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Clinical trials demonstrated that SARS-CoV-2 vaccines reduce COVID-19-related mortality and morbidity. We describe the effect of vaccination on COVID-19-patients admitted at our hospital. Retrospective, single-center study conducted in Genoa, Italy, including patients ≥18years hospitalized for COVID-19 from May to December 2021. Demographical and clinical data were collected, vaccinated (group-A) and not-vaccinated (group-B) patients were compared. Impact of vaccination on mortality, ICU admission, and oxygen need was studied using Cox proportional hazards and logistic regression models after adjusting for propensity scores. Overall, 395 patients SARS-CoV-2 infected were included, of which 150 (38%) were vaccinated and 245 (62%) were not vaccinated. Patients in group-A were older, more disable, and with higher morbidity. Overall, 64 patients (16%) died within 30 days from admission, 34 in Group A (23%), and 30 in group B (12%). However, no statistically significant differences were observed (group-A versus group-B: HR 0.83, 95% CI 0.49-1.40, p  = 0.483). On the other hand, vaccination was protective in terms of ICU admission (OR = 0.23, p  = 0.046) and oxygen need (OR = 0.33, p  = 0.008). Our study confirms that SARS-CoV-2 vaccination reduces morbidity among patients hospitalized for COVID-19. The still high mortality in our cohort of vaccinated individuals could be partially due to vulnerable conditions of our patients.

Background: The containment measures linked to the COVID-19 pandemic negatively affected the phyco-physical well-being of the population, especially older adults with neurocognitive disorders (NCDs). This study aims to evaluate whether the frailty of NCD patients was associated with different changes in multiple health domains, in particular in relation to loneliness and social isolation, pre- and post-lockdown., Materials and Methods: Patients were recruited from 10 Italian Centers for Cognitive Disorders and Dementia. Data were collected in the pre-pandemic period (T0), during the pandemic lockdown (T1), and 6-9 months post-lockdown (T2). The UCLA Loneliness Scale-3, Activities of Daily Living (ADL), Instrumental ADL (IADL), Mini-Mental State Examination, and Neuropsychiatric Inventory (NPI) were administered. Caregivers' burden was also tested. Patients were categorized as non-frail, pre-frail, and frail according to the Fatigue, Resistance, Ambulation, Illness, and Loss of Weight scale., Results: The sample included 165 subjects (61.9% women, mean age 79.5 ± 4.9 years). In the whole sample, the ADL, IADL, and NPI scores significantly declined between T0 and T2. There were no significative variations in functional and cognitive domains between the frail groups. During lockdown we recorded higher Depression Anxiety Stress Scales and Perceived Stress Scale scores in frail people. In multivariable logistic regression, frailty was associated with an increase in social isolation, and a loss of IADL., Conclusions: We observed a global deterioration in functional and neuro-psychiatric domains irrespective of the degree of frailty. Frailty was associated with the worsening of social isolation during lockdown. Frail patients and their caregivers seemed to experience more anxiety and stress disorders during SARS-CoV-2 pandemic., (© 2023 The Authors. Psychogeriatrics published by John Wiley & Sons Australia, Ltd on behalf of Japanese Psychogeriatric Society.)

Identifying oncological applications for drugs that are already approved for other medical indications is considered a possible solution for the increasing costs of cancer treatment. Under the hypothesis that nutritional stress through fasting might enhance the antitumour properties of at least some non-oncological agents, by screening drug libraries, we find that cholesterol biosynthesis inhibitors (CBIs), including simvastatin, have increased activity against cancers of different histology under fasting conditions. We show fasting's ability to increase CBIs' antitumour effects to depend on the reduction in circulating insulin, insulin-like growth factor-1 and leptin, which blunts the expression of enzymes from the cholesterol biosynthesis pathway and enhances cholesterol efflux from cancer cells. Ultimately, low cholesterol levels through combined fasting and CBIs reduce AKT and STAT3 activity, oxidative phosphorylation and energy stores in the tumour. Our results support further studies of CBIs in combination with fasting-based dietary regimens in cancer treatment and highlight the value of fasting for drug repurposing in oncology., (© 2023. The Author(s).)

