Current Pharmaceutical Design - Volume 20, Issue 38, 2014

Worldwide, the percentage of people aged over 60 years is growing up quicker than any other age group, as a result of both longer life expectancy and declining birth rates as well as a success of the public health policies and the socioeconomic development. The World Health Organization (WHO) has been pointed out recently that: “currently, one in every nine people in the world is 60 years of age or older. This is expected to increase to one in five people by 2050”. This success (the transition to a much older population) is a challenge for the modern society that shall maximize the health and the functional ability of older people as well as their social participation and safety to achieve an “active ageing”. “Health” refers to physical, mental and social well being as expressed in the WHO definition of health: “maintaining autonomy and independence for the older people is a key goal in the policy framework for active ageing”. “Active” refers to “continuing participation in social, economic, cultural, spiritual and civic affairs, not just the ability to be physically active or to participate in the labour force”. In this issue Alzetta et al. (University of Genoa, Italy) reviews the grounds and patterns of the structuring of longevity and ageing in our society [1]. The older people, even in poor countries, die of non-communicable diseases (NCDs), such as heart disease, cancer or diabetes, rather than of infectious or parasitic diseases. On 2010, the UN General Assembly passed the resolution A/RES/64/265NCD recognizing “the enormous human suffering, premature death and the seriously negative socioeconomic impact caused by the growing burden of NCD” and called for “global and national action at the highest level to address this development issue”. In this special issue Bousquet et al. (Inserm, France) review the complexity of NCDs intertwined with ageing, show an overview of the problem and propose practical examples of System Medicine (SM) applied to NCDs [2]. Moreover, Cesario et al. (IRCCS “San Raffaele Pisana”, Italy) review the novel system approaches to NCDs, discuss the passage from System Biology (SM) to SM and present the scientific and clinical background of a SM platform [3]. In this issue different pathologies, clinical conditions and pharmacological approaches are reviewed considering the role of ageing. Mazzucco et al. (Catholic University, Italy) review breast cancer in various age-groups and the response to Trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor [4]. Piotrowicz et al. (Jagiellonian University, Poland) review the pharmacological management of hypertension [5], Matera et al. (Second University of Naples) propose new treatment for chronic obstructive pulmonary disease (COPD) [6], and Zanandrea et al. (University of Toulose, France) review the treatment of sarcopenia [7]. As the population ages, the burden of neurodegenerative disorders, including Alzheimer disease (AD), will increase creating an unsustainable healthcare challenge due to a lack of effective treatment. In this issue Hasnain and Vieweg (Memorial University of Newfoundland, Canada) overview the vascular risk factors in AD and vascular dementia [8]. AD is characterized by disturbance of various high pre- and cortical functions. Cholinergic projections innervate the prefrontal cortex and reduced cholinergic function is associated with cognitive deficits. Cholinergic neurons are specific neurons that synthesize and release acetylcholine (ACh). ACh acts at nicotinic receptors (nAChR) and muscarinic receptors (mAChR). U.S. Food and Drug Administration (FDA) and The European Medicines Agency (EMA) approved several prescription drugs to treat people who have been diagnosed with AD. The drugs include: Razadyne® (galantamine), Exelon® (rivastigmine), and Aricept® (donepezil). These drugs target acetylcholinesterase (defined acetylcholinesterase inhibitors: AChEI) and, in principle, elevate cholinergic signaling. Another drug is known as Namenda® (Memantine), an N-methyl D-aspartate (NMDA) antagonist. None of these medications stops the disease itself: they help to maintain thinking, memory, and speaking skills but don’t influence the disease’ progression. Unfortunately these drugs are effective only for some patients, and may help only for a limited period of time. In this issue different authors describe new pharmacological approaches to neurodegenerative diseases beyond AChEI. Russo et al. (IRCCS “San Raffaele Pisana”, Italy) in this issue describe the neurobiology of the

If longevity is a biological and demographic indicator to determine human lifetime extension, hyper-longevity notion can represent a heuristic tool to better disentangle the complex bio-psycho-social implications of ageing and elderly in Western developed globalised countries. Departing from the assumption of a holistic approach to human condition understanding, it is possible to reveal the grounds and patterns of a multilayered and multidimensional structuring of longevity and ageing in our societies that would lead to a form of hyper-longevity. Socio-cultural processes, underlying hyper-longevity notion, rise the question of transition from modern/ latemodern societies to post-modern ones and it offers room for a cultural analysis of concepts, such as space time compression, digital capitalism, knowledge and mass information society. These are relevant ideas that can contribute to reshape and rethink the boundaries and traits of ageing experience in 21st century societies. To better catch the point emerging social category of Baby Boomers is presented and used to provide a concrete context related example on how hyper-longevity can better explain complex social evidences in many cultural respects and social domains. As a conclusive step some preliminary reflections, largely centered on the relation between Baby Boomers, hyper-longevity and bio-medical sciences are presented and discussed to provide a starting point for further future analyses within a trans and inter-disciplinary framework.

