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This can be applied to the elderly population in the community and in a variety of care settings. Frailty may also be useful for risk assessment in surgical patients and those with cardiovascular diseases, cancer, or human immunodeficiency virus infection, as well as for assessment of vaccine effectiveness in older adults. Currently, exercise and comprehensive geriatric interdisciplinary assessment and treatment are key interventions for frailty.

As understanding of the biologic basis and complexity of frailty further improves, more effective and targeted interventional strategies and innovative geriatric-care models will likely be developed.

Immunology 201: Application of the Basic Concepts to People

Keywords: frailty, inflammation, IL-6, aging, older adults. Identification of older individuals who are frail or at risk of becoming frail with appropriate subsequent evaluation and intervention constitutes a cornerstone of geriatric medicine and quality care for the ever-growing elderly population. Efforts have also been made internationally to reach frailty consensus. This article provides an overview of the current state of our knowledge about the frailty syndrome: its definitions and pathogenesis, as well as clinical applications and potential preventative and therapeutic interventions.

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Frailty is conceptually defined as a clinically recognizable state of older adults with increased vulnerability, resulting from age-associated declines in physiologic reserve and function across multiple organ systems, such that the ability to cope with everyday or acute stressors is compromised. The phenotypic definition of frailty as a geriatric syndrome was proposed by Fried et al and tested in the CHS, a large-cohort study of over 5, community-dwelling older men and women in the US.

A prefrail stage, in which one or two criteria are present, identifies a subset at high risk of progressing to frailty. Older individuals with none of the above five criteria are classified as nonfrail. However, the main features of frailty, such as decreased functional reserve, impairment or dysregulation in multiple physiological systems, and reduced ability to regain physiological homeostasis after a stressful and destabilizing event, make the distinction of frailty from disability or comorbidity relatively easy.

While many but not all frail individuals are disabled, not all disabled persons are frail. For example, older patients who suffer severe disability secondary to a major accident or stroke may maintain relatively intact function in other physiological systems, and thus are not frail. Comorbidity indicates the presence of multiple chronic diseases. Not surprisingly, comorbidity is associated with increased risk of adverse clinical outcomes, as evidenced by higher short-term and long-term mortality and significantly increased physical disability compared with those without diseases.

However, the mere presence of two or more clinical diagnoses in itself may not identify the vulnerable group of older patients or those who are frail. Frailty in older adults: evidence for a phenotype. Figure 1 Venn diagram of the frailty syndrome, activities of daily living ADL disability, and comorbidity two or more diseases in the Cardiovascular Health Study dataset, demonstrating frailty as a distinct geriatric syndrome with some overlap with disability and comorbidity. It increases with age from 3. It also appears to have geographic differences.

The FI was developed by Rockwood et al based on a comprehensive geriatric assessment by counting the number of deficits accumulated, including diseases, physical and cognitive impairments, psychosocial risk factors, and common geriatric syndromes other than frailty. Compared to the FP definition described earlier, the FI appears to be a more sensitive predictor of adverse health outcomes, because of its more finely graded risk scale and inclusion of deficits that likely have causal relationships with adverse clinical outcomes.

In addition, the FI does not attempt to distinguish frailty from disability or comorbidity. Instead, it includes them or their associated deficits. Moreover, counting the number of accumulated deficits does not constitute a clinical geriatric syndrome per se. As such, the FI makes it difficult, if not impossible, to further investigate underlying mechanisms and etiology of frailty.

Ebook Handbook On Immunosenescence Basic Understanding And Clinical Applications

Therefore, recent advances in the pathogenesis of frailty described in the following section are almost exclusively based on the FP definition. Frailty is characterized by multisystem dysregulations, leading to a loss of dynamic homeostasis, decreased physiologic reserve, and increased vulnerability for subsequent morbidity and mortality.

This is often manifested by maladaptive response to stressors, leading to a vicious cycle toward functional decline and other serious adverse health outcomes. Chronic inflammation is likely a key underlying mechanism that contributes to frailty directly and indirectly through other intermediate pathophysiologic processes Figure 2. This section provides a brief overview of our current understanding of each of these key pathophysiologic processes.

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Figure 2 Pathogenesis of the frailty syndrome: current understanding of potential underlying mechanisms and hypothetical modal pathways leading to frailty. Abbreviation: CMV, Cytomegalovirus. Direct association between frailty and elevated circulating levels of interleukin IL -6, a proinflammatory cytokine, was first observed in community-dwelling older adults.

Subsequent studies in cell culture, mouse model, and large older-adult cohorts have confirmed the association between elevated IL-6 levels and frailty. Drastic increase above the normal range of total white blood cell WBC count, which is routinely measured as part of the complete blood counts in clinical practice, is recognized as a laboratory indicator for systemic inflammation frequently secondary to acute bacterial infections.

Recent studies have demonstrated direct associations between frailty and increased total WBC count, albeit still under the upper limit of the normal range, and counts of its specific subpopulations including neutrophils and monocytes. As discussed earlier, the relationship between frailty and common molecular and cellular inflammatory mediators is well documented.

The critical question is whether chronic inflammation plays a role in the pathogenesis of frailty. Individual inflammatory molecules, such as IL-6, may directly contribute to frailty or its central components such as decreased muscle mass, strength, and power, and slowed motor performance. However, factors other than chronic inflammation may also be important in the pathogenesis of frailty, as no consistent associations were observed between elevated IL-6 levels and prevalent or incident frailty in some studies 53 , 54 and the use of statins, which are known to have anti-inflammatory effects, had no association with reduction of incident frailty.

Given that weakness and slowed motor performance are cardinal features of the frailty syndrome, sarcopenia is likely a key pathophysiologic contributor to frailty.

Claudio Franceschi (Author of Aging and Cellular Defense Mechanisms)

In fact, investigators in Europe and Asia consider sarcopenia research a potentially useful initial step toward interventional studies of the frailty syndrome. It can be further accelerated by chronic diseases, and is a major contributor to disability. As discussed earlier, chronic inflammation is also an important contributor to sarcopenia. Skeletal muscle provides important support for bone health. The frailty syndrome has also been shown to have direct relationships with osteopenia and osteoporosis.

Sex steroids and IGF-1 are essential to skeletal muscle metabolic dysregulation. For example, age-related rapid decrease of estrogen in postmenopausal women and gradual decrease of testosterone in older men lead to decline in muscle mass and muscle strength. Circulating levels of the sex hormone dehydroepiandrosterone sulfate and IGF-1, a signaling target of GH, are significantly lower in frail than nonfrail older adults.

For example, a positive association between higher levels of evening cortisol, hour mean cortisol, and blunted diurnal variation of cortisol with frailty burden and clinical presentation has been observed in frail older women living in the community. Figure 2 provides a simplified illustration of current understanding of the pathogenesis of the frailty syndrome.


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However, much remains to be learned about the complex multifactorial etiology of this geriatric syndrome. For example, Blaum et al showed significant association between obesity and frailty defined by FP in community-dwelling women aged 70—79 years. They may also mimic the clinical manifestation of frailty. Moreover, acute episodes of illness or exacerbation of chronic conditions may accelerate the development of frailty or worsen its clinical presentation and adverse outcomes.

Therefore, further clinical and biological investigations are needed to delineate the complex multifactorial etiology of frailty.

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As frailty is conceptualized as a vulnerable state associated with high risk for increased morbidity and mortality when exposed to a stressor, the frailty syndrome is considered a useful clinical tool for risk stratification in the highly heterogeneous elderly population. Evidence supporting this notion includes data from several large-cohort studies that demonstrated that frailty predicts increased falls, hospitalization, dependence, and mortality. The European Union has placed special emphasis on defining frailty, as frail elders are high users of community resources, hospitalization, and nursing homes.

A frailty consensus has recently been established through concerted international effort. Emerging evidence suggests that frailty is a useful risk assessment tool for preoperative evaluation in elderly patients who undergo surgery. Both the FI and FP have been shown to be predictive for increased postoperative complications. Frailty assessment may provide novel insight into heightened vulnerability and risk stratification of older patients with cancer. This is because traditional tools, including chronological age and the Eastern Cooperative Oncology Group performance status, do not assess physiological reserve and have poor predictive value for poor clinical outcomes in this patient population.

Specific cancers may play an important etiologic role in the development of frailty. Other areas of active research include human immunodeficiency virus HIV infection and aging. In two large-cohort studies of HIV infection, frailty or frailty-related phenotype was shown to have a significant association with mortality and accelerated immune-function deterioration.

here Moreover, it is unclear whether these terms add significant values beyond mild cognitive impairment or dementia. Broadly speaking, interventions for the frailty syndrome should aim to 1 prevent, delay, reverse, or reduce the severity of frailty, and 2 prevent or reduce adverse health outcomes in those whose frailty is not reversible. Effective interventional strategies likely have large benefits for elderly individuals, their families, and the whole society.

To date, exercise is the interventional modality that has most consistently shown benefit in treating frailty and its key components. A large number of trials albeit validated FP or FI was often not used at baseline or follow-up have demonstrated the positive impact of exercise intervention on key components of the frailty syndrome, including muscle strength and functional mobility.

However, evidence supporting its efficacy is currently lacking, and vigorous clinical evaluation is needed. Effects of a pharmacological approach in the treatment of the frailty syndrome have not been adequately evaluated. Such hormonal therapy as testosterone, while it improves muscle strength, has significant systemic side effects. While vitamin D and angiotensin-converting enzyme inhibitors have favorable pharmacological and safety profiles, their clinical utility in the prevention and treatment of frailty has yet to be investigated. Another important area of interventions is to prevent biological, socioeconomic, and environmental stressors and improve clinical outcomes in elderly patients whose frailty is not reversible.

Comprehensive geriatric interdisciplinary assessment and treatment has been demonstrated to improve health outcomes in frail older adults. The overall objectives of this interventional modality are to improve physical and psychological function, reduce hospitalization and iatrogenic adverse events, develop adaptive strategies addressing disability and dependence, improve quality of life, and decrease early mortality in older adults. The interdisciplinary assessment and care team usually consists of a geriatrician, a gerontologically trained nurse, a social worker, a pharmacist, and occupational and physical therapists.