Molecular-Based Therapeutic Approaches in Treatment of Anorexia of Aging and Cancer Cachexia

Hamerman, David

doi:10.1093/gerona/57.8.m511

Cited by 27 publications

(22 citation statements)

References 127 publications

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“…Evidence from laboratory and clinical studies has demonstrated that EPA has antitumor and anticachectic effects. Initial studies using animal models have demonstrated that NFkB is upregulated in CC increasing proteolysis and inducing apoptosis in myotubes [43, 44]. Several recent laboratory studies have shown that EPA may attenuate protein degradation, by preventing NFkB accumulation in the nucleus [43, 44].…”

Section: Treatmentmentioning

confidence: 99%

Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

Kumar

Kazi

Smith

et al. 2010

Curr. Treat. Options in Oncol.

104

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Opinion statementThe complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status.

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Section: Treatmentmentioning

confidence: 99%

Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

Kumar

Kazi

Smith

et al. 2010

Curr. Treat. Options in Oncol.

104

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“…One of the systems that is particularly affected with aging is that which regulates food intake and energy balance, leading to a decreased ability to maintain body weight and lean body mass in response to illness or disease (15,16,20,23,34,36,46,47). One of the key factors appears to be failure of appetite to increase after weight loss (7,36,48,49).…”

mentioning

confidence: 99%

“…In addition, older people report less hunger after an overnight fast and report greater degrees of satiation to meals than do younger subjects (7,49). This apparent insensitivity to metabolic cues can lead to inappropriate weight loss in response to acute or chronic illness or other stressors, including surgery, resulting in greater morbidity and mortality associated with frailty in geriatric populations (15,20,36).…”

mentioning

confidence: 99%

Peripheral ghrelin treatment stabilizes body weights of senescent male Brown Norway rats at baseline and after surgery

Yukawa¹,

Weigle²,

Davis³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In addition, older people report less hunger after an overnight fast and report greater degrees of satiation to meals than do younger subjects (8,44,56). This apparent insensitivity to metabolic cues can lead to inappropriate weight loss in response to acute or chronic illness or other stressors, resulting in greater morbidity and mortality in geriatric populations (19,25,38).Our laboratory uses the Brown Norway (BN) rat to study aging-related decrements in reproductive function and regulation of body weight (22,36). Male BN rats are an excellent model for human aging: they have long disease-free survival rates (52) and a maximum life span of ϳ36 mo, with 50% surviving to 30 mo (comparable to 80 yr of age in humans), and 10% surviving to 32 mo of age (52).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding responses to AgRP in aging male Brown Norway rats

Wolden‐Hanson¹,

Marck²,

Matsumoto³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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Aging mammals lose the ability to maintain energy balance, exhibiting decreased appetite (anorexia) and impaired ability to maintain body weight. To determine the contribution of hypothalamic neuropeptides, two experiments were performed in male Brown Norway rats. To assess the hypothalamic neuropeptide response to food deprivation, young (Y; 4 mo old), middle-aged (M; 13 mo), and old (O; 25 mo) rats were either ad libitum fed or fasted for 72 h (n = 10/group) and killed. Hypothalamic levels of agouti-related peptide (AgRP), proopiomelanocortin (POMC), and cocaine-amphetamine-regulated transcript (CART) mRNA were assessed by in situ hybridization. With aging, arcuate AgRP gene expression decreased and CART mRNA increased, but POMC mRNA did not change. Fasting-induced changes in gene expression of all neuropeptides studied were attenuated with aging. To test the food intake response to appetite-stimulating neuropeptides, Y, M, O, and very old (VO; 33 mo) rats (n = 4-8/group) received one intracerebroventricular injection of each of three treatments: 0.1 nmol AgRP, 2.34 nmol NPY, and saline control. AgRP increased food intake of all groups by 10-20%, compared with saline, and this effect persisted up to 7 days after injection. VO animals were more sensitive to the effects of AgRP than younger animals. In contrast, NPY increased food intake more in Y than in older animals and its effects did not last >24 h. We conclude that the mechanisms by which arcuate nucleus neurons influence appetite are differentially affected by age and speculate that the melanocortin system may be a useful target for treatment of the anorexia of aging.

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Molecular-Based Therapeutic Approaches in Treatment of Anorexia of Aging and Cancer Cachexia

Cited by 27 publications

References 127 publications

Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

Peripheral ghrelin treatment stabilizes body weights of senescent male Brown Norway rats at baseline and after surgery

Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding responses to AgRP in aging male Brown Norway rats

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