i.e. Chronological age ≠ Biological age



Very few DNA variants discovered that explain human ageing Perl et al (GWAS) – overall <10 genes replicated



Can we take same approach as we did with fitness and use RNA analysis to produce a predictor of human ageing?

Building a diagnostic for healthy tissue ageing Cross-sectional – discovery Healthy

Young (25y) Human muscle

Classification Healthy

Old (65y) Human muscle

Key - Physiologically phenotyped drug-free snap-frozen human clinical samples – not biobank ‘junk’ ‘RNA’ Gene-chips

Longitudinal 20y follow-up application

1992

Rank by RNA score

2012

Medical Status

Q. Is the induction of this signature beneficial ?

STEP 1: Build the first accurate healthy muscle ‘ageing’ signature We use 146 RNAs (0.7%) and can muscle diagnose age with 93% accuracy None of the RNAs are regulated by exercise or common disease (database of >5000 RNAs) % 100 90 90 (n=300 subjects) 100 96 87 96 80 70 85 60 50 C LA S S IF IE R T R A IN IN G * C A M P B E LL ¥ D E R B Y H O FF M A N TR A P P E K R A U S Does this diagnostic work in other tissues?

Kazmi et al 2014 under review

STEP 2: Demonstrate biological ‘ageing’ signature works in brain

Fig 2

The muscle age RNA signature distinguishes young from old human brain with up to 91% accuracy

We can also diagnose age in skin, kidney….

100 90 80 70 93 81 91 84 72 84 60 50 MU SC LE BR AI N* SU PE R IO R F G YR U S PO ST C EN TR A L G TO R H IN A L C O R TE X EN H IP PO C A MP U S Post mortem ‘healthy’ human brain (n=200)

By 60yr, a person can biologically be < ‘50y’ or > ‘70y’! Kazmi et al 2014 under review; Philips et al Plos Genetics 2013

Is the 146 RNA tissue age diagnostic, prognostic ?

146 AGE genes ULSAM 20y Longitudinal study

1990

Median Rank score

2011

Medical Status



Subject ranked 1 st ( low median gene score) - had failed activate the ‘age’ program to



Subject ranked 108 th ( high activated the ‘age’ program median gene score) - had strongly



Renal function, physical status and mortality at follow-up?

Kazmi et al 2014 under review

Indication of prognostic potential in 20y study Induction of the ‘age signature ’ = lower risk of death over 20y period (p=0.05, n=108) Induction of the ‘age signature’ = better renal function(p=0.0092, n=108) Age signature predicts health outcomes in ULSAM but is not related to physical activity

Does exercise alter the Age gene network ?

20wks Resistance training 10wk Endurance training

Exercise does nothing to the biological ageing signature

Genes coloured RED= up-regulated and Genes coloured BLUE= down-regulated

Prediction of biological ageing – why bother ?

Actual Demand for Renal transplant 

A 60yr can have a profile = to <50yr or >70yrs !



Older, Expanded Criteria Donor kidneys accounted for 53% of donors in 2011



A highly accurate determination of organ biological age can expand the donor pool or improve outcomes

Arnau et al 2012, Gomez etal 2012; Gingell et al 2013

The surprising truth about exercise (& ageing) There is a common age signature across all human organs – a 60yr person has a wide biological age and exercise does not directly modulate this age-signature Kazmi et al 2014 under review

Summary: the surprising truth about exercise (& ageing)



All types of exercise yield non and adverse responders



You can modify diabetes risk factors with 3 min of HIT per week and your diabetes risk over 10yrs with life-style changes



Public health guidelines for ‘exercise’ don’t work (time), are misleading (out-dated) and potentially unethical (adverse responders; carbon footprint)



Personalise medical advice is required to deliver genuine evidence-based health-care to the individual

Most good ideas are old ideas…

Caleb Parry

(1755-1822)

“

It is much more important to know what kind of

patient

has a disease, than to know what kind of

disease

a patient has

”

Acknowledgments

Timmons Lab Iain Gallagher Valentina Gburcik Hannah Crossland Nabila Kazmi Kristian Wennmalm Sanjana Sood Pernille Keller Asif Nakhuda Dr Michael Moseley et al Collaborators Stuart Phillips (McMaster) Lauren Koch (Uni Michigan) Steve Britton (Uni Michigan) Thomas Gustafsson (Karolinska) Steen Knudsen (Medical Prognosis Institute) Phil Atherton (Derby) Bethan Phillips (Derby) Niels Vollaard (Bath) Claes Wahlestedt (Florida) Bill Kraus (Duke) Ola Larsson (Karolinska) Olav Rooyackers (Karolinska)

Impact of 6 weeks of 15min MAX HIT on VASCULAR regulation ‘15min’ HIT is equally effective as classic training for improving vascular function in young healthy people MacDonald et al 2008

Predictor RNA’s are not activated by exercise but regulate blood vessel growth genes

Pre-training Post-training 200% 150% 100% 50% 0% SV SL I L C 22 A3 /O C T3 N R P2 ER BB 4 TT N H1 9 ID 3 MI PE P C PV L D EP D

Muscle RNA profile

C 6 BT AF 1 D IS 3 L Ne t

80 connections Ingenuity Systems

Timmons et al PCT/US09/56057 & Keller et al JAP 2011

Out-bred artificial rodent model for ‘trainability’

After 15 generations of selective out-breeding, low and high responder families for gains in aerobic fitness are created Just like humans, if you are a non responder rat for gains in aerobic fitness you can’t grow blood vessels very well

Koch, Lessard, Goodyear, Timmons, et al Diabetes J 2013