at Bay! Janet M Lord BSc PhD MRC-ARUK Centre for Musculoskeletal - PowerPoint PPT Presentation

Healthy Ageing: Keeping Frailty at Bay! Janet M Lord BSc PhD MRC-ARUK Centre for Musculoskeletal Ageing Research This event has been organised by Sanofi Pasteur MSD and Shropshire Council. Sanofi Pasteur MSD has provided funding, speakers, a buffet lunch and reviewed the presentations and content of the event. UK17388g(1) 11/14

The Ageing population UK Statistics Between 1984-2009 :  Number of individuals aged ≥65 years increased by 1.7 million  Number of individuals aged ≥85 years more than doubled to 1.4 million By 2034:  23% of population ≥65 years  5% of population ≥85 years National Statistics online, June 2010 UK17388g (1) 11/14

House of Lords Report: Ageing: Scientific Aspects. July 2005 UK17388g (1) 11/14

Just 8 stops on the cross city line increases life expectancy by 9 years! UK17388g (1) 11/14

Ageing = Increasing frailty of an organism with time that reduces the ability to deal with stress, resulting in increased chance of disease and death. UK17388g (1) 11/14

Cancer Cancer Research CVD Heart Disease Research Ageing Alzheimers Alzheimers Research Arthritis Arthritis Research Hearing Loss Deafness Research Blindness Vision loss Research UK17388g (1) 11/14

yeast C. elegans rhesus Caloric Restriction rat Daphnia mouse Drosophila medfly UK17388g (1) 11/14

Control CR Reduced cancer, CVD, diabetes, neurodegeneration UK17388g (1) 11/14 Colman RJ et al Science 2009

CR in humans: Okinawan Japanese • Highest fraction of centenarians in the world (18.5 per 100,000 population, C.f. 4.5, Japan as a whole) • Eat less calories Kids: 60% of recommended calories Adults: 80% of recommended calories UK17388g (1) 11/14

UK17388g (1) 11/14 Okinawan Japanese Okinawans, compared to Americans: • 75% more likely to retain cognitive ability • Get 80% fewer breast and prostate cancers • Get 50% fewer ovarian and colon cancers • Have 20% fewer hip fractures • Have 80% fewer heart attacks • Have high DHEA levels • No data on immunity, but caloric restriction improves immunity in many species including primates See www.okicent.org

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Only person verified to have  lived beyond 120 Took up fencing at 85, rode  her bike daily till 100 Lived independently till 114  Smoked until she was 117 (2  per day) Had a glass of port every day  and ate 1kg of chocolate per week! Put her long life down to  eating lots of olive oil and rubbing it on her skin every day! Mme Jeanne-Louise Calment 1875-1997 UK17388g (1) 11/14

Assess the relationship between lifestyle factors, health and mortality cross-sectionally and longitudinally in elderly individuals 1. Baseline a) 2621 babies measured between 1920-1930 2. Follow-Up 1 a) 717 individuals measured in 1994 b) Aged 63-73 years old 3. Follow-Up 2 a) 294 Individuals measured in 2004 b) Aged 72-83 years old c) Of the 717 at 1 st follow-up 122 died UK17388g (1) 11/14 Syddall HE et al Int J Epidemiol 2010

10 15 10 *** *** A C E 8 8 IFN-  (pg . ml -1 ) IL-10 (pg . ml -1 ) IL-6 (pg . ml -1 ) 10 6 6 4 4 5 2 2 0 0 0 Baseline Follow-up Baseline Follow-up Baseline Follow-up *** * 30 6000 B D TNF-  (pg . ml -1 ) CRP (ng . ml -1 ) 20 4000 10 2000 0 0 Baseline Follow-up Baseline Follow-up Bartlett D et al Aging Cell 2012 UK17388g (1) 11/14

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 Chronic inflammatory disease is associated with increased muscle atrophy – COPD, Rheumatoid Arthritis  Inflammatory cytokines promote muscle loss, e.g. Cancer cachexia and sepsis  Induction of muscle loss by pro-inflammatory cytokines via several mechanisms:  Activation of catabolic pathways: Muscle specific E3 ligases (atrogenes MAFBX, MurF1), calpains  Inhibition of myocyte differentiation (myostatin) UK17388g (1) 11/14

Not Climbing Slow Walking Regular Car Travel Smoking Stairs (1.7 times risk) (1.6 times risk) (2.5 times risk) (4.5 times risk) Inflammageing UK17388g (1) 11/14 Bartlett D et al (unpublished data)

5 VO 2 max; n=49, 60-77 yrs Physical activity, n=189; 60-80 yrs 7 r (187)=-.183, p =.006 6 4 r (187)=-.183, p =.006 5 CRP (mg/L) CRP (mg/L) 3 4 3 2 P<0.008 * 2 P<0.001 1 * 1 0 0 0 200 400 600 800 1000 1200 1400 Sedentary Moderate Trained Steps/Hour Physical Activity Status Bartlett D unpublished data UK17388g (1) 11/14

 40 subjects (21-60 yrs) 4.5  HIIT for 10 wks (3 x 4 per week) 3.5 3  Reduced IL6 (p=0.03, Cytokine (pg/ml) 2.5 CRP (p = 0.028), 2 Leptin (p=0.04) 1.5 1 0.5 0 C HIIT C HIIT 1 2 3 CRP IL6 Bartlett D unpublished data UK17388g (1) 11/14

Physical inactivity causes  6% of all deaths from the major non-communicable diseases (coronary heart disease, type 2 Diabetes, and breast/ colon cancers) Inactivity causes  approximately 3·2 million deaths worldwide each year 43% of men and 20% of  women aged 75-84 meet activity guidelines (less than 10% in >85s). 1. WHO factsheet no 385 Physical Activity 2. Scholes and Mindell. HSE 2012 vol 1, UK17388g (1) 11/14 ch 2 Physical activity in adults.