Chronic diseases are diseases of long duration and slow progression. Major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases, diabetes, rheumatologic diseases and mental health) represent the predominant health problem of the Century. The prevention and control of NCDs are the priority of the World Health Organization 2008 Action Plan, the United Nations 2010 Resolution and the European Union 2010 Council. The novel trend for the management of NCDs is evolving towards integrative, holistic approaches. NCDs are intertwined with ageing. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has prioritised NCDs. To tackle them in their totality in order to reduce their burden and societal impact, it is proposed that NCDs should be considered as a single expression of disease with different risk factors and entities. An innovative integrated health system built around systems medicine and strategic partnerships is proposed to combat NCDs. It includes (i) understanding the social, economic, environmental, genetic determinants, as well as the molecular and cellular mechanisms underlying NCDs; (ii) primary care and practice-based interprofessional collaboration; (iii) carefully phenotyped patients; (iv) development of unbiased and accurate biomarkers for comorbidities, severity and follow up of patients; (v) socio-economic science; (vi) development of guidelines; (vii) training; and (viii) policy decisions. The results could be applicable to all countries and adapted to local needs, economy and health systems. This paper reviews the complexity of NCDs intertwined with ageing. It gives an overview of the problem and proposes two practical examples of systems medicine (MeDALL) applied to allergy and to NCD co-morbidities (MACVIA-LR, Reference Site of the European Innovation Partnership on Active and Healthy Ageing).

Non-Communicable Diseases (NCDs) are among the most pressing global health problems of the twenty-first century. Their rising incidence and prevalence is linked to severe morbidity and mortality, and they are putting economic and managerial pressure on healthcare systems around the world. Moreover, NCDs are impeding healthy aging by negatively affecting the quality of life of a growing number of the global population. NCDs result from the interaction of various genetic, environmental and habitual factors, and cluster in complex ways, making the complex identification of resulting phenotypes not only difficult, but also a top research priority. The degree of complexity required to interpret large patient datasets generated by advanced high-throughput functional genomics assays has now increased to the point that novel computational biology approaches are essential to extract information that is relevant to the clinical decision-making process. Consequently, system-level models that interpret the interactions between extensive tissues, cellular and molecular measurements and clinical features are also being created to identify new disease phenotypes, so that disease definition and treatment are optimized, and novel therapeutic targets discovered. Likewise, Systems Medicine (SM) platforms applied to extensively-characterized patients provide a basis for more targeted clinical trials, and represent a promising tool to achieve better prevention and patient care, thereby promoting healthy aging globally. The present paper: (1) reviews the novel systems approaches to NCDs; (2) discusses how to move efficiently from Systems Biology to Systems Medicine; and (3) presents the scientific and clinical background of the San Raffaele Systems Medicine Platform.

Indication for the use of trastuzumab was given in Italy in 2000 for the treatment of HER-2 metastatic breast cancer and in 2006 for early stage breast cancer. Information on trastuzumab use and on its possible variation with age in Italy is however limited. Using health care administrative databases, we evaluated the prevalence of the use of trastuzumab, and the probability for administration since the first hospitalization for breast cancer in various age groups, in two series of Italian women diagnosed with breast cancer in the Lombardy region (2004-2009) and in the Palermo district. The ratio between trastuzumb users and patients with a hospitalization for breast cancer increased from 2.9% in 2004 up to 17.2% in 2009 in Lombardy. Patients aged <65 years were more frequent users (9.6%) compared to those aged ≥ 75 years (1.3%). Similarly, in the Palermo district the ratio increased from 10.6% in 2006 to 28.5% in 2008, with subjects aged <65 years more frequently using trastuzumab (19.1%), than subjects aged ≥ 75 years (6.2%). The age ratio between younger and older patients decreased over time in both settings (from 15 in 2004 to 10.2 in 2006, and 5.2 in 2009 in Lombardy, and from 4.0 in 2006 to 2.3 in 2009 in the Palermo district). The proportion of breast cancer patients using trastuzumab increased over time both in Lombardy and in Palermo district, though geographical differences persisted. Younger breast cancers patients were more likely to receive a trastuzumab treatment than elderly ones, but the difference declined over calendar period.