Optimizing the functional status of patients of any age is a major global public health goal. Rehabilitation is a process in which a person with disabilities is accompanied to achieve the best possible physical, functional, social, intellectual, and relational outcomes. The Intermediate Care Unit within the O.U. of Geriatrics and Gerontology of the San Martino Hospital in Genoa is focused on the treatment and motor reactivation of patients with geriatric pathologies. The objective of this study was to identify which factor, among the characteristics related to the patient and those identified by the geriatric evaluation, had the greatest impact on rehabilitation outcomes. Our findings revealed significant correlations between the Barthel Index delta, the 4AT Screening Test, and the number of drugs taken. This association highlights the potential benefits of medication management in enhancing the overall well-being and functional abilities of frail older adults, despite the literature suggesting that polypharmacotherapy is associated with a reduction in functional status and an increase in mortality. These findings underscore the significance of a multidimensional geriatric assessment. Refining and optimising these multidisciplinary approaches is the objective of a more effective geriatric rehabilitation strategy.

It's still undetermined whether ultra-old persons, aged >90 years, are able to tolerate hip fracture surgical stress while maintaining their functional reserve, and even fewer studies have investigated the role of frailty on the risk of mortality, disability, or morbidity in the ultra-old. This is a prospective study performed at the Orthogeriatrics Ward of the IRCCS Policlinico San Martino (Genoa, Italy) that consecutively enrolled 205 older adult patients with hip fractures due to low-energy trauma. Namely, 85 patients were categorized as ultra-old, and 120 patients (64-89 years) were the younger control group. Demographic data, perioperative data, and rehabilitation data were collected. Here we estimated the overall survival and related predictive variables in hospitalized ultra-old hip fracture patients based on a methodologically robust frailty stratification (Rockwood 40-item tool). The median OS for the ultra-old was 18.7 months, which also showed a doubled 1-year mortality risk. Our findings assessed that frailty in the presence of malnutrition, delayed verticalization, and post-operative respiratory complications was associated with a two-fold increase in the risk of long-term mortality, irrespective of advanced chronological age in the ultra-old. Although the higher mortality rate in these patients may be related to a priori lower life expectancy, chronological age alone is an insufficient prognostic determinant for unfavorable outcomes. Our multicomponent prognostic score can be used in combination to stratify frailty in the ultra-old for timely screening and to deliver goals of care discussions prior to surgery, potentially targeting new orthogeriatric pathways for the improvement of appropriateness and treatment intensity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tiso, Pizzonia, Giannotti, Tagliafico, Signori, Nencioni and Monacelli.)

Background: Apathy is a frequent behavioral symptom of Alzheimer's disease (AD). The Apathy Evaluation Scale (AES) is a tool exploring the perception of apathy by both caregivers (CG-AES) and patients (PT-AES), and the discrepancy in their ratings is a proxy of patients' disease unawareness., Objective: To assess in a cohort study of patients with amnesic mild cognitive impairment (aMCI) whether apathy and awareness of apathy predict progression to dementia and timing., Methods: From the global AES scores of 110 patients with aMCI and their caregivers, we obtained two principal indices for analysis: 1) 'Apathy', the mean of PT-AES and CG-AES, and 2) 'Discrepancy', obtained by subtracting CG-AES from PT-AES. Patients were followed with visits every six months for three years or until dementia. AES indices and the principal demographical/neuropsychological variables were filtered from multicollinearity. The most robust variables entered a logistic regression model and survival analyses (Cox regression, log-rank test of Kaplan-Meier curves) to estimate which predicted the risk and timing of progression, respectively., Results: Sixty patients (54.5%) developed dementia (57 AD) after 6.0-36.0 months, 22 (20%) remained in an MCI stage, and 28 (25.5%) dropped out. 'Discrepancy' was a robust and accurate predictor of the risk of progression (AUC = 0.73) and, after binarization according to a computed cutoff, of timing to dementia., Conclusion: A structured evaluation of apathy, both self-assessed and estimated by caregivers, can provide useful information on the risk and timing of progression from aMCI to dementia. The discrepancy between the two estimates is a fairly reliable index for prediction purposes as a proxy of disease unawareness.

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain., Competing Interests: Declaration of interests V.D.L. has equity interest in L-Nutra, which develops and sells medical food for the prevention and treatment of diseases. A patent on this work has been filed by the University of Southern California, which has equity interest in L-Nutra (Fasting-mimicking Diet (FMD) as an Intervention for Alzheimer’s Disease (AD), US 62/840,762, Filed Apr 15, 2019)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Depriving cancer cells of sufficient NAD levels, mainly through interfering with their NAD-producing capacity, has been conceived as a promising anti-cancer strategy. Numerous inhibitors of the NAD-producing enzyme, nicotinamide phosphoribosyltransferase (NAMPT), have been developed over the past two decades. However, their limited anti-cancer activity in clinical trials raised the possibility that cancer cells may also exploit alternative NAD-producing enzymes. Recent studies show the relevance of nicotinic acid phosphoribosyltransferase (NAPRT), the rate-limiting enzyme of the Preiss-Handler NAD-production pathway for a large group of human cancers. We demonstrated that the NAPRT inhibitor 2-hydroxynicotinic acid (2-HNA) cooperates with the NAMPT inhibitor FK866 in killing NAPRT-proficient cancer cells that were otherwise insensitive to FK866 alone. Despite this emerging relevance of NAPRT as a potential target in cancer therapy, very few NAPRT inhibitors exist. Starting from a high-throughput virtual screening approach, we were able to identify and annotate two additional chemical scaffolds that function as NAPRT inhibitors. These compounds show comparable anti-cancer activity to 2-HNA and improved predicted aqueous solubility, in addition to demonstrating favorable drug-like profiles.

