Ageing, Frailty and Sarcopenia

1. Taipei Veterans General HospitalGeriatric Fellows updateAugust 29-31st 2010 Ageing, Frailty and Sarcopenia Dr Finbarr C Martin Consultant Geriatrician Guys and St Thomas’ Hospital and Kings College London

2. It’s a new thing for most people to die old Humans 2010 % survival 1850 wild rectangularisation Time since birth maximum lifespan This change is not due to evolution

3. Ageing and Mortality - The Disposable Soma Theory • We are not “programmed” to die • We are “programmed” to survive but for effective reproduction did not need this to be ….. for ever • During life there is accumulation of changes resulting from biological activity which compromise cell function • These did not “need” to be evolved out and were not subject to evolutionary pressure • They are therefore common and numerous by the time most people die

4. This results in healthy life expectancy lagging behind longevity Life expectancy and healthy life expectancy at 65, England This means: longer periods of ill health more need of social and healthcare

5. But people are different • “usual” older people are heterogenous re • sensory impairments • physiological ‘abnormalities’ eg lung function • metabolic changes eg glucose impairment • psychosocial factors eg. cognition, engagement • but also Social engagement, income etc • And many of the changes are reversible/preventable.

6. Human Aging: Usual and SuccessfulRowe JW and Khan RL. Science 1987 Research in aging has emphasized average age related losses and neglected the substantial heterogeneity of older persons. The effects of the aging process itself have been exaggerated, and the modifying effects of diet, exercise, personal habits, and psychosocial factors underestimated. Within the category of normal aging, a distinction can be made between usual aging, in which extrinsic factors heighten The effects of aging alone, and successful aging, in which Extrinsic factors play a neutral or positive role.

7. Differences through the lifespan Genetics and maternal factors Lifestyle etc Events and illnesses Ageing impairments Specific diseases References from Davey-Smith, David Blane, Diane Kuh and others

8. The WHO ICF model of health and functioning Ageing Disease Impairments Activity / Capacity Reduced Participation/Handicap

9. Functional reserve and thresholds Impairment eg. muscle strength reserve threshold 30 Age (time) 80

10. Development of the WHO model Ageing Disease Impairments frailtythreshold Activity / Capacity Disuse etc Reduced Participation/Handicap

11. Lets look at the transitions involved (based on the WHO ICF model) Usual ageing Disease Lifestyle Impairments Capacity Dependency Events cause loss of physiological or psychosocial reserve leading to step change in function Social Role, Participation

12. Frailty and unstable disabilityCampbell AJ and Buckner DM. Unstable disability and the fluctuations of frailty. Age Ageing 1997; 26(4): 315-318 ‘a condition or syndrome which results from a multi-system reduction in reserve capacity to the extent that a number of physiological systems are close to, or past, the threshold of symptomatic failure. As a result the frail person is at increased risk of disability or death from minor external stresses’.

13. Transitions to disability are multi-factorial (Gill T et al, 1996) • shared risk factors: • Incontinence, falls and ADL dependency in community dwelling older people are predicted by • cognitive impairment • gait and balance decline • visual impairment

14. A Life Course Approach to Healthy Aging, Frailty, and Disability Kuh D et al The Journals of Gerontology; Jul 2007; 62A, 7; 717-717

15. But the decline is not usually linear eg. muscle strength Acute illnesses decreased activity Usual ageing 30 Age (time) 80

16. But what exactly is frailty? Several approaches • a condition which is predictive of a high rate of future death or disability • A bio-psycho-social condition which leads to deterioration

17. Fried’s definition is criterion basedFried LP et al J Gerontol A Biol Sci Med Sci 2001; 56: M146-56Cardiovascular Health Study. 5,317 men & women 65 years +

18. Frailtywas defined by > 3/5 of: • Unintentional weight loss (>10 pounds in a year) • Self-reported exhaustion • Weakness as measured by grip strength • Slow walking speed • Low physical activity This is NOT suitable for clinical practice but may be useful for epidemiology

19. By this definition, frailty is distinct from disability and co-morbidity

20. But predicts a worse outcome(Survival curves over 4 years)

21. Pathophysiological frailty model • multi-system reduction in reserve capacity in a number of physiological systems. • associated with underlying physiological and metabolic changes, which may be inter-related, and • which drive progressive physical and cognitive impairments….. • Which result in loss of functional capacity • often made worse by acute or chronic disease or injury.

