Fatigue is believed to be a common complaint among older adults; however, multiple studies of self-reported fatigue across the lifespan have found this may not be the case. To explain this paradox, this article considers "fatigability"-a phenotype characterized by the relationship between an individual's perceived fatigue and the activity level with which the fatigue is associated. Fatigability may be measured by combining self-report measures of fatigue with performance of physical or cognitive activities, provided that the work of the activity is known or can be standardized. Doing so prevents self-pacing and allows meaningful comparisons across subjects and between studies. Increased fatigability with aging may arise from a variety of factors including age-related changes in energy production or utilization, and inflammatory mechanisms. A few published intervention studies have targeted fatigue in older adults, though none have examined fatigability specifically. Because fatigue may represent a physiologic warning system, future clinical studies may benefit from a focus on fatigability, where both symptoms and function are considered.

Caspases are a family of mammalian proteases related to the ced-3 gene of Caenorhabditis elegans. They mediate many of the morphological and biochemical features of apoptosis, including structural dismantling of cell bodies and nuclei, fragmentation of genomic DNA, destruction of regulatory proteins, and propagation of other pro-apoptotic molecules. Based on their substrate specificities and DNA sequence homologies, the 14 currently identified caspases may be divided into three groups: apoptotic initiators, apoptotic executioners, and inflammatory mediators. Caspases are activated through two principal pathways, known as the "extrinsic pathway," which is initiated by cell surface death receptor ligation, and the intrinsic pathway, which arises from mitochondria. Endogenous inhibitors, such as the inhibitors of apoptosis (IAP) family, modulate caspase activity at various points within these pathways. Upon activation, caspases appear to play an important role in sequelae of traumatic brain injury, spinal cord injury, and cerebral ischemia. In addition, they may also play a role in mediating cell death in chronic neurodegenerative conditions such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. This article reviews the current literature on the role of caspases in acute and chronic CNS injury, and provides evidence for the potential therapeutic use of caspase inhibitors in the setting of these conditions.

Older persons who report fatigue had significantly poorer functional status than those who did not report this symptom. The causal link between fatigue and these outcomes should be further investigated.

LF power reflects baroreflex function, not cardiac sympathetic innervation.

Abstract-Supine hypertension occurs commonly in primary chronic autonomic failure. This study explored whether supine hypertension in this setting is associated with orthostatic hypotension (OH), and if so, what mechanisms might underlie this association. Supine and upright blood pressures, hemodynamic responses to the Valsalva maneuver, baroreflex-cardiovagal gain, and plasma norepinephrine (NE) levels were measured in pure autonomic failure (PAF), multiple-system atrophy (MSA) with or without OH, and Parkinson's disease (PD) with or without OH. Controls included age-matched, healthy volunteers and patients with essential hypertension or those referred for dysautonomia. Baroreflex-cardiovagal gain was calculated from the relation between the interbeat interval and systolic pressure during the Valsalva maneuver. PAF, MSA with OH, and PD with OH all featured supine hypertension, which was equivalent in severity to that in essential hypertension, regardless of fludrocortisone treatment. Among patients with PD or MSA, those with OH had higher mean arterial pressure during supine rest (109Ϯ3 mm Hg) than did those lacking OH (96Ϯ3 mm Hg, Pϭ0.002). Baroreflex-cardiovagal gain and orthostatic increments in plasma NE levels were markedly decreased in all 3 groups with OH. Among patients with PD or MSA, those with OH had much lower mean baroreflex-cardiovagal gain (0.74Ϯ0.10 ms/mm Hg) than did those lacking OH (3.13Ϯ0.72 ms/mm Hg, Pϭ0.0002). In PAF, supine hypertension is linked to both OH and low baroreflex-cardiovagal gain. The finding of lower plasma NE levels in patients with than without supine hypertension suggests involvement of pressor mechanisms independent of the sympathetic nervous system. Key Words: hypertension, essential Ⅲ hypotension Ⅲ Parkinson's disease Ⅲ autonomic nervous system Ⅲ sympathetic nervous system Ⅲ norepinephrine P rimary chronic autonomic failure has been classified clinically into 3 forms: pure autonomic failure (PAF), multiple-system atrophy (MSA), and autonomic failure in the setting of Parkinson's disease (PD). 1 All 3 forms typically include orthostatic hypotension (OH), wherein reflexive increases in sympathetic neurocirculatory tone fail to compensate adequately for decreased venous return to the heart.Patients with primary chronic autonomic failure also often have supine hypertension. 2 Because of widespread use of the salt-retaining steroid fludrocortisone to treat OH and literature documenting increases in blood pressure secondary to mineralocorticoid administration, 3,4 supine hypertension in primary chronic autonomic failure might be a side effect of treating the OH and not part of the disease; however, supine hypertension has been reported in a substantial proportion of untreated patients. 5 Analogously, levodopa is a mainstay in the treatment of PD, and based on literature that levodopa produces OH, 6 OH in PD might be a side effect of treating the movement disorder and not part of the disease; however, OH occurs in at least some patients with PD who are off or have never been ...

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The American Geriatrics Society, with support from the National Institute on Aging and the John A. Hartford Foundation, held its fifth Bedside-to-Bench research conference, “Idiopathic Fatigue and Aging,” to provide participants with opportunities to learn about cutting-edge research developments, draft recommendations for future research, and network with colleagues and leaders in the field. Fatigue is a symptom that older persons, especially by those with chronic diseases, frequently experience. Definitions and prevalence of fatigue may vary across studies, across diseases, and even between investigators and patients. The focus of this review is on physical fatigue, recognizing that there are other related domains of fatigue (such as cognitive fatigue). Many definitions of fatigue involve a sensation of “low” energy, suggesting that fatigue could be a disorder of energy balance. Poor energy utilization efficiency has not been considered in previous studies but is likely to be one of the most important determinants of fatigue in older individuals. Relationships between activity level, capacity for activity, a tolerable rate of activity, and a tolerable fatigue threshold or ceiling underlie a notion of fatiguability. Mechanisms probably contributing to fatigue in older adults include decline in mitochondrial function, alterations in brain neurotransmitters, oxidative stress, and inflammation. The relationships between muscle function and fatigue are complex. A number of diseases (such as cancer) are known to cause fatigue and may serve as models for how underlying impaired physiological processes contribute to fatigue, particularly those in which energy utilization may be an important factor. A further understanding of fatigue will require two key strategies: to develop and refine fatigue definitions and measurement tools and to explore underlying mechanisms using animal and human models.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK, and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.