Update on Frailty and Sarcopenia

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Esmond Lee
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1 Update on Frailty and Sarcopenia Dr Pushpa Suriyaarachchi Staff specialist, Rehabilitation Medicine, Nepean hospital Clinical A/Lecturer, Musculoskeletal Ageing Research Program Nepean Clinical School, University of Sydney

2 Intro: Frailty & Sarcopenia Frailty & sarcopenia often co-exist and both have physical function impairment as a core component Generating lot of Research interest

3 New Advances Biomarkers For improving diagnostic performance, monitor the progression of the condition(s), predict outcomes, assess treatment response Pharmacological interventions to reverse muscle loss Selective Androgen Receptor Modulators (SARMs), Myostatin (powerful inhibitor of muscle growth) antagonists

4 Myostatin antagonists Myostatin null animals exhibit increased muscle mass. Adult myostatin null mice demonstrating increased size (right) as compared to wildtype (left) animals Clinical trials : sporadic inclusion body myositis (2013) Lee SJ, McPherron AC Curr Opin Genet Dev 1999:5:

5 Frailty & Sarcopenia Case illustration Frailty definition & Pathophysiology Sarcopenia Frailty & Sarcopenia Management

6 Mrs PC 81y Lives with husband Few falls at home has started using a walking stick

7 B/g IHD/CABG x3 CCF AF on warfarin Type 2 Diabetes Mellitus Hypothyroidism

8 Mrs PC.. Fall at home with resultant #NOF Exacerbation of cardiac failure secondary to pneumonia ICU Recurrent UTI Slow progress, extremely fatigable ++, needs constant s/v, prompting Multiple Pace calls for low BP Few falls in the rehab ward legs giving way Two months in rehabilitation poor progress

10 Frailty The explanation for down ward spiral in many elderly patients after acute illness Not present in all elderly, incidence increase with ageing (3-7% between 65-75y 30% over 90y) Not an inevitable process in ageing Reflects biological age that predicts mortality better than chronological age

11 Frailty A biological syndrome of decreased reserve and resistance to stressors, resulting from cumulative decline across multiple physiological systems, causing vulnerability to adverse outcomes

12 The Cardiovascular Health Study (U.S. communities prospective observational study >65y n= From , Ax 0,3,7 years) Linda Fried characterised frailty as a phenotype with presence of 3/5 components 1. Slow walking speed 2. Poor hand grip strength 3. Self reported exhaustion 4. Unintentional weight loss ( 10 pounds or 5% of weight loss in the last year) 5. Decreased physical activity Linda Fried etal, Journal of Gerontology, 2001;56A:M

13 Frailty Criteria Normal/Non-frail/fit/ robust (no factors) Intermediate/ Pre-Frail (one or two factors)-likely to be reversible Frail (three or more factors)

14 Triggers.. insult can be minor (new drug, surgery, infection) will lead to disproportionate change in health status Lack of activity Inadequate nutritional intake Stress Depression

15 Vulnerability to sudden changes in health Lancet 2013, 381(9868):

16 Frailty: Potential aetiologies Strong association with number of major chronic diseases Cardiovascular diseases, Pulmonary diseases, diabetes (possible aetiological association) Greater likelihood of frailty when two or more diseases are present Subset with none of above diseases Physiological changes of ageing not disease based (ageing related sarcopenia or anorexia of ageing) Linda Fried etal, Journal of Gerontology, 2001;56A:M

17 Cycle of frailty

18 Adverse outcomes Frailty increases the susceptibility to Acute illness Delirium Falls Disability Institutionalization and death

19 Sociodemographic & Psychological Factors Frailty is higher among women (low lean muscle mass than aged matched men, living alone more often) Lower socioeconomic status associated with frailty Strong relationship between depressive symptoms and onset of frailty Rockwood K etal, Drugs Ageing.2000,17:

20 Multidimensional nature Frailty is a dynamic state Complex interaction between one or more domain of human functioning Physical, psychological & social Actual level of frailty positioned on continuum between frail and not frail, can change over time in either direction

21 Pathophysiology of frailty Cumulative decline in multiple physiological systems

22 Frail Skeletal muscle (sarcopenia) Weakness and fatigue are central to almost all definitions of frailty Sarcopenia (age associated loss of skeletal muscle mass & function) is likely a key component of these symptoms

23 The frail endocrine system Changes to IGF signalling (Insulin-like growth factor-1) Low levels of sex hormone, dehydroepiandrosterone sulfate (DHEA), precursor of testosterone Chronically elevated diurnal cortisol levels (increased catabolism) Low 25(OH)D levels

24 Effects of inflammation Markers of inflammation are also associated with the frailty syndrome IL-6, CRP Serum levels of interleukin 6 (IL-6) and C-reactive protein elevated in community-dwelling frail older adults IL-6 is strongly associated with adverse physiologic effects such as sarcopenia, weight loss, and an increased susceptibility to infection

25 Haematological effects IL-6 also contribute to anaemia Directly inhibiting production of erythropoietin or by interfering with normal iron metabolism In a cohort of community dwelling older adults, subclinical normocytic anaemia observed in frail Inverse correlation between serum IL-6 & Hb Activation of the clotting cascade