22. Candidates in the pathophysiological causal pathway • Puts MTE et al. Endocrine and inflammatory markers as predictors of frailty. Clin Endocrinol 2005: 63: 403-411. • Abate M et al. Frailty in the elderly: the physical dimension. Europa Medicophysica 2006; 42: • Leng SX et al (Fried’s group) J Am Geriatr Soc. 2007; 55(6):864-71 • Cytokines (both pre and anti inflammatory) • High levels of inflammatory interleukins • CRP • Low levels of anti-inflammatory • Hormones (dwindling anabolic milieu) • eg IGF-I, insulin resistance, DHEA • Nutrition (micro and macronutrients)

23. In the pathophysiological pathway to frailty, muscle function is very important

24. Sarcopenia = the loss of muscle mass + Either reduced strength Or reduced function Or Both (severe sarcopenia)

25. The nature of sarcopenia Loss of muscle mass by 5% /decade from age 40+ • Motor unit loss due to denervation with 50% fibre loss by age 80 • Shift towards type I fibres (aerobic) • Muscle fibre atrophy, especially type II b • Reduced strength / unit of cross sectional area

26. Consequences of sarcopenia Cross-sectional comparison of 50 healthy men & women 65–89 yrs Skelton et al. Age Ageing 1994; 23: 371-377 Differences • isometric strength losses of 1–2% per year • leg extensor power losses of 3 % per year • Functional activities were reduced • timed rise from a low chair • lifting a weighted bag • stepping up • Isometric knee extensor strength influenced chair rise time • Power influenced chair rise time and step height. • .

27. Processes which may play a role • Ageing – muscle and systemic control of muscle • Alteration in level of exercise • Alteration in responses of ageing muscle to exercise • Co-morbidities acting systemically • Age changes in susceptibility to muscle damage • Age changes in ability to recover from damage

28. Trajectories to functional loss (due to sarcopenia) eg. muscle strength Acute illnesses decreased activity Usual ageing 30 Age (time) 80

29. Trajectories to functional loss (due to sarcopenia) habitual activity is insufficient or less responsive to usual stimuli: so gradual disuse wasting eg. muscle strength Acute illnesses decreased activity Usual ageing 30 Age (time) 80

30. Trajectories to functional loss (due to sarcopenia) eg. muscle strength Catabolic factors are more common or more prolonged Acute illnesses decreased activity Usual ageing 30 Age (time) 80

31. Trajectories to functional loss (due to sarcopenia) eg. muscle strength Acute illnesses Partial recoveries decreased activity Usual ageing 30 Age (time) 80

32. Trajectories to functional loss muscle loss eg. muscle strength Acute illnesses Partial recoveries decreased activity Usual ageing Impaired anabolic processes 30 Age (time) 80

33. Possible Biological Mechanisms of Sarcopenia • Reduced proliferation of myoblasts • Reduced protein synthesis • Mitochondrial dysfunction • Reduced net anabolic hormone profile, • at rest • on recovery from illness • or in response to growth promoting exercise

34. 2 muscle isoforms of IGF-I • IGF-IEa (the systemic form) • Responds to GH (which falls with age) • Maintenance of muscle, stimulates protein synthesis • Mechano growth factor (MGF) • Less GH responsive • Responds to mechanical load • stimulates proliferation of myoblasts from satellite stem cells • Acts independently of IGF-I receptors

35. Ageing and Mechanogrowth factor • Old muscle is less able to recover from injury • Less responsive to mechanical loading Both alterations may be mediated via reduced post translational splicing into MGF Why?? Age related altered cytoskeleton responses may result in reduced mechanical stimulus to MGF production.

36. “Counter-regulation” by myostatin • Myostatin was first found in association with muscle hypertrophy when the myostatin gene was absent • Seems to keep the satellite cells in quiescent phase • Sarcopenia and muscle wasting diseases are associated with increased myostain • Heavy exercise reduces myostatin (presumably to allow regenerative recovery) • Antagonists to myostatin may have therapeutic benefit • GH reduces myostatin so MGF predominates • So low GH might lead to reduced anabolic effect

37. r-hGH treatment and functional outcomes • enhances muscle mass and reduces fat • but the potentially beneficial changes in muscle and other lean body tissue have not translated into consistent or impressive functional outcomes • (of high functioning older people) • one RCT showed better recovery from pneumonia • one RCt showed better recovery from hip fractures • excessive side effects at high doses

38. In contrast, exercise is effective Exercise programmes have proven ability to enhance muscle mass and strength, even in very frail elderly people, equivalent to 10 years difference - from a 13 week programme Adding r-hGH treatment to an exercise intervention has produced no or marginal additional benefit for healthy males. Eg. Yarasheski KE et al, , Am J Physiol 1995; 268: E268-276

39. Combining rhGH with Testosterone • Potential synergistic effects • Lower dose of rhGH (better tolerance) Blackman M et al JAMA 2002 Brill KT et al JCEM 2002 • Our RCT showed that titrated doses are safer and produce 25% increase in VO 2 max Giannoulis M et al JCEM 2006

40. Additional factors operating on sarcopenia • Nutritional state • Insulin, vitamin D • Pro-inflammatory cytokines, TNF alpha • Eg. higher IL-6 is associated with poorer clinical outcomes, increased mortality and slower recovery from delirium • (Adamis D et al.APOE and cytokines as biological markers for recovery of prevalent delirium in elderly medical inpatients. .Int J Geriatr Psychiatry. 2007 Jul;22(7):688-94)

41. Conclusion • Frailty is vulnerability to adverse change • It is a multi-impairment state • It may have multiple biological factors involved • In the future geriatrics may involve treatments for these changes as well as treatment for specific conditions