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The present document describes a nutritional approach that is nested in the European Innovation Partnership for Active and Healthy Aging (EIP-AHA) and aims to provide the first common European program translating an integrated approach to nutritional frailty in terms of a multidimensional and transnational methodology. The document has been developed by the A3 Nutrition Action Area of the EIP-AHA and aims at providing a stepwise approach to malnutrition in older citizens, identifying adequate interventions based on a unified assessment and ICT-supported solutions. “NutriLive” is an integrated nutritional approach, represented by a structured Screening-Assessment-Monitoring-Action-Pyramid-Model (SAM-AP). Its core concept is the stratification of the nutritional needs, considered by the working group as the key for targeted, effective, and sustainable interventions. “NutriLive” tries to close gaps in epidemiological data within an aging population, creating a unified language to deal with the topic of nutrition and malnutrition in Europe. By assembling all the validated screening, assessment, and monitoring tools on malnutrition in a first pyramid, which is interrelated to a second intervention pyramid, the A3 Nutrition WG identifies a common, integrated vision on the nutritional approach to frailty, which applies to the various health care settings.

Arteriosclerosis is a degenerative process that is physiological in aging but can be accelerated by number of risk factors, such as hypertension, diabetes, obesity, smoking, familial history. Healthy vessel walls harbour vascular smooth muscle cells, fibroblasts, endothelial cells, whereas in arteriosclerotic vessels inflammatory cells such as activated macrophages are also present. The biology of all these cells is tuned by calcium, that regulates both acute and adaptive, chronic events. Calcium signalling plays an important role in the regulation of cell proliferation through the crosstalk between multifunctional Calcium-Calmodulin dependent kinases (CaMKs) and a number of other signalling pathways, such as Erk. Nevertheless, how these cellular pathways interact with each other has yet to be investigated. Our recent studies demonstrate that a murine model lacking CaMKIV presents early onset arteriosclerosis, as well as increased CaMKII activity in selected cell types, thus implying a role for calcium signaling in the process. The recent genome-wide analysis of the Framingham Heart Study 100K Project shows an association between elevated diastolic blood pressure and the rs10491334 T/C Single Nucleotide Polymorphism of human CaMKIV gene. This finding suggests for this kinase, whose expression was once thought to be confined to the nervous tissue, a yet undisclosed role in vascular responses. We also obtained evidences of the existence of a crosstalk between CaMKII and CaMKIV, involved in the regulation of cell cycle progression. These results indicate a novel interplay between CaMKs, that has never been investigated in the modulation of cell proliferative responses, and might have tremendous implications in arteriosclerosis.

The natural process of aging determinates several cardiac modifications with increased susceptibility to heart diseases and ultimately converging on development of chronic heart failure as final stage. These changes mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity, as demonstrated in several humans and animal models of aging. While different theories have been proposed to explain the natural process of aging, it is clear that most of the alterations affect mechanisms involved in cell homeostasis and maintenance. Latest research studies have in particular focused on role of mitochondrial oxidative stress, energy production and mitochondria quality control. This article reviews the central role played by this organelle in aging and the role of new molecular players involved into the progression toward heart failure and potentially susceptible of new "anti-aging" strategies.

Background and aims Atherosclerosis is a degenerative process of the arterial wall implicating activation of macrophages and proliferation of vascular smooth muscle cells. Calcium-calmodulin dependent kinase type II (CaMKII) in vascular smooth muscle cells (VSMCs) regulates proliferation, while in macrophages, this kinase governs diapedesis, infiltration and release of extracellular matrix enzymes. We aimed at understanding the possible role of CaMKII in atherosclerosis plaques to regulate plaque evolution towards stability or instability. Methods Clinically defined stable and unstable plaques obtained from patients undergoing carotid end arteriectomy were processed for evaluation of CaMKs protein expression, activity and localization. Results The larger content of CaMKII was found in CD14 + myeloid cells that were more abundant in unstable rather than stable plaques. To test the biological effect of activated CD14 + myeloid cells, VSMCs were exposed to the conditioned medium (CM) of macrophages extracted from carotid plaques. CM induced attenuation of CaMKs expression and activity in VSMCs, leading to the reduction of VSMCs proliferation. This appears to be due to the CaMKII dependent release of cytokines. Conclusions These results indicate a pivotal role of CaMKs in atherosclerosis by regulating activated myeloid cells on VSMCs activity. CaMKII could represent a possible target for therapeutic strategies based on macrophages specific inhibition for the stabilization of arteriosclerotic lesions.

The discovery of the anti-proliferative activity of nelfinavir in HIV-free models has encouraged its investigation as anticancer drug. Although the molecular mechanism by which nelfinavir exerts antitumor activity is still unknown, its effects have been related to Akt inhibition. Here we tested the effects of nelfinavir on cell proliferation, viability and death in two human breast cancer cell lines and in human normal primary breast cells. To identify the mechanism of action of nelfinavir in breast cancer, we evaluated the involvement of the Akt pathway as well as the effects of nelfinavir on reactive oxygen species (ROS) production and ROS-related enzymes activities. Nelfinavir reduced breast cancer cell viability by inducing apoptosis and necrosis, without affecting primary normal breast cells. The antitumor activity of nelfinavir was related to alterations of the cell redox state, coupled with an increase of intracellular ROS production limited to cancer cells. Nelfinavir treated tumor cells also displayed a downregulation of the Akt pathway due to disruption of the Akt-HSP90 complex, and subsequent degradation of Akt. These effects resulted to be ROS dependent, suggesting that ROS production is the primary step of nelfinavir anticancer activity. The analysis of ROS-producers and ROS-detoxifying enzymes revealed that nelfinavir-mediated ROS production was strictly linked to flavoenzymes activation. We demonstrated that ROS enhancement represents the main molecular mechanism required to induce cell death by nelfinavir in breast cancer cells, thus supporting the development of new and more potent oxidizing molecules for breast cancer therapy.

Aging is one of the most important societal challenges that western societies face, as a result of longer life expectancy and reduced natality rates. Aging is a success story of our health and social systems, but raises sustainability issues that are linked to the increased need for services of older adults, due to the reduction of their independence and to the co-existence of multiple chronic diseases. The metabolic syndrome can be considered an age-related disease, since its prevalence increases with age. Current demographic trends in the population highlight aging-related dysfunctions that contribute to the onset of several metabolic diseases, and the need for innovative, effective and sustainable approaches. This review describes the correlation between the metabolic syndrome and aging, and the underlying common molecular mechanisms, focusing on calcium signaling and its crosstalks.

AIMS: Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization. METHODS AND RESULTS: In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat-CN17β, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat-CN17β pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17β. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart. CONCLUSION: These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy.