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

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

Jun 18, 2023 287 likes •814 views

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

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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

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The Ageing population

UK Statistics  Number of individuals aged ≥65 years increased by 1.7 million  Number of individuals aged ≥85 years more than doubled to 1.4 million Between 1984-2009: By 2034:  23% of population ≥65 years  5% of population ≥85 years

National Statistics online, June 2010 UK17388g (1) 11/14

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House of Lords Report: Ageing: Scientific Aspects. July 2005

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Just 8 stops on the cross city line increases life expectancy by 9 years!

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Ageing = Increasing frailty of an organism with time that reduces the ability to deal with stress, resulting in increased chance of disease and death.

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Ageing

Cancer CVD Alzheimers Arthritis Hearing Loss Blindness Cancer Research Heart Disease Research Alzheimers Research Arthritis Research Deafness Research Vision loss Research

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Caloric Restriction

rat medfly yeast rhesus

  • C. elegans

Drosophila Daphnia mouse

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Reduced cancer, CVD, diabetes, neurodegeneration

Control CR

Colman RJ et al Science 2009

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  • 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

CR in humans: Okinawan Japanese

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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

Okinawan Japanese

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

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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 1st follow-up 122 died Syddall HE et al Int J Epidemiol 2010

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A B C D

Baseline Follow-up 2 4 6 8 10

***

IL-6 (pg.ml-1)

E

Baseline Follow-up 2 4 6 8 10

***

IL-10 (pg.ml-1)

Baseline Follow-up 10 20 30

***

TNF- (pg.ml-1)

Baseline Follow-up 5 10 15

IFN- (pg.ml-1)

Baseline Follow-up 2000 4000 6000

*

CRP (ng.ml-1)

Bartlett D et al Aging Cell 2012

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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)

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Inflammageing Slow Walking

(1.7 times risk)

Regular Car Travel

(1.6 times risk)

Not Climbing Stairs

(4.5 times risk)

Smoking

(2.5 times risk)

Bartlett D et al (unpublished data)

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1 2 3 4 5 Sedentary Moderate Trained Physical Activity Status CRP (mg/L) * * 1 2 3 4 5 6 7 200 400 600 800 1000 1200 1400 CRP (mg/L) Steps/Hour r (187)=-.183, p=.006

VO2max; n=49, 60-77 yrs Physical activity, n=189; 60-80 yrs

r (187)=-.183, p=.006

P<0.008 P<0.001

Bartlett D unpublished data

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 40 subjects (21-60 yrs)  HIIT for 10 wks (3 x

per week)

 Reduced IL6 (p=0.03,

CRP (p = 0.028), Leptin (p=0.04)

0.5 1 1.5 2 2.5 3 3.5 4 4.5 1 2 3 Cytokine (pg/ml)

C HIIT C HIIT

CRP IL6 Bartlett D unpublished data

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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,

ch 2 Physical activity in adults.

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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 VO2max, 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

J Appl Physiol. 2010 May;108(5):1034-40

This effect was twice as great in older adults

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 Chemotaxis  Phagocytosis  Bacterial killing:

ROS generation NET generation

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10000 20000 30000 40000 50000 60000 70000 80000 90000

Total cases

Under 64 65-75 over 75 500 1000 1500 2000 2500 3000 Total cases Under 64 65-75 over 75

April 2007-June 2010 April 2007-June 2010

  • C. Difficile MRSA

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 Speed (Chemokinesis)  Velocity (Chemotaxis)  Persistence (changes in

direction)

 Chemotactic Index

(accuracy)

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Chemokinesis and chemotaxis towards IL-8

0.5 1 1.5 2 2.5 3 3.5 4 Chemokinesis Chemotaxis m/min Age < 35 Age > 65 *

Sapey E et al 2014 Blood

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* ** * * Sapey E et al 2014 Blood

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Burns et al, Physiol Rev (2003) Area of tissue damage 1.3m

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Elderly neutrophils cause 40% more tissue damage during migration.

Young Elderly Sapey E et al unpublished data

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5 10 15 20 25 1 2 NE activity (AaVal360 nM)

P<0.006 Old Young TNF (nM) 1.6 0.56 p<0.03 hsCRP (mg/dl) 3.4 1.1 p<0.01 Sapey E et al 2014 Blood

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Young subjects Older subjects N Age 5 27 (24 – 32) 5 79 (75 – 86) Bacteria cultured Streptococcus pneumoniae 5 5 Median bacterial load 6 x 109 cfu/ml (3.6 – 7.8) 8 x 109 cfu/ml (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 Median plasma CRP 15 x 10 6/ml (11 – 25) mg/dl (21 – 98) 23 x 106/ml (14 – 30)$ 102 mg/dl (52 – 139) * Blood absolute neutrophil counts 16.9 x 106/ml (12 – 23) 17.1 x 106/ml (11 – 24) NE activity (AαVal360) 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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King and Insall 2008

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Young Pp85 c β-actin Old Pp85 β-actin c Sapey E et al 2014 Blood

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0.5 1 1.5 2 2.5 Age < 35 Age > 65 65 + LY294002 65 + Simvastatin

Chemotaxis (um/min)

Sapey E et al 2014 Blood

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Accuracy of movement Accuracy of movement µm/min µm/min

Sapey E et al 2014 Blood

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King and Insall 2008

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Chemotaxis Accuracy Chemokinesis

Sapey E unpublished data

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 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 Sapey E unpublished data

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0.5 1 1.5 2 2.5

Baseline Statins Baseline Statins Baseline Statins Negative control IL8 fMLP

um/min Chemotaxis with Simvastatin 80mg PO 2/52

* p = 0.001 * p=0.02 Bartlett D unpublished data

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Hainz et al (2005)

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Old Young

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Baseline 1-month 6-month B/Malaysia Mean antibody titre

100 200 300 400 500 600

Caregivers Controls

Gallagher S et al 2008

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* * *

Bereavement Life Events Subscale

bereaved not bereaved

Change in Logged Antibody Titer at 1 Month

0.0 0.1 0.2 0.3 0.4

A/Panama B/Shangdong

*

Phillips AC et al 2006

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Kohut ML et al (2004) 10 months regular aerobics classes

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Kohut M et al (2005)

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H1N1 H3N2 Ranadive SM et al (2014) Exercise – 40 min aerobics at 55-60% VO2max prior to vaccination

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 Systemic Inflammation increases with age  Inflammageing contributes to musculoskeletal

decline and frailty

 Many factors influence inflammageing including low

physical activity and immune ageing

 Extended periods of inactivity contribute to physical

frailty, though how little is detrimental is unknown

 Increased physical activity and statin use decrease

inflammaging and improve neutrophil function

 Stressed older adults have reduced vaccination

responses

 Exercise improves vaccination response

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Art is me, Science is we!

Jon Hazeldine Liz Sapey Hannah Greenwood Steve Butcher Niharika Duggal Rob Insall Georgia Walton Richard Carter Hema Chahal David Bartlett

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