This paper summarizes the evidence supporting the pharmacological treatment of hypertension in the elderly as well as some the remaining controversies. The world is becoming progressively older and with that, the prevalence of hypertension is increasing. A peculiar form of hypertension, most prevalent among the elderly, is isolated systolic hypertension (ISH). Hypertension in the elderly, especially when systolic blood pressure (SBP) exceeds 160 mm Hg should be treated. Lowering the SBP to less than 150 mm Hg confers substantial cardiovascular protection. This has been demonstrated in both older and newer drugs for ISH and systolo-diastolic hypertension and is beneficial in both younger individuals (60-79 years) and uncomplicated elderly (80+ years) individuals suffering from hypertension. However, a number of issues remain controversial. Firstly, the 140 mm Hg cut-off for SBP cannot be applied to all age groups. It is conceivable that lowering the SBP below 140mm Hg in some patients, particularly in the elderly may not be beneficial. Hence, the generalizations made in clinical trials should be approached with caution. Additionally some drugs, such as beta-blockers, thiazide diuretics may be associated with significantly less benefit in the elderly patients. More research is needed, especially in the areas where we lack data: the first stage of uncomplicated ISH or hypertension in the elderly with associated co-morbidities.

In elderly people the respiratory function is affected by anatomical and physiological modifications caused by aging. Elderly COPD patients are characterized by a complexity due to an increasing prevalence of comorbidities related to the age that suggest peculiar care in prescribing the therapy in those patients, also considering other disabilities that are not related with respiratory disorders as physical and mental limitations. Nowadays a therapy that allows modifying the long-term decline in lung function of patients suffering from COPD does not yet exist and, therefore, the treatment of this disease is mainly focused on the administration of bronchodilators and the use of inhaled glucocorticoids. As for younger subjects, also in elderly patients the main classes of bronchodilators used in the treatment of COPD include β2-agonists, anticholinergics and methylxanthines. The inflammatory response suppression represents another mechanistic approach for treating COPD in the elderly, although the use of inhaled corticosteroids is limited to specific indications. Indeed, nowadays there is a strong medical need for novel treatments of COPD in the elderly. These are mainly represented by agents that reduce the spillover of inflammatory mediators from the lung and by compounds that inhibit the chronic systemic inflammatory syndrome. The therapeutic approach of COPD in elderly patients remains a topic of increasing interest, however the development of novel compounds for preventing the COPD progression in the elderly, other than bronchodilators and corticosteroids, remains a challenge.

The term "sarcopenia" describes the age-related loss of skeletal muscle mass and function. It represents a major risk factor for functional loss and disability in older persons. Multiple underlying pathophysiological mechanisms have been posed at the basis of the sarcopenia phenomenon, including intrinsic (e.g., age-related modifications of the skeletal muscle, the central nervous system, and hormones) and extrinsic (e.g., sedentariness, poor protein dietary intake) factors. Several interventions have been explored in the last years to counteract the age-related muscle decline. These include protein supplementations, physical exercise, testosterone replacement (as well as other anabolic androgens) in men, estrogen replacement in women, growth hormone replacement, and treatment of vitamin D deficiency. To date, adequate protein intake and resistance training are the most promising interventions able to prevent and/or delay the decline of muscle mass and function. An intense debate is currently ongoing about the best operational definition able to capture the complexity of this aging condition. In the context of identifying the optimal treatment for a specific condition, this is not a trivial issue because it sets the target of the intervention as well as the population at risk. Nevertheless, despite the current methodological issues, it is important to preliminarily test the possible strategies that might be implemented in the future, when the sarcopenia condition will finally be more univocally defined and its clinical relevance recognized. Aim of the present review is to describe and discuss available evidence about the possible interventions potentially serving at acting against sarcopenia. Pharmacological as well as non-pharmacological interventions are presented.

The contribution of vascular risk factors to Alzheimer-vascular spectrum dementias is increasingly being recognized. We provide an overview of recent literature on this subject. Overweight and obesity as well as underweight during midlife predict cognitive decline and dementia later in life. Hypertension during midlife is also associated with dementia later in life and the association is stronger for untreated hypertension. Calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin-1 receptor-blockers may be particularly beneficial in diminishing the risk of dementia associated with hypertension. Studies have fairly consistently shown that type 2 diabetes is a risk factor for dementia. Episodes of hypoglycemia add to this risk. Regular physical exercise during any point in the lifespan protects against cognitive decline and dementia. Most benefit is realized with physical exercise during early and midlife. Dyslipidemia also increases the risk of dementia but the findings are less consistent. Findings on the possible benefit of lipid-lowering agents (statins) are conflicting. Earlier studies identified smoking as protective of dementia but recent better designed studies have consistently shown that smoking increases the risk of dementia. The association of vascular risk factors with dementia is more robust for vascular dementia than Alzheimer’s disease. Heterogeneity of studies and lack of trials specifically designed to assess cognition as an endpoint make firm conclusions difficult. But considering the expected global burden of dementia and projected attributable risk of vascular risk factors to it, there is sufficient evidence to promote vascular risk factor reduction strategies as dementia prevention interventions.