The Comprehensive Geriatric Assessment (CGA) and the corresponding geriatric interventions are beneficial for community-dwelling older persons in terms of reduced mortality, disability, institutionalisation and healthcare utilisation. However, the value of CGA in the management of older cancer patients both in terms of clinical outcomes and in cost-effectiveness remains to be fully established, and CGA is still far from being routinely implemented in geriatric oncology. This narrative review aims to analyse the available evidence on the cost-effectiveness of CGA adopted in geriatric oncology, identify the relevant parameters used in the literature and provide recommendations for future research. The review was conducted using the PubMed and Cochrane databases, covering published studies without selection by the publication year. The extracted data were categorised according to the study design, participants and measures of cost-effectiveness, and the results are summarised to state the levels of evidence. The review conforms to the SANRA guidelines for quality assessment. Twenty-nine studies out of the thirty-seven assessed for eligibility met the inclusion criteria. Although there is a large heterogeneity, the overall evidence is consistent with the measurable benefits of CGA in terms of reducing the in-hospital length of stay and treatment toxicity, leaning toward a positive cost-effectiveness of the interventions and supporting CGA implementation in geriatric oncology clinical practice. More research employing full economic evaluations is needed to confirm this evidence and should focus on CGA implications both from patient-centred and healthcare system perspectives.

Objectives: Delirium is commonly seen in older adults with multimorbidity, during a hospitalization, resulting from the interplay between predisposing factors such as advanced age, frailty, and dementia, and a series of precipitating factors. The association between delirium and specific multimorbidity is largely unexplored so far although of potential key relevance for targeted interventions. The aim of the study was to check for a potential association of multimorbidity with delirium in a large cohort of older patients hospitalized for an acute medical or surgical condition., Design: This is a cross-sectional study nested in the 2017 Delirium Day project., Setting and Participants: The study includes 1829 hospitalized patients (age: 81.8, SD: 5.5). Of them, 419 (22.9%) had delirium., Methods: Sociodemographic and medical history were collected. The 4AT was used to assess the presence of delirium. The Charlson Comorbidity index was used to assess multimorbidity., Results: The results identified neurosensorial multimorbidity as the most prevalent, including patients with dementia, cerebrovascular diseases, and sensory impairments. In light of the highest co-occurrence of 3 neurosensorial chronic conditions, we could hypothesize that a baseline altered brain functional and neural connectivity might determine the vulnerability signature for incipient overall system disruption in presence of acute insults., Conclusions and Implications: Eventually, our findings moved a step forward in supporting the key importance of routine screening for sensory impairments and cognitive status of older patients for the highest risk of in-hospital delirium. In fact, preventive interventions could be particularly relevant and effective in preventing delirium in such vulnerable populations and might help refining this early diagnosis., (Copyright © 2021. Published by Elsevier Inc.)

Background: Information on prevalence, pathophysiology, and clinical assessment of paratonia are scarce. In a previous study, we suggested that surface electromyography (EMG) can be used to assess paratonia., Objective: To assess clinical and EMG features of paratonia in both patients with cognitive impairment and healthy subjects., Methods: We examined 18 patients with Alzheimer's disease (AD), 21 patients with mild cognitive impairment (MCI), 30 healthy seniors (seniors), and 30 healthy juniors (juniors). Paratonia was assessed using the "Paratonia Scale". EMG bursts were recorded from biceps and triceps during manually applied passive movements of elbow joint. Continuous (sinusoidal) and discontinuous (linear) movements were applied at 2 different velocities (fast and slow)., Results: In comparison to juniors, seniors had higher clinical scores. In comparison to seniors, AD had higher oppositional scores, while MCI had higher facilitatory scores. EMG activity during passive movements correlated with paratonia clinical scores, was velocity-dependent and increased with movement repetition, most effectively for sinusoidal movements. Similar EMG activity was detected in not paratonic muscles., Conclusion: Paratonia increases with normal aging and cognitive decline progression. While facilitatory paratonia is due to involuntary contraction of the shortening muscle, oppositional paratonia is due, at least partially, to involuntary contraction of the lengthening muscle. Most characteristic feature of this muscle contraction is the progressive increase with movement repetition, that helps distinguish oppositional paratonia from spasticity and rigidity. A similar EMG activity is detected in not paratonic muscles, showing that, during tone assessment, the descending motor system is incompletely inactivated also in normotonic muscles.

