Current Pharmaceutical Design - Volume 20, Issue 18, 2014

Improvements in health care have increased human life expectancy in recent decades, and the elderly population is thus increasing in most developed countries. Unfortunately this still means increased years of poor health or disability. Since it is not yet possible to modify our genetic background, the best anti-aging strategy is currently to intervene on environmental factors, aiming to reduce the incidence of risk factors of poor health. Calorie restriction (CR) with adequate nutrition is the only non-genetic, and the most consistent non-pharmacological intervention that extends lifespan in model organisms from yeast to mammals, and protects against the deterioration of biological functions, delaying or reducing the risk of many age-related diseases. The biological mechanisms of CR’s beneficial effects include modifications in energy metabolism, oxidative stress, insulin sensitivity, inflammation, autophagy, neuroendocrine function and induction of hormesis/xenohormesis response. The molecular signalling pathways mediating the anti-aging effect of CR include sirtuins, peroxisome proliferator activated receptor G coactivator-1α, AMP-activated protein kinase, insulin/insulin growth factor-1, and target of rapamycin, which form a pretty interacting network. However, most people would not comply with such a rigorous dietary program; research is thus increasingly aimed at determining the feasibility and efficacy of natural and/or pharmacological CR mimetic molecules/ treatments without lowering food intake, particularly in mid- to late-life periods. Likely candidates act on the same signalling pathways as CR, and include resveratrol and other polyphenols, rapamycin, 2-deoxy-D-glucose and other glycolytic inhibitors, insulin pathway and AMP-activated protein kinase activators, autophagy stimulators, alpha-lipoic acid, and other antioxidants.

The present review points out the role of oxidative stress in aging and the potential therapeutic targets of modern antioxidant therapies. Mitochondria are essential for several biological processes including energy production by generating ATP through the electron transport chain (ETC) located on the inner mitochondrial membrane. Due to their relevance in cellular physiology, defects in mitochondria are associated with various human diseases. Moreover, several years of research have demonstrated that mitochondria have a pivotal role in aging. The oxidative stress theory of aging suggests that mitochondria play a key role in aging as they are the main cellular source of reactive oxygen species (ROS), which indiscriminately damage macromolecules leading to an age-dependent decline in biological function. In this review we will discuss the mitochondrial dysfunction occurring in aging. In particular, we will focus on the novel mitochondria targeted therapies and the new selective molecules and nanocarriers technology as potentially effective in targeting mitochondrial dysfunction and diseases involving oxidative stress and metabolic failure.

Degradation of the extracellular matrix is an important feature of embryonic development, morphogenesis, angiogenesis, tissue repair and remodeling. It is precisely regulated under physiological conditions, but when dysregulated it becomes a cause of many diseases, including atherosclerosis, osteoarthritis, diabetic vascular complications, and neurodegeneration. Various types of proteinases are implicated in extracellular matrix degradation, but the major enzymes are considered to be metalloproteinases such as matrix metalloproteinases (MMPs) and disintegrin and metalloproteinase domain (ADAMs) that include ADAMs with a thrombospondin domain (ADAMTS). This review discusses involvement of the major metalloproteinases in some age-related chronic diseases, and examines what is currently known about the beneficial effects of their inhibitors, used as new therapeutic strategies for treating or preventing the development and progression of these diseases.

Scientific evidence links physical activity to several benefits. Recently, we proposed the idea that exercise can be regarded as a drug. As with many drugs, dosage is of great importance. However, to issue a public recommendation of physical activity in aging is not an easy task. Exercise in the elderly needs to be carefully tailored and individualized with the specific objectives of the person or group in mind. The beneficial effects of exercise in two of the main age-related diseases, sarcopenia and Alzheimer's Disease, are dealt with at the beginning of this report. Subsequently, dosage of exercise and the molecular signaling pathways involved in its adaptations are discussed. Exercise and aging are associated with oxidative stress so the paradox arises, and is discussed, as to whether exercise would be advisable for the aged population from an oxidative stress point of view. Two of the main redox-sensitive signaling pathways altered in old skeletal muscle during exercise, NF-κB and PGC-1α, are also reviewed. The last section of the manuscript is devoted to the age-associated diseases in which exercise is contraindicated. Finally, we address the option of applying exercise mimetics as an alternative for disabled old people. The overall denouement is that exercise is so beneficial that it should be deemed a drug both for young and old populations. If old adults adopted a more active lifestyle, there would be a significant delay in frailty and dependency with clear benefits to individual well-being and to the public’s health.

Tocopherols, with a phytyl side chain in its chroman ring, belong to vitamin E family and have several effects on organisms. They are also classified as therapeutics against different types of human diseases. Especially important roles in cell signaling and gene regulatory mechanisms make tocopherols crucial as therapeutic agents. Aging is accompanied with several degenerative disorders including cardiovascular, neuronal and metabolic diseases. The role of free radical damage in aging has been identified and tocopherols were shown to be involved in age related disorders. Recent studies and future directions will be focused in this review regarding the molecular functions of tocopherols.

