Down Syndrome And Hpa Axis

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Primary

Causes of Frailty:

Age-related molecular changes Genetic variation

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Figure 57.2 Physiologic Model Pathway illustrating age-related (primary) and disease-related (secondary) triggers for the altered physiology that is hypothesized to underlie frailty. Adapted from Walston et al. (2004).

Secondary Causes of Frailty:

Depression Cancer

Chronic Infection CHF

Figure 57.2 Physiologic Model Pathway illustrating age-related (primary) and disease-related (secondary) triggers for the altered physiology that is hypothesized to underlie frailty. Adapted from Walston et al. (2004).

investigators have been able to identify frail and intermediate frail subjects, and then compare inflammatory, endocrinologic, hematologic, and metabolic variables hypothesized to underlie declines in multiple other physiologic systems and ultimately frailty. Figure 57.2 illustrates a hypothesized physiological model of frailty where circulating mediators that are components of inflammatory and endocrine systems influence skeletal muscle, red blood cell production, and ultimately frailty and other poor healthcare outcomes of disability and death.

In this model, the altered physiology is hypothesized to be triggered by both aging conditions and chronic disease (Walston et al., 2003). The development of this hypothesized physiologic model pathway toward frailty was based in part on known interactions between inflammatory cytokines, endocrine systems, CNS/SNS activity, and skeletal muscle observed in both human and animal studies. For example, there is a large body of rheumatoid arthritis and other specific inflammatory disease literature that suggests that circulating inflammatory mediators, such as IL-6, TNF-alpha, and IL-1B, trigger the loss of total body cell mass in those with inflammatory disease, perhaps via activation of apoptotic pathways (Roubenoff et al., 2003). There are also multiple lines of evidence that demonstrate a biologic link between elevated IL-6 and bone and muscle loss, anemia, insulin resistance, and altered immune system modulation and hypothalamic-pituitary-adrenal (HPA) axis stimulation, making it less likely that IL-6 is simply a benign biologic marker (Ershler et al., 2000). In addition, there is also evidence that inflammatory cytokines such as IL-6 may interfere with anabolic function of sex steroids, growth hormone, and probably IGF-1 (Lazarus et al., 1993; Papanicolaou et al., 1998). Conversely, it is also apparent that loss of estrogen, and perhaps testosterone, leads to the uncovering of important inflammatory gene transcriptional elements, leading to increased production of IL-6 and other inflammatory mediators in several cell types (Ershler et al., 2000).

These relationships have been tested in cross-sectional studies performed in at least three different groups of community-dwelling older adults. Significant positive relationships were identified between frailty and the inflammatory cytokine interleukin-6 (IL-6), C-reactive protein (CRP), and increased numbers of monocytes, and total white blood cells (Leng et al., 2002; Walston et al., 2002; Leng et al., 2005). Higher levels of these same inflammatory mediators correlate with increased vulnerability to disability and mortality in other studies of older adults, further supporting a role for these biologically active molecules and systems in the development of poor health outcomes (Roubenoff et al., 2003). Although none of the mean values of increased inflammatory markers observed in frailty appear to reach the high levels observed in inflammatory diseases such as rheumatoid arthritis or malignancy, they are suggestive of a chronic, low-level activation of inflammatory mechanisms in frail, compared to nonfrail, older adults, and support the need for further study of these pathways in the development of frailty.

Like the inflammatory system, the endocrine and neuroendocrine systems are composed of several separate, but related, organs or tissues that secrete specific hormones and stimulate components of the central and sympathetic nervous system that regulate multiple physiologic processes. The sex steroids and the growth hormone axis have frequently been postulated to contribute to aging-related changes in body composition, and potentially, to frailty (Ershler et al., 2000). The decline of these hormone levels also triggers inflammatory mediator transcription, and interactions between endocrine and inflammatory systems (Ershler et al., 2000). Trajectories in the declines of each of these hormones may prove predictive in the development of frailty, but have yet to be studied.

The adrenal androgen DHEA-S and the growth hormone messenger molecules IGF-1 both decline with age. Importantly, low levels of both DHEA-S and

IGF-1 are associated with at least one frailty definition in older adults (Leng et al., 2005). IGF-1 plays an important role in the development of skeletal muscle cells and is likely an important factor in muscle mass maintenance with increasing age. There is also evidence for interaction between IGF-1 and IL-6, which suggests that inflammation may drive IGF-1 levels down (Cappola et al., 2003). Furthermore, increasing evidence suggests that DHEA-S suppresses NFKB-induced inflammation (Iwasaki et al., 2004). Hence lower levels of DHEA-S observed in frailty may contribute to chronic inflammation and ultimately to frailty.

In addition to these endocrinologic and inflammatory findings, activation of clotting pathways and altered metabolism as represented as increased glucose intolerance have been identified in at least one study of frail older adults (Walston et al., 2002). In this study, those who were frail had significantly higher levels of fasting glucose, and higher levels of insulin and glucose two hours after an oral glucose tolerance test, even after adjustment for multiple potential confounders (Walston et al., 2002). In addition, the frail subset had significantly higher levels of both Factor VIII, fibrinogen, and d-dimers, suggesting a low-grade clotting process (Walston et al., 2002). Although none of these cross-sectional findings can evaluate causality, they support the need for further longitudinal studies and studies of interactions between these important physiologic systems. In addition, they support the need to identify specific aging or disease related triggers that may activate inflammatory pathways and alter endocrinologic systems, and studies of interactions between these pathways (Walston, 2004).

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