RESUMEN

BACKGROUND: Exceptional longevity as manifested by the lower incidence and delayed onset of age-related disabilities/diseases that include cardiovascular disease, Alzheimer's disease, cancer is believed to be influenced by inherent protective molecular factors in exceptionally long-lived individuals. Unraveling these protective factors could lead to the discovery of therapeutic target(s) and interventions to promote healthy aging. METHODS: In this context, the National Institute on Aging has established a collection of translational longevity research projects (ie, the Long-Life Family Study, the Longevity Consortium, Longevity Genomics, and the Integrative Longevity Omics) which are generating large omics data sets spanning the human genome to phenome and have embarked on cross-species multiomic data analyses integrating human and nonhuman species that display wide variation in their life spans. RESULTS: It is expected that these studies will discover key signaling pathways that influence exceptional health span and identify therapeutic targets for translation to enhance health and life span. Other efforts related to translational longevity research include the "Comprehensive Evaluation of Aging-Related Clinical Outcomes and Geroproteins study," which focuses on potential effects in humans of polypeptides/proteins whose circulating levels change with age, and for which experimental evidence indicates reversal or acceleration of aging changes. The "Predictive Human Mechanistic Markers Network" is devoted to the development of predictive markers of aging, for target engagement when testing novel interventions for healthy aging. CONCLUSION: We describe here the significance, the unique study design, categories of data sets, analytical strategies, and a data portal to facilitate open science and sharing of resources from these longevity studies to identify and validate potential therapeutic targets for healthy aging.

Asunto(s)

RESUMEN

Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.

Asunto(s)

RESUMEN

Breast cancer is a heterogeneous disease and new clinical markers are needed to individualise disease management and therapy further. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown frequently especially in the luminal breast cancer subtypes, suggesting a cross-talk between ER and PI3K/AKT. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies. In vitro studies have shown protein tyrosine phosphatase, non-receptor type 2 (PTPN2) as a previously unknown negative regulator of the PI3K/AKT pathway. Here, we evaluate possible genomic alterations in the PTPN2 gene and its potential as a new prognostic and treatment predictive marker for endocrine therapy benefit in breast cancer. PTPN2 gene copy number was assessed by real-time PCR in 215 tumour samples from a treatment randomised study consisting of postmenopausal patients diagnosed with stage II breast cancer 1976-1990. Corresponding mRNA expression levels of PTPN2 were evaluated in 86 available samples by the same methodology. Gene copy loss of PTPN2 was detected in 16% (34/215) of the tumours and this was significantly correlated with lower levels of PTPN2 mRNA. PTPN2 gene loss and lower mRNA levels were associated with activation of AKT and a poor prognosis. Furthermore, PTPN2 gene loss was a significant predictive marker of poor benefit from tamoxifen treatment. In conclusion, genomic loss of PTPN2 may be a previously unknown mechanism of PI3K/AKT upregulation in breast cancer. PTPN2 status is a potential new clinical marker of endocrine treatment benefit which could guide further individualised therapies in breast cancer.

Asunto(s)

RESUMEN

The purposes of this article were to 1) provide an overview of the science of physical activity-related energy expenditure in older adults (≥65 yr), 2) offer suggestions for future research and guidelines for how scientists should be reporting their results in this area, and 3) present strategies for making these data more accessible to the layperson. This article was meant to serve as a preliminary blueprint for future empirical work in the area of energy expenditure in older adults and translational efforts to make these data useful and accurate for older adults. This document was based upon deliberations of experts involved in the Strategic Health Initiative on Aging Committee of the American College of Sports Medicine. The article was designed to reach a broad audience who might not be familiar with the complexities of assessing energy expenditure, especially in older adults.

Asunto(s)

RESUMEN

Theoretical calculations suggest that small daily reductions in energy intake can cumulatively lead to substantial weight loss, but experimental data to support these calculations are lacking. We conducted a 1-year randomized controlled pilot study of low (10%) or moderate (30%) energy restriction (ER) with diets differing in glycemic load in 38 overweight adults (mean +/- s.d., age 35 +/- 6 years; BMI 27.6 +/- 1.4 kg/m(2)). Food was provided for 6 months and self-selected for 6 additional months. Measurements included body weight, resting metabolic rate (RMR), adherence to the ER prescription assessed using (2)H(2)(18)O, satiety, and eating behavior variables. The 10%ER group consumed significantly less energy (by (2)H(2)(18)O) than prescribed over 12 months (18.1 +/- 9.8%ER, P = 0.04), while the 30%ER group consumed significantly more (23.1 +/- 8.7%ER, P < 0.001). Changes in body weight, satiety, and other variables were not significantly different between groups. However, during self-selected eating (6-12 months) variability in % weight change was significantly greater in the 10%ER group (P < 0.001) and poorer weight outcome on 10%ER was predicted by higher baseline BMI and greater disinhibition (P < 0.0001; adj R(2) = 0.71). Weight loss at 12 months was not significantly different between groups prescribed 10 or 30%ER, supporting the efficacy of low ER recommendations. However, long-term weight change was more variable on 10%ER and weight change in this group was predicted by body size and eating behavior. These preliminary results indicate beneficial effects of low-level ER for some but not all individuals in a weight control program, and suggest testable approaches for optimizing dieting success based on individualizing prescribed level of ER.

Asunto(s)

RESUMEN

BACKGROUND: There remains no consensus about the optimal dietary composition for sustained weight loss. OBJECTIVE: The objective was to examine the effects of 2 dietary macronutrient patterns with different glycemic loads on adherence to a prescribed regimen of calorie restriction (CR), weight and fat loss, and related variables. DESIGN: A randomized controlled trial (RCT) of diets with a high glycemic load (HG) or a low glycemic load (LG) at 30% CR was conducted in 34 healthy overweight adults with a mean (+/-SD) age of 35 +/- 6 y and body mass index (kg/m(2)) of 27.6 +/- 1.4. All food was provided for 6 mo in diets controlled for confounding variables, and subjects self-administered the plans for 6 additional months. Primary and secondary outcomes included energy intake measured by doubly labeled water, body weight and fatness, hunger, satiety, and resting metabolic rate. RESULTS: All groups consumed significantly less energy during CR than at baseline (P < 0.01), but changes in energy intake, body weight, body fat, and resting metabolic rate did not differ significantly between groups. Both groups ate more energy than provided (eg, 21% and 28% CR at 3 mo and 16% and 17% CR at 6 mo with HG and LG, respectively). Percentage weight change at 12 mo was -8.04 +/- 4.1% in the HG group and -7.81 +/- 5.0% in the LG group. There was no effect of dietary composition on changes in hunger, satiety, or satisfaction with the amount and type of provided food during CR. CONCLUSIONS: These findings provide more detailed evidence to suggest that diets differing substantially in glycemic load induce comparable long-term weight loss.

Asunto(s)

Asunto(s)