Introduction: Older adults are more susceptible to severe COVID-19, with increased all-cause mortality. This has been attributed to their multimorbidity and disability. However, it remains to be established which clinical features of older adults are associated with severe COVID-19 and mortality. This information would aid in an accurate prognosis and appropriate care planning. Here, we aimed to identify the chronic clinical conditions and the comorbidity clusters associated with in-hospital mortality in a cohort of older COVID-19 patients who were admitted to the IRCCS Policlinico San Martino Hospital, Genoa, Italy, between January and April 2020. Methods: This was a retrospective cohort study including 219 consecutive patients aged 70 years or older and is part of the GECOVID-19 study group. During the study period, upon hospital admission, demographic information (age, sex) and underlying chronic medical conditions (multimorbidity) were recorded from the medical records at the time of COVID-19 diagnosis before any antiviral or antibiotic treatment was administered. The primary outcome measure was in-hospital mortality. Results: The vast majority of the patients (90%) were >80 years; the mean patient age was 83 ± 6.2 years, and 57.5% were men. Hypertension and cardiovascular disease, along with dementia, cerebrovascular diseases, and vascular diseases were the most prevalent clinical conditions. Multimorbidity was assessed with the Cumulative Illness Rating Scale. The risk of in-hospital mortality due to COVID-19 was higher for males, for older patients, and for patients with dementia or cerebral-vascular disease. We clustered patients into three groups based on their comorbidity pattern: the Metabolic-renal-cancer cluster, the Neurocognitive cluster and the Unspecified cluster. The Neurocognitive and Metabolic-renal-cancer clusters had a higher mortality compared with the Unspecified cluster, independent of age and sex. Conclusion: We defined patterns of comorbidity that accurately identified older adults who are at higher risk of death from COVID-19. These associations were independent of chronological age, and we suggest that the identification of comorbidity clusters that have a common pathophysiology may aid in the early assessment of COVID-19 patients with frailty to promote timely interventions that, in turn, may result in a significantly improved prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mahmoud, Carmisciano, Tagliafico, Muzyka, Rosa, Signori, Bassetti, Nencioni, Monacelli and the GECOVID Study Group.)

Loss of bone and muscle mass and strength (i. e., osteosarcopenia) is a highly prevalent clinical condition in older adults, associated with an increased risk of fragility fractures and unfavorable clinical outcomes. Although sarcopenia is a potential risk factor for osteoporosis and subsequent fracture, and the management of this hazardous duet is the key to preventing osteoporotic fracture, evidence pertaining to the treatment of sarcopenia for the purpose of preventing fragile fractures remains insufficient. Given this scenario we aimed at prospectively compare the long-term effectiveness of bisphosphonates vs. denosumab, on bone and muscle, in a cohort of old age hip fractured patients by virtue of a timely osteo-metabolic and sarcopenic assessment. Ninety-eight patients consecutively enrolled at the IRCCS Hospital San martino, Genoa, Italy, received at baseline comprehensive geriatric assessment and Bone Densitometry (DXA) with the quantitative and quantitative bone analysis and evaluation of relative skeletal muscle index (RSMI) and longitudinally after 1 year form hip surgery. The results showed a slightly and non-significant osteo-metabolic improvement in the Alendronate group compared to the Denosumab group, and a positive trend of RSMI measurements in the Denosumab group. Although preliminary in nature, this is the first report to longitudinally analyze osteosarcopenia in a real-world cohort of very old age patients after hip fracture and moved a step forward in the understanding of the best osteo-metabolic therapy for long- term treatment, exploring as well the potential dual role of denousumab as antiresorptive and muscle strength specific drug for osteosarcopenia in this vulnerable population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pizzonia, Casabella, Natali, Petrocchi, Carmisciano, Nencioni, Molfetta, Giannotti, Bianchi, Giusti, Santolini and Monacelli.)

Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor, but it also acts as a substrate for NAD-consuming enzymes, regulating cellular events such as DNA repair and gene expression. Since such processes are fundamental to support cancer cell survival and proliferation, sustained NAD production is a hallmark of many types of neoplasms. Depleting intratumor NAD levels, mainly through interference with the NAD-biosynthetic machinery, has emerged as a promising anti-cancer strategy. NAD can be generated from tryptophan or nicotinic acid. In addition, the "salvage pathway" of NAD production, which uses nicotinamide, a byproduct of NAD degradation, as a substrate, is also widely active in mammalian cells and appears to be highly exploited by a subset of human cancers. In fact, research has mainly focused on inhibiting the key enzyme of the latter NAD production route, nicotinamide phosphoribosyltransferase (NAMPT), leading to the identification of numerous inhibitors, including FK866 and CHS-828. Unfortunately, the clinical activity of these agents proved limited, suggesting that the approaches for targeting NAD production in tumors need to be refined. In this contribution, we highlight the recent advancements in this field, including an overview of the NAD-lowering compounds that have been reported so far and the related in vitro and in vivo studies. We also describe the key NAD-producing pathways and their regulation in cancer cells. Finally, we summarize the approaches that have been explored to optimize the therapeutic response to NAMPT inhibitors in cancer.

Bipolar disorder (BD) is a chronic and disabling psychiatric condition that is linked to significant disability and psychosocial impairment. Although current neuropsychological, molecular, and neuroimaging evidence support the existence of neuroprogression and its effects on the course and outcome of this condition, whether and to what extent neuroprogressive changes may impact the illness trajectory is still poorly understood. Thus, this selective review was aimed toward comprehensively and critically investigating the link between BD and neurodegeneration based on the currently available evidence. According to the most relevant findings of the present review, most of the existing neuropsychological, neuroimaging, and molecular evidence demonstrates the existence of neuroprogression, at least in a subgroup of BD patients. These studies mainly focused on the most relevant effects of neuroprogression on the course and outcome of BD. The main implications of this assumption are discussed in light of specific shortcomings/limitations, such as the inability to carry out a meta-analysis, the inclusion of studies with small sample sizes, retrospective study designs, and different longitudinal investigations at various time points., Competing Interests: The authors declare no conflict of interests.

Given that the patterns and clinical correlates related to antidepressant drugs (ADs) prescription for Bipolar Disorder (BD) remain generally unclear, this study aimed to compare socio-demographic and clinical features of BD patients treated vs. not treated with ADs. The sample consists of 287 currently euthymic bipolar patients. Among participants (mean age=51.9±15.02), 157 54.7% were receiving ADs. Based on the main findings, subjects given ADs were older and more frequently retired than those without receiving ADs. Moreover, patients given ADs were more likely to have had a first major depressive episode. Lifetime substance abuse/dependence history was less frequently reported among patients given ADs. Furthermore, ADs given patients had a higher number of affective episodes, and longer duration of their illness. Additionally, subjects treated with ADs reported higher hopelessness levels, and lower positive reinterpretations than those who were not treated with ADs. Factors associated with ADs-use by multivariate modeling were reduced personal autonomy (OR=.070), and hopelessness levels (OR=1.391). These results may help clinicians to better understand the clinical correlates of BD subtypes and improve their differential management. Additional studies are needed to replicate these findings, and facilitate the differential trajectories of BD patients based on socio-demographic/clinical profiles., (Copyright © 2020. Published by Elsevier B.V.)

Background: Sirtuin 6 (SIRT6) is a NAD + -dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. However, the mechanisms through which SIRT6 exerts its pro-oncogenic effects in BC remain unclear. Here, we sought to define the role of SIRT6 in BC cell metabolism and in mouse polyoma middle T antigen (PyMT)-driven mammary tumors., Methods: We evaluated the effect of a heterozygous deletion of Sirt6 on tumor latency and survival of mouse mammary tumor virus (MMTV)-PyMT mice. The effect of SIRT6 silencing on human BC cell growth was assessed in MDA-MB-231 xenografts. We also analyzed the effect of Sirt6 heterozygous deletion, of SIRT6 silencing, and of the overexpression of either wild-type (WT) or catalytically inactive (H133Y) SIRT6 on BC cell pyruvate dehydrogenase (PDH) expression and activity and oxidative phosphorylation (OXPHOS), including respiratory complex activity, ATP/AMP ratio, AMPK activation, and intracellular calcium concentration., Results: The heterozygous Sirt6 deletion extended tumor latency and mouse survival in the MMTV-PyMT mouse BC model, while SIRT6 silencing slowed the growth of MDA-MB-231 BC cell xenografts. WT, but not catalytically inactive, SIRT6 enhanced PDH expression and activity, