Genetic Evidence for Causal Associations of Sarcopenia with Cardiometabolic Disease And Alzheimer's Disease and the Mediating Role of Insulin Resistance
Chaojie YeLijie KongYiying WangMin XuJie ZhengYu XuMian LiZhiyun ZhaoJieli LuYuhong ChenWeiqing WangGuang NingYufang BiTiange Wang
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Background: The causal influence of sarcopenia on major cardiometabolic diseases and Alzheimer’s disease and whether and to what extent insulin resistance plays a mediation role remains unclear.Methods: We performed two-step, two-sample Mendelian randomization analyses, applying genetic instruments of grip strength, appendicular lean mass [ALM], and whole body lean mass [WBLM] from genome-wide association studies (GWASs) in UK Biobank (up to 461,026 participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer’s disease extracted from reliable European-descent GWASs and to assess the proportions of the causal effects mediated by insulin resistance. Insulin resistance was estimated by fasting insulin based on GWAS from the Meta-Analyses of Glucose and Insulin-related traits Consortium (151,013 European participants).Findings: Each 1-SD lower genetically determined grip strength, ALM, and WBLM were associated with higher risks of diabetes (20%-57%), non-alcoholic fatty liver disease [NAFLD] (33%-130%), hypertension (12%-32%), coronary heart disease [CHD] (20%-42%), myocardial infarction [MI] (18%-45%), small vessel stroke (25%-29%), and Alzheimer’s disease (10%-28%). Insulin resistance mediated 10%-25% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished towards null with adjustment for insulin resistance. The robustness of all causal findings from the random-effect inverse-variance weighted method was validated by several sensitivity analyses.Interpretation: Sarcopenia, measured by low muscle strength and muscle mass, was causally associated with higher risks of major cardiometabolic diseases and Alzheimer’s disease, with insulin resistance mediating a substantial proportion of sarcopenia-related cardiometabolic risk.Funding Information: This work was supported by the grants from the National Natural Science Foundation of China (82022011, 81970706, 82088102, 81970728, 81941017), the Chinese Academy of Medical Sciences (2018PT32017, 2019PT330006), the “Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support” from Shanghai Jiao Tong University School of Medicine (20171901 Round 2), the Shanghai Shenkang Hospital Development Center (SHDC12019101, SHDC2020CR1001A, SHDC2020CR3064B), the Shanghai Jiao Tong University School of Medicine (DLY201801), and the Ruijin Hospital (2018CR002).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: All the summary-level genome-wide association study (GWAS) data used in the analyses are publicly available, and therefore ethical approval was not imperative for this study. Ethical approval for the GWASs can be found in the corresponding GWAS publications cited in the manuscript.Surgical oncology
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Background: Early detection and prevention of sarcopenia are essential for maintaining the functional health of older adults. There is a close association between sarcopenia and physical activity levels. Possible sarcopenia is a precursor to sarcopenia, which can accurately predict sarcopenia
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This study aimed to describe the frequency of sarcopenia and verify the agreement between instruments for diagnosis. This a cross-sectional study, where we used the algorithm proposed by the European Consensus Sarcopenia (EWGSOP), calf circumference (CC), muscle mass and body mass index. 167 elderly were evaluated with a mean age of 68.03 ± 6.12 years. The elderly frequency diagnosed by EWGSOP sarcopenia and CC was as follows: 40 (24.0%) and 15 (9.0%). A low degree of agreement between CC and the EWGSOP (P = 0.101) was found. However, these instruments due to the low financial cost and easy applicability are important auxiliary tools for the screening and diagnosis of sarcopenia in elderly.
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Sarcopenia is one of geriatric syndromes, characterized by decreased muscle mass accompanied by decreased muscle strength and/or performance. It is more prevalent with increase in age, and the prevalence depends on the criteria applied and the characteristic of the elderly. Sarcopenia has a higher risk of morbidity and mortality in elderly patients. The definition criteria of sarcopenia are still controversial, but diagnostic criteria from the Asian Working Group for Sarcopenia and the European Working Group on Sarcopenia in Older People (EWGSOP) are the most used criteria for clinical practice. Pathogenesis sarcopenia involved a multifactorial process and is divided into intrinsic and extrinsic factors. Risk factors for sarcopenia include constitutional factors, aging, lifestyle, changes in body condition, and chronic diseases. Based on that, sarcopenia is divided into primary and secondary sarcopenia. There are three stage of sarcopenia, which are pre-sarcopenia, sarcopenia, and severe sarcopenia. Nutrition and exercise are the two main pillars to manage sarcopenia.