Effects of 2-week reduction in ambulatory activity (8,000-1500 steps per day) in otherwise healthy individuals Parameter Pre-intervention Post-intervention Mean SEM Mean SEM P Value VO 2max , ml·min −1 ·kg − 1 48 1.3 45 1 <0.01 Total body mass, kg 71 1.9 70 2 <0.001 Leg lean mass, kg 19 0.5 18 0.5 <0.001 This effect was twice as great in older adults J Appl Physiol. 2010 May;108(5):1034-40 UK17388g (1) 11/14

 Chemotaxis  Phagocytosis  Bacterial killing: ROS generation NET generation UK17388g (1) 11/14

UK17388g (1) 11/14 C. Difficile MRSA April 2007-June 2010 April 2007-June 2010 3000 90000 80000 2500 70000 Total cases 60000 2000 Total cases 50000 1500 40000 1000 30000 20000 500 10000 0 0 Under 64 65-75 over 75 Under 64 65-75 over 75 UK17388g 08/14

 Speed (Chemokinesis)  Velocity (Chemotaxis)  Persistence (changes in direction)  Chemotactic Index (accuracy) UK17388g (1) 11/14

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UK17388g (1) 11/14

Chemokinesis and chemotaxis towards IL-8 4 3.5 3 2.5  m/min Age < 35 2 Age > 65 1.5 1 * 0.5 0 Chemokinesis Chemotaxis UK17388g (1) 11/14 Sapey E et al 2014 Blood

* ** * * UK17388g (1) 11/14 Sapey E et al 2014 Blood

Area of tissue damage 1.3  m UK17388g (1) 11/14 Burns et al, Physiol Rev (2003)

Young Elderly Elderly neutrophils cause 40% more tissue damage during migration. Sapey E et al unpublished data UK17388g (1) 11/14

25 P<0.006 20 NE activity (AaVal360 nM) 15 10 5 0 Old Young 1 2 TNF (nM) 1.6 0.56 p<0.03 hsCRP (mg/dl) 3.4 1.1 p<0.01 UK17388g (1) 11/14 Sapey E et al 2014 Blood

UK17388g (1) 11/14 Young subjects Older subjects N 5 5 Age 27 (24 – 32) 79 (75 – 86) Bacteria cultured Streptococcus pneumoniae 5 5 6 x 10 9 cfu/ml 8 x 10 9 cfu/ml Median bacterial load (3.6 – 7.8) (4.8 – 9.8) * Median sputum mediator concentrations CXCL1 16.7 nM (6 - 30) 20.1nM (3 – 30) CXCL8 33.9 nM (17 - 46) 60.0 nM (43 - 64) * 47.3 nM (14 - 72) 74.1nM (18 - 84) TNFa 15.6 pM (10 – 28) 40.3pM (24 – 51) * IL-1b 17.2pM ( 9 - 22) 40.1pM (22 - 63) * Sputum absolute neutrophil counts 15 x 10 6 /ml (11 – 25) 23 x 10 6 /ml (14 – 30) $ Median plasma CRP mg/dl (21 – 98) 102 mg/dl (52 – 139) * Blood absolute neutrophil counts 16.9 x 10 6 /ml (12 – 23) 17.1 x 10 6 /ml (11 – 24) NE activity (A α Val360) 85.5 ± 16.2 nM 411.8 ± 97.1 nM ** Chemokinesis towards sputum 5.1 + 0.5 4.6 +0.3 Chemotaxis towards sputum 2.2 + 0.2 0.5 + 0.1 ** Accuracy of movement 0.47 + 0.03 0.09 + 0.02 ** Sapey E et al unpublished data

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UK17388g (1) 11/14 King and Insall 2008

Young Old c Pp85 Pp85 c β -actin β -actin UK17388g (1) 11/14 Sapey E et al 2014 Blood

2.5 Chemotaxis (um/min) 2 1.5 1 0.5 0 Age < 35 Age > 65 65 + LY294002 65 + Simvastatin UK17388g (1) 11/14 Sapey E et al 2014 Blood

UK17388g (1) 11/14 Accuracy of µm/min movement Accuracy of µm/min movement Sapey E et al 2014 Blood

King and Insall 2008 UK17388g (1) 11/14

UK17388g (1) 11/14

Chemotaxis Accuracy Chemokinesis UK17388g (1) 11/14 Sapey E unpublished data

 20 healthy volunteers aged over 65 (mean 71.3; range 65-93)  2 weeks 80mg daily Simvastatin or placebo  1 month washout  2 weeks 80mg daily Simvastatin or placebo UK17388g (1) 11/14 Sapey E unpublished data