Current Pharmaceutical Design - Volume 25, Issue 39, 2019

The extraordinary rise in the old population in the Western world underscores the importance of studies on aging and longevity to decrease the medical, economic and social problems associated with the increased number of non-autonomous individuals affected by invalidating pathologies. Centenarians have reached the extreme limits of the human life span. They are the best example of extreme longevity, representing selected individuals in which the appearance of major age-related diseases has been consistently delayed or avoided. There is growing evidence that the genetic component of longevity becomes higher with survival at the age of over 90 years. For centenaries, it reaches up to 33% for women and 48% for men. Therefore, exceptional longevity is a complex, hereditable trait that runs across generations. Longevity should correlate either with the presence of protective alleles or the absence of detrimental alleles. The aim of this review is to discuss the possible attainment of successful aging in the context of the lessons learned from centenarian genetics.

Patterns of DNA methylation, the best characterized epigenetic modification, are modulated by aging. In humans, different studies at both site-specific and genome-wide levels have reported that modifications of DNA methylation are associated with the chronological aging process but also with the quality of aging (or biological aging), providing new perspectives for establishing powerful biomarkers of aging. In this article, the role of DNA methylation in aging and longevity has been reviewed by analysing literature data about DNA methylation variations occurring during the lifetime in response to environmental factors and genetic background, and their association with the aging process and, in particular, with the quality of aging. Special attention has been devoted to the relationship between nuclear DNA methylation patterns, mitochondrial DNA epigenetic modifications, and longevity. Mitochondrial DNA has recently been reported to modulate global DNA methylation levels of the nuclear genome during the lifetime, and, in spite of the previous belief, it has been found to be the target of methylation modifications. Analysis of DNA methylation profiles across lifetime shows that a remodeling of the methylome occurs with age and/or with age-related decline. Thus, it can be an excellent biomarker of aging and of the individual decline and frailty status. The knowledge about the mechanisms underlying these modifications is crucial since it might allow the opportunity for targeted treatment to modulate the rate of aging and longevity.

Aging is a multifactorial process that affects the organisms at genetic, molecular and cellular levels. This process modifies several tissues with a negative impact on cells physiology, tissues and organs functionality, altering their regeneration capacity. The chronic low-grade inflammation typical of aging, defined as inflammaging, is a common biological factor responsible for the decline and beginning of the disease in age. A murine parabiosis model that combines the vascular system of old and young animals, suggests that soluble factors released by young individuals may improve the regenerative potential of old tissue. Therefore, circulating factors have a key role in the induction of aging phenotype. Moreover, lifestyle can influence the physiological status of multiple organs, via epigenetic mechanisms. Recently, microRNAs are considered potential sensors of aging.

With advancing age, immune responses of human beings to external pathogens, i.e., bacteria, viruses, fungi and parasites, and to internal pathogens - malignant neoplasm cells - become less effective. Two major features in the process of aging of the human immune system are immunosenescence and inflammaging. The immune systems of our predecessors co-evolved with pathogens, which led to the occurrence of effective immunity. However, the otherwise beneficial activity may pose problems to the organism of the host and so it has builtin brakes (regulatory immune cells) and - with age - it undergoes adaptations and modifications, examples of which are the mentioned inflammaging and immunosenescence. Here we describe the mechanisms that first created our immune systems, then the consequences of their changes associated with aging, and the mechanisms of inflammaging and immunosenescence. Finally, we discuss to what extent both processes are detrimental and to what extent they might be beneficial and propose some therapeutic approaches for their wise control.

Aging is characterized by a general decline in a range of physiological functions, with a consequent increase in the risk of developing a variety of chronic diseases and geriatric syndromes. Additionally, increasing age is accompanied by a progressive decline in both innate and acquired immune system, referred to as immunosenescence. This impaired ability to mount an efficient immune response after exposure to microorganisms or vaccines represents a major challenge in acquiring protection against pathogens in aging. Therefore, there is still a great need for vaccines that are tailored to optimally stimulate the aged immune system, thus promoting more successful aging. Various strategies can be used to improve vaccine efficacy in old people. Despite this, metaanalyses have clearly shown that the magnitude of protection obtained remains lower in older adults. Recent studies show that stimulation of Toll-like receptors, using stimulatory ligands, can enhance vaccine efficacy by a number of mechanisms, including the activation of innate immune cells and the consequent production of inflammatory cytokines. Therefore, a possible strategy for more effective vaccination in the older population is the triggering of multiple TLRs, using a combined adjuvant for the synergistic activation of cellular immunity. Preliminary in vitro data suggest that in humans the presence of multiple TLR agonists can result in the greater stimulation of antigen-specific immune responses in immune cells both in the young healthy and in the immune senescent older donors. These data suggest that appropriately selected combinations of TLR agonists could enhance the efficacy of vaccination mediated immunity in older people.