The science and study of the biological basis of aging, biogerontology, is now a well-established field with solid scientific base. A paradigm-shift in gerontology has occurred by realising the fact that biological aging occurs in spite of the presence of complex homeodynamic pathways of maintenance, repair and defence, and there is no “enemy within”. This viewpoint separates the modulation of aging from the treatment of one or more age-related diseases. A promising strategy in biogerontology is to slow down aging and to extend healthspan by hormetin-mediated hormesis. Physical, nutritional and mental hormetins, which initiate stress responses and strengthen the homeodynamics, are potentially effective aging modulators. As a biomedical issue, the biological process of aging underlies all major diseases, and while the optimal treatment of every disease is a social and moral necessity, preventing the onset of agerelated diseases by intervening in the basic process of aging is the best approach for designing novel pharmaceutical interventions.

A number of studies reported a relation between longevity, oxidative stress and age-related diseases. Every aerobic organism is inevitably exposed to a permanent flux of free radicals and oxidants. Due to the limited activity of antioxidant and repair mechanisms, levels of reactive oxygen species can increase during aging. Protein damage caused by elevated levels of free radicals or oxidants has an important influence on cellular viability and leads to malfunction of proteins in aged cells. In addition, modified and impaired proteins can cross-link and form the bases of many senescence-associated alterations and also of neurodegenerative diseases. To ensure the maintenance of normal cellular functions, eukaryotic cells exert proteolysis through two systems: the proteasomal system and the lysosomal system, which is degrading cellular components after autophagy. During cellular differentiation and aging, both systems are subject to extensive changes that significantly affect their proteolytic activity. It has been suggested that highly modified proteins and undegradable protein aggregates also affect the intracellular proteolytic systems. Therefore, it is essential to understand the relationship between protein oxidation, intracellular proteolytic systems and cellular defence mechanisms.

Aging is a stage of life of all living organisms. According to the free-radical theory, aging cells gradually become unable to maintain cellular homeostasis due to the adverse effects of reactive oxygen species (ROS). ROS can cause irreversible DNA mutations, protein and lipid damage which are increasingly accumulated in the course of time if cells could not overcome these effects by the antioxidant defence system. Accrued damaged molecules in cells may either induce cellular death or contribute to develop various pathologies. Hence, programmed cell death mechanisms, apoptosis and autophagy, play a vital role in the aging process. Although they are strictly controlled by various interconnected signalling pathways, alterations in their regulations may contribute to severe pathologies including cancer, Alzheimer’s and Parkinson’s diseases. In this review, we summarized our current understanding and hypotheses regarding oxidative stress and age-related dysregulation of cell death signalling pathways.

Frailty has emerged as one of the most relevant clinical syndromes in older patients. This term relates to the loss of functional reserve that can occur in some older people following exposure to one or more low-intensity stressors placing them at high risk for developing a number of adverse outcomes such as disability, falls, hospitalization and death. Frailty is the outcome of two combined effects: the ageing process and other superimposed injuries like chronic disease or, indeed, psychological and social stressors. The mechanisms leading to frailty typically involve several systems: mainly hormones, oxidative stress, inflammation, immunity, and vascular system. One of the most outstanding pillars of the frailty syndrome is the loss of muscle quantity and function, referred to as sarcopenia. The main bulk of experimental pharmacological interventions addressing the clinical problem of frailty have been focused on the use of hormones, as replacement therapy in subjects with low or normal circulating basal levels of the hormone. Results have been disappointing, except for the case of testosterone that have shown some benefits. The effectiveness of other potential therapeutic interventions (antioxidants, anti-inflammatory agents, nutritional supplements) appears to be limited or has not been explored in detail until now. In conclusion, there is an available path to prevent the development of disability in older people through the treatment of frailty, its main risk factor. Aditional research and further experimental testing will help to identify new targets and help to make this journey successful.

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder representing the most common form of dementia and the most feared highly disabling age-related condition of our time. Hallmarks of AD include a dramatically increasing number of cases due to prospected demographics and the absence of a cure. AD is incurable as it escapes the formula “one disease, one mechanism, one drug”. AD has a multifaceted pathophysiology only in part uncovered. Even the proven chronological primacy of free radical-related damage in AD-related neurodegeneration has not yield successful oxidative stress – lowering trial designs. As a consequence, clinical trials of antioxidants in AD have brought largely negative conclusions. The aims of this review are to discuss 1. rationale for antioxidant trials, 2. reasons for failure of antioxidants in AD therapy, 3. potential preventive benefits of natural nutrition against AD onset and 4. the enormous relevance of detecting and treating AD risk factors as long as possible prior to AD manifestation.