The neuronal nicotinic alpha7-acetylcholine receptor (α7-nAChR) is a promising and attractive drug target for improving cognitive deficits in neuropsychiatric and neurological disorders such as Alzheimer's disease (AD). α7-nAChR belongs to the family of ligand gated ion channels. α7-nAChR is expressed in key brain regions (e.g. pre- and frontal cortex, hippocampus). It is involved in essential cognitive functions such as memory, thinking, comprehension, learning capacity, calculation, orientation, language, and judgment. α7-nAChR binds to amyloid peptide (Aβ) inducing either receptor activation or inhibition in an Aβ concentration-dependent mode. Aβ oligomers induce Τ phosphorylation via α7-nAChR activation. α7-nAChR agonists and/or α7-nAChR positive allosteric modulators may be useful in AD therapy. The current review enlightens: (i) α7-nAChR neurobiology, (ii) α7-nAChR role in cognition and (iii) in AD, and (iv) the clinical status of the most promising molecules for the treatment of cognitive dysfunction in AD.

Developing microRNA therapeutics for neurological diseases is both a promising opportunity and an extremely challenging topic for several reasons. The promise stems from the very small size of microRNAs, which makes them amenable for manipulation via short synthetic oligonucleotides or engineered viruses. Also, the fact that each microRNA may regulate numerous target transcripts of the same pathway predicts that such manipulations may affect an entire pathway rather than a single gene and gives reason to hope that low dose therapeutic targeting of the top microRNA in such a hierarchic pyramid would suffice to induce a focused change in the entire pyramid. However, these same features, which make microRNAs such promising targets for therapeutic manipulations also present great challenges. Thus the plethora of functional targets for each microRNA in specific cell types is yet far from being elucidated, which implies that the targets to be affected may not be those planned to be manipulated (a risk of ‘off-target’ effects). Also, the hierarchic order of microRNA regulation is yet unknown, which predicts a risk of complex, multi-leveled consequences following the manipulation of a single microRNA; and the delivery of oligonucleotide therapeutics into the brain is a challenge due to the blood-brain barrier. In this chapter, we briefly outline the current state of knowledge regarding microRNA regulation in different neuropathologies and sketch the emerging principles for the development of microRNA therapeutics for these diseases.We address issues such as modes of delivery and consideration of the inherited and acquired variability between individuals in the susceptibility to such treatments. We further refer in a somewhat more in-depth manner to the issue of manipulating microRNA functioning in the parasympathetic system and the pathway of cholinergic signaling. Beyond the brain and within it, cholinergic signaling controls inflammatory reactions, and microRNA changes would likely affect this function as well. Furthermore, microRNA regulation of cholinergic signaling involves the elements of complexity and hierarchy noted above, and is relevant to numerous neuropathologies and neurodegenerative syndromes. Research and translational efforts that lead to the development of microRNA therapeutics merit thorough discussion.

Many neurodegenerative diseases, referred to as misfolding diseases, are characterized by the formation and accumulation of pathological extracellular and intracellular misfolded aggregates. Ageing is considered the major risk factor for neurodegenerative disorders and, due to increase of mean lifespan, the clinical relevance is growing dramatically with a urgent need to find new effective therapeutic approaches. The intracellular antibody technology is a gene-based strategy which exploits the specificity of recombinant antibodies to neutralize or modify the function of intracellular and extracellular target antigens. Intrabodies can potentially recognize all the pathological conformers of a misfolding-prone protein, and therefore they are emerging as therapeutic agents for the treatment of misfolding diseases as well as molecular tools for the understanding of their pathogenesis. Here we focus on the application of intrabodies against two major age-related neurodegenerative disorders, Alzheimer’s disease (AD) and Parkinson’s disease (PD) and the description of in vivo gene delivery systems available for their potential entering in the clinical setting.

Obesity and pain are common problems affecting the older adult and a possible relationship between the two is considered. Obesity and pain themselves are significant burdens on the individual, the healthcare system, and society as a whole and they can lead to emotional conditions such as stress, anxiety, and depression – which lead to further healthcare utilization and burden. Cross-sectional studies have revealed a high correlation between pain and obesity and a few longitudinal studies implicate obesity as a risk factor for the development of pain and the associated reduction in quality of life. Obesity leads to pain due to mechanical stress and metabolic disruptions, so mitigating obesity may help reduce the risk of developing pain and improve recovery from pain. More research is warranted to elucidate the mechanistic links between obesity and pain and to determine the optimal treatment strategies for reducing these comorbities. Reducing obesity could reduce pain medication burden.

Chronic pain is a widespread healthcare problem affecting not only the patient but in many ways all the society. Chronic pain is a disease itself that endures for a long period of time and it is resistant to the majority of medical treatments that provide modest improvements in pain and minimum improvements in physical and emotional functioning. More co-existing chronic pain conditions may be present in the same individual (patient). The α9α10 nicotinic acetylcholine receptor (nAChR) may be a potential target in the pathophysiology of chronic pain, as well in the development of breast and lung cancers. α-conotoxins (α-CNT) are small peptides used offensively by carnivorous marine snails known as Conus that target nAChR. Among α-CNT there are potent and selective antagonists of α9α10 nAChR such as RgIA and Vc1.1 that produces both acute and long lasting analgesia. Moreover, these peptides accelerate the recovery of nerve function after injury, likely through immune/inflammatory-mediated mechanisms. We review the background, findings, implications and problems in using compounds that act on 910 nAChR.

Immune activation not only accompanies inflammation in various disorders including infections, autoimmune syndromes and cancer, but it also represents a characteristic feature of ageing. Immune deviations which are most widely expressed in the elderly include increased neopterin production and tryptophan breakdown. These biochemical events result from the activation of the immune system and are preferentially triggered by pro-inflammatory stimuli, such as the Th1-type cytokine interferon-γ. They seem to play a role in the development of several age-related disorders and might be involved in the pathogenesis of common symptoms, including neurobehavioral disorders (e.g., cognitive and mood disturbances), anemia, cachexia, weight-loss but also immunodeficiency. Concentrations of the biomarkers neopterin and Kyn/Trp were found to be predictive of overall disease specific mortality in coronary artery disease, infections and various types of cancer. Immune activation and inflammation are also accompanied by high output of reactive oxygen species and thereby may lead to the development of oxidative stress and contribute to the vitamin deficiency which is often observed in the elderly. Accordingly, increases in neopterin were found to correlate with a substantial decline in key vitamins, including folate and vitamin-B6, - B12, -C, -D and -E.

Our understanding of the determinants of human life span and longevity has increased markedly during the last few decades. A number of environmental, lifestyle and genetic factors associated with longevity have been identified, and the intricate interplay between these components has been recognized. Various therapeutic approaches, especially those at the somatotropic and immunological axes, have been presented as means to reverse some of the impairments that accompany the aging process. Nevertheless, a considerable level of unexplained interindividual variation exists in the human life span, and despite promising results in animal models, many of the rejuvenation trials in humans have yet to be successful. This review discusses the genetic component of human longevity and its phenotypic effectors: the biomarkers and their target pathways. The focus is set on the somatotropic and immunological axes. In addition, a new longevity biomarker candidate, a circulating cell-free DNA (cf-DNA), is presented. cf-DNA is unique in that virtually any dying or senescent cell type can release it, making it a sensitive and compelling biomarker for aging research. Lastly, this review discusses several of the rejuvenation strategies proposed to augment senescent phenotypes. Because there is a growing interest in personalized treatment modalities and risk prediction scores in various age-related disorders, we highlight some of the genetic and age- and sex-specific factors that can modulate the response to such interventions.

This monographic issue of Current Pharmacological Design discusses extensively on the innovative paradigms for disease control in Active and Healthy Ageing. Wellness, as a status to be achieved and maintained in our lives, getting longer and hopefully healtier, is the new and comprehensive declination of “health” itself, leading the shaping of research and research policy in the health domain worldwide. Many of the contributions describe the state of the art –and beyond- approaches for the most common diseases based on the available medical knowledge; two, in particular (Bousquet J et al., Cesario A, et al.), extend to the innovative approaches defined in the framework of the holistic and integrative philosophy of the Predictive, Preventive, Personalized and Participatory (P4) Systems Medicine. The availability of more and more powerful technologies to extract data coupled with the inclusion of information coming from the nonstrictly- medical sphere of the patient/individual and his/her lifestyle along with the increase in computational power, will definitely set the stage for a paradigm-shift in bio-medicine with deep ethical and societal impact. The brief comment that follows speculates about the implications of this transition from the educational perspective taking stock of the direct experience of the Authors in the consultation process active in the scientific community.