Chronic neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative age-associated disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson’s disease, and dementia. In particular, persistent low-grade inflammation may disrupt the brain endothelial barrier and cause a significant increase of pro-inflammatory cytokines and immune cells into the cerebral tissue that, in turn, leads to microglia dysfunction and loss of neuroprotective properties. Nowadays, growing evidence highlights a strong association between persistent peripheral inflammation, as well as metabolic alterations, and neurodegenerative disorder susceptibility. The identification of common pathways involved in the development of these diseases, which modulate the signalling and immune response, is an important goal of ongoing research. The aim of this review is to elucidate which inflammation-related molecules are robustly associated with the risk of neurodegenerative diseases. Of note, peripheral biomarkers may represent direct measures of pathophysiologic processes common of aging and neuroinflammatory processes. In addition, molecular changes associated with the neurodegenerative process might be present many decades before the disease onset. Therefore, the identification of a comprehensive markers panel, closely related to neuroinflammation, could be helpful for the early diagnosis, and the identification of therapeutic targets to counteract the underlying chronic inflammatory processes.

Increasing age is a strong, independent risk factor for atherosclerosis and cardiovascular disease. Key abnormalities driving cardiovascular risk in old age include endothelial dysfunction, increased arterial stiffness, blood pressure, and the pro-atherosclerotic effects of chronic, low-grade, inflammation. The identification of novel therapies that comprehensively target these alterations might lead to a major breakthrough in cardiovascular risk management in the older population. Systematic reviews and meta-analyses of observational studies have shown that methotrexate, a first-line synthetic disease-modifying anti-rheumatic drug, significantly reduces cardiovascular morbidity and mortality in patients with rheumatoid arthritis, a human model of systemic inflammation, premature atherosclerosis, and vascular aging. We reviewed in vitro and in vivo studies investigating the effects of methotrexate on endothelial function, arterial stiffness, and blood pressure, and the potential mechanisms of action involved. The available evidence suggests that methotrexate might have beneficial effects on vascular homeostasis and blood pressure control by targeting specific inflammatory pathways, adenosine metabolism, and 5' adenosine monophosphate-activated protein kinase. Such effects might be biologically and clinically relevant not only in patients with rheumatoid arthritis but also in older adults with high cardiovascular risk. Therefore, methotrexate has the potential to be repurposed for cardiovascular risk management in old age because of its putative pharmacological effects on inflammation, vascular homeostasis, and blood pressure. However, further study and confirmation of these effects are essential in order to adequately design intervention studies of methotrexate in the older population.

Melatonin, an indoleamine secreted mainly by the pineal gland, is known to modulate a wide range of circadian functions. However, this neurohormone is also synthesized within the eye and acts directly on ocular structures to mediate a variety of physiological processes. This review is focused on the role and therapeutic potential of melatonin in ocular diseases. We summarize data indicating that melatonin may represent a powerful tool to counteract ocular dysfunctions such as uveitis, glaucoma, age-related macular degeneration, and diabetic retinopathy. A search strategy was conducted to identify studies in PubMed (January 1990 to September 2017). In particular, we included experimental studies, clinical trials, and reviews to provide suitable insights and elucidations regarding the action of melatonin on age-related ocular disorders. Literature data suggest that melatonin could potentially protect ocular tissues by decreasing the production of free radicals and pro-inflammatory mediators. Additionally, melatonin appears to be safe and well-tolerated, even at high doses, and no adverse/side effects were reported. Although this topic remains under intense investigation, we can conclude that melatonin, as a single agent or in combination with other drugs, is an attractive pharmacological candidate for age-related ocular diseases.

Background: Most of the anticancer chemotherapies are hampered via the development of multidrug resistance (MDR), which is the resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, changes in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-ΚB are also responsible for MDR. Methods: In this study, we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. Pubmed and Scopus have been searched using Wnt, β-catenin, cancer, MDR and multidrug resistance as keywords. The last search was done in March 2019. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. The main focus of the manuscript is regulation of MDR related transporters by canonical Wnt signaling pathway. Result and conclusion: Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical pathways. Aberrant activation of Wnt/β- catenin signaling leads to the induction of cancer MDR mainly through the overexpression and/or over-activation of MDR related transporters. Accordingly, Wnt/β-catenin signaling can be a potential target for modulating cancer MDR.

Background: Traumatic brain injury (TBI) can cause disorders of consciousness (DOC) by impairing the neuronal circuits of the ascending reticular activating system (ARAS) structures, including the hypothalamus, which are responsible for the maintenance of the wakefulness and awareness. However, the effectiveness of drugs targeting ARAS activation is still inadequate, and novel therapeutic modalities are urgently needed. Methods: The goal of this work is to describe the neural loops of wakefulness, and explain how these elements participate in DOC, with emphasis on the identification of potential new therapeutic options for DOC induced by TBI. Results: Hypothalamus has been identified as a sleep/wake center, and its anterior and posterior regions have diverse roles in the regulation of the sleep/wake function. In particular, the posterior hypothalamus (PH) possesses several types of neurons, including the orexin neurons in the lateral hypothalamus (LH) with widespread projections to other wakefulness-related regions of the brain. Orexins have been known to affect feeding and appetite, and recently their profound effect on sleep disorders and DOC has been identified. Orexin antagonists are used for the treatment of insomnia, and orexin agonists can be used for narcolepsy. Additionally, several studies demonstrated that the agonists of orexin might be effective in the treatment of DOC, providing novel therapeutic opportunities in this field. Conclusion: The hypothalamic-centered orexin has been adopted as the point of entry into the system of consciousness control, and modulators of orexin signaling opened several therapeutic opportunities for the treatment of DOC.