26 Glucose Intolerance Fasting/ post prandial glucose and insulin levels elevated in frail elderly (odds ratio )

27 Pathophysiology of frailty Lancet 2013, 381(9868):

28 Sarcopenia

29 Sarcopenia The term sarcopenia was coined by Rosenberg (1989) to indicate the loss of muscle mass that accompanies aging there is probably no decline in structure and function more dramatic than the decline in lean body mass or muscle mass over the decades of life (Rosenberg, 1997)

Sarcopenia Muscle mass begins to decline at 40 yrs by about 1-2%/yr, accelerate after 65y The European Working group on sarcopenia diagnosis is based on loss of muscle mass combined with decreased

30 Sarcopenia Muscle mass begins to decline at 40 yrs by about 1-2%/yr, accelerate after 65y The European Working group on sarcopenia diagnosis is based on loss of muscle mass combined with decreased strength and or poor physical performance Sarcopenia, the age-related loss of muscle mass and strength, is a major cause of impaired physical function Cruz-Jantoff, 2012 McLean and Kiel, JBMR, April 2015*

31 Sarcopenia Loss of muscle mass (DXA, MRI, Bioimpedance analysis, CT) Decreased strength (grip strength, knee extension strength) Poor physical performance (gait velocity, TUG) Staging Presarcopenia low muscle mass no impact on strength or physical performance Sarcopenia low muscle mass +low strength or physical performance Severe sarcopenia all three criteria

32 Mechanisms of Sarcopenia Cruz- Jentoft, Age and ageing, 2010:39;

33 Pathophysiology of Sarcopenia Disproportionate loss & atrophy of type IIa (fast) muscle fibres Adaptive conversion of fibre II into fibre I Inter- and intra- fibre fat infiltration Decrease in synthesis rates of myosin heavy chain proteins (major anabolic protein) Motor unit denervation with ageing High levels of inflammatory cytokines Decline in anabolic hormones

34 Sarcopenic Obesity Combination of obesity and sarcopenia in the elderly potentiate each other, maximizing their effects on disability, morbidity and mortality Higher fat mass relative to fat free mass (body composition scans) Body composition scan

35 Osteosarcopenia Fracture risk increase dramatically with age much greater than corresponding BMD decline Sarcopenia can explain the increase in fracture risk attributed to age

36 Osteosarcopenia

37 Osteosarcopenia (OS) Clinical Outcomes The OS (SOP) group showed the higher self-reported prevalence of falls and fractures as compared with the other groups Huo R, Suriyaarachchi P, Duque G et al. J Nutr Health Ageing, 2014

38 Sarcopenia & Osteopenia/Osteoporosis Pathophysiological pathways have several similarities Age related Progressive loss of tissue mass Physical inactivity and poor nutrition accelerate both conditions Fat infiltration of muscle & bone High levels of inflammatory cytokines (TNF,IL6)

39 Sarcopenia & Osteopenia/Osteoporosis Common risk factors Low Vitamin D associated with high PTH Low levels of anabolic hormone in men Menopause in women Use of corticosteroids Malnutrition Frailty

40 Frailty Management

41 Frailty Consensus: A Call to Action All Persons Older Than 70 Years Should Be Screened for Frailty & frailty interventions implemented Both primary care physicians and specialists need to screen for frailty General measures 1. Optimise co-morbidities 2. Optimise sensory inputs 3. Assess cognition and mood

42 Frailty Consensus: A Call to Action Treatments that are effective in the treatment of frailty 1. Exercise (resistance and aerobic)?dose 2. Caloric and protein support Protein supplementation increases muscle mass, reduces complications, improves grip strength, produces weight gain, may act synergistically with resistance exercise in older persons. 3. Vitamin D Vitamin D supplementation will improve muscle function, reduce falls, hip fractures & mortality 4. Reduction of polypharmacy Polypharmacy is recognized as a possible major contributor to the pathogenesis of frailty. John Morley etal, JAMDA June ; 14(6):

Exercise likely to benefit even the frailest of older adults In a group of nursing home patients whose average age was 87years Fiatarone et al* showed resistance training increased muscle strength

43 Exercise likely to benefit even the frailest of older adults In a group of nursing home patients whose average age was 87years Fiatarone et al* showed resistance training increased muscle strength more than 100% muscle size in the lower extremities by 3% gait velocity by 12% training associated with increased mobility and spontaneous physical activity even with low levels increase muscle strength * (N Engl J Med.1994, 23;330(25): Exercise training and nutritional supplementation for physical frailty in very elderly people)

Acknowledgements MSK Ageing Research Program Gustavo Duque Diyana Staneva Wei Li Christopher Vidal Krishanthi Gunaratnam Markus Herrmann Derek

47 Acknowledgements MSK Ageing Research Program Gustavo Duque Diyana Staneva Wei Li Christopher Vidal Krishanthi Gunaratnam Markus Herrmann Derek Boersma Oddom Demontiero Piumali Gunawardene Bona Treder Emma Thembani Department of Aged care & Rehabilitation Nepean Laurence Chu Anita Sharma

48 The end Thankyou for your attention

Frailty in Older Adults. Farshad Sharifi, MD, MPH Elderly Health Research Center

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