Evolving definitions of frailty, and improved understanding of molecular and physiological declines in multiple systems that may increase vulnerability in frail, older adults has encouraged investigators from many disciplines to contribute to this emerging field of research. This article reports on the results of the 2004 American Geriatrics Society/National Institute on Aging conference on a Research Agenda on Frailty in Older Adults, which brought together a diverse group of clinical and basic scientists to encourage further investigation in this area. This conference was primarily focused on physical and physiological aspects of frailty. Although social and psychological aspects of frailty are critically important and merit future research, these topics were largely beyond the scope of this meeting. Included in this article are sections on the evolving conceptualization and definitions of frailty; physiological underpinnings of frailty, including the potential contributions of inflammatory, endocrine, skeletal muscle, and neurologic system changes; potential molecular and genetic contributors; proposed animal models; and integrative, system biology approaches that may help to facilitate future frailty research. In addition, several specific recommendations as to future directions were developed from suggestions put forth by participants, including recommendations on definition and phenotype development, methodological development to perform clinical studies of individual-system and multiple-system vulnerability to stressors, development of animal and cellular models, application of population-based studies to frailty research, and the development of large collaborative networks in which populations and resources can be shared. This meeting and subsequent article were not meant to be a comprehensive review of frailty research; instead, they were and are meant to provide a more-targeted research agenda-setting process.

Interleukin-6 (IL-6) is a proinflammatory cytokine that is normally tightly regulated and expressed at low levels, except during infection, trauma, or other stress. Among several factors that down-regulate IL-6 gene expression are estrogen and testosterone. After menopause or andropause, IL-6 levels are elevated, even in the absence of infection, trauma, or stress. IL-6 is a potent mediator of inflammatory processes, and it has been proposed that the age-associated increase in IL-6 accounts for certain of the phenotypic changes of advanced age, particularly those that resemble chronic inflammatory disease [decreased lean body mass, osteopenia, low-grade anemia, decreased serum albumin and cholesterol, and increased inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A]. Furthermore, the age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer's disease. This overview discusses the data relating IL-6 to age-associated diseases and to frailty. Like the syndrome of inappropriate antidiuretic hormone, it is possible that certain clinically important late-life changes are due to an inappropriate presence of IL-6.

Background Red cell distribution width (RDW), a component of an electronic complete blood count, is a measure of heterogeneity in the size of circulating erythrocytes. In patients with symptomatic cardiovascular disease (CVD), RDW is associated with mortality. However, it has not been demonstrated that RDW is a predictor of mortality independent of nutritional deficiencies or in the general population. Methods RDW was measured in a national sample of 8175 community-dwelling adults aged 45 and older who participated in the 1988–1994 National Health and Nutrition Examination Survey; mortality follow-up occurred through December 31, 2000. Deaths from all causes, CVD, cancer, and other causes were examined as a function of RDW. Results Higher RDW values were strongly associated with an increased risk of death. Compared to the lowest quintile of RDW, the following were adjusted hazard ratios (HR) for all-cause mortality (and 95 percent confidence intervals): second quintile, 1.1 (0.9–1.3); third quintile, 1.2 (1.0–1.4); fourth quintile, 1.4 (1.2–1.8); fifth quintile, 2.1 (1.7–2.6). For every 1 percent increment in RDW, all-cause mortality risk increased by 22% [HR = 1.22 (1.15–1.30); p<0.001]. Even when analyses were restricted to non-anemic participants or to those in the normal range of RDW (11–15%) without iron, folate, or vitamin B12 deficiency, RDW remained strongly associated with mortality. The prognostic effect of RDW was observed in both middle-aged and older adults for multiple causes of death. Conclusions RDW is a widely-available test that is a strong predictor of mortality in the general population of adults aged 45 and older.

RDW is a routinely reported test that is a powerful predictor of mortality in community-dwelling older adults with and without age-associated diseases. The biologic mechanisms underlying this association merit investigation.

ERalpha exhibited bimodal age frequency distribution with a dichotomous pattern for age-specific rates, racial, and prognostic factor profiles. Menopause had a greater effect on ERN than ERP. Possible implications for breast carcinogenesis and cancer prevention are discussed in the text.

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Interleukin-6 (IL-6) is a multifunctional cytokine that presumably plays its major role as a mediator of several of the acute phase inflammatory responses. These include inflammatory cell and lymphocyte activation and hepatocellular stimulation of acute phase protein synthesis. IL-6 expression is normally low, and serum levels are usually non-detectable in the absence of inflammation. However, with advancing age, serum levels become detectable, and it is proposed that this reflects an age-associated loss in the normal regulation of gene expression for this molecule. The cause of this is most likely multi-factorial, but there is evidence that it relates to an age-associated loss of T cell immunoregulatory functions as well as menopausal loss of estrogen. In any event, the "inappropriate" presence of IL-6 results in many changes typical of chronic inflammation. There is also speculation that IL-6 may contribute to the pathogenesis of several diseases of late-life including lymphoma, osteoporosis, and Alzheimer's disease. In this review the biology of this important cytokine is presented and its relevance to gerontology is highlighted.

Asthma in the elderly (AIE) is under diagnosed and under treated and there is a paucity of knowledge. The National Institute on Aging convened this workshop to identify what is known, what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of AIE. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger individuals but co-morbid illnesses and the psychosocial effects of aging may affect the diagnosis, clinical presentation and care of asthma in this population. At least two phenotypes exist among elderly asthma; those with long-standing asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiological mechanisms of AIE are likely to be different from those seen in young asthmatics and these differences may influence the clinical course and outcomes of asthma in this population.