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Background: Early detection and prevention of sarcopenia arecritical. There is a close association between sarcopenia and physical activity levels. Possible sarcopenia is a precursor to sarcopenia, which can accurately predict sarcopenia. According to the tertiary prevention system, the diagnosis of possible sarcopenia has significant implications for the early detection of sarcopenia and the reduction of its prevalence.
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Senescence
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Population Ageing
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Sarcopenia can be classified as age-, activity-, nutrition-, and disease-related. Hospital-associated sarcopenia, acute sarcopenia, and iatrogenic sarcopenia are activity-, nutrition-, and disease-related, not age-related. There is considerable overlap between hospital-associated sarcopenia and acute sarcopenia; however, they are distinct concepts. Some causes of hospital-associated sarcopenia and acute sarcopenia are iatrogenic. Sarcopenia is important in primary care because it is a loss of skeletal muscle mass and function that causes bedridden, dysphagia, and respiratory dysfunction. However, the percentage of primary care physicians who are familiar with sarcopenia is quite low at 18.8%.1 The causes of sarcopenia can be classified into age, activity, nutrition, and disease. Therefore, sarcopenia can occur in people who are not old due to activity, nutrition, or disease. Sarcopenia often occurs during hospitalization in acute care hospitals. Hospital-associated sarcopenia refers to sarcopenia resulting from hospitalization and is related to hospital-associated deconditioning and hospital-associated disability. Hospital-associated sarcopenia occurs not only in acute care hospitals but also in rehabilitation and long-term care hospitals. Acute sarcopenia refers to sarcopenia that occurs primarily during an acute hospitalization.2 However, acute sarcopenia can occur in institutional and home medical care. Hospital-associated sarcopenia and acute sarcopenia are distinct concepts, although there is considerable overlap. The causes of hospital-associated sarcopenia and acute sarcopenia are activity, nutrition, and disease, not age. In addition, the causes of hospital-associated sarcopenia and acute sarcopenia are classified into non-iatrogenic and iatrogenic (Figure 1). Iatrogenic sarcopenia refers to sarcopenia caused by the activities of medical staff including doctors, nurses, or other healthcare professionals in healthcare facilities.3 Activity-related sarcopenia occurs in bed rest required for medical treatment. For example, if the patient is hemodynamically unstable and sitting causes arrhythmias and dyspnea, bed rest is required. Nutrition-related sarcopenia occurs when the patient's food intake is inadequate despite medically appropriate nutritional care management. Disease-related sarcopenia occurs with trauma, fractures, cancer, chronic organ failure, and chronic inflammatory diseases and medically necessary surgery. Activity-related sarcopenia occurs during medically unnecessary bed rest. For example, when the patient is hospitalized for aspiration pneumonia, the physician orders tentative bed rest without appropriate assessment. Nutrition-related sarcopenia results from medically inappropriate nutritional care management. For example, nutritional care management is often inadequate in hospitalized patients with aspiration pneumonia who do not take oral nutrition. Disease-related sarcopenia occurs with iatrogenic diseases or drug-related adverse events. Rehabilitation nutrition4 and rehabilitation pharmacotherapy5 can be useful in the prevention of hospital-associated sarcopenia and acute sarcopenia, both non-iatrogenic and iatrogenic. Rehabilitation nutrition and rehabilitation pharmacotherapy are defined as helping people with disabilities and frail older people to achieve the highest possible body functions, activities, participation, and quality of life (QOL), using holistic evaluation by the International Classification of Functioning, Disability and Health (ICF), rehabilitation nutrition care process, and rehabilitation pharmacotherapy management. The combination of rehabilitation, appropriate nutritional care management, and medication review from the day of admission can prevent sarcopenia during hospitalization to some extent. Prevention of iatrogenic sarcopenia is possible and should be done at all costs. However, prevention of sarcopenia due to non-iatrogenic disease is difficult. Primary care physicians working in acute care hospitals should be responsible for managing not only diseases causing hospitalization but also hospital-associated sarcopenia and acute sarcopenia and should provide rehabilitation nutrition and rehabilitation pharmacotherapy. Clinical practice guidelines for sarcopenia and rehabilitation nutrition are available for primary care physicians. The Global Leadership Initiative in Sarcopenia (GLIS) will develop new consensus papers for sarcopenia.6 For prevention of sarcopenia, it is desirable to include hospital-associated sarcopenia and acute sarcopenia, as well as age-related sarcopenia in the GLIS. The author has stated explicitly that there are no conflicts of interest in connection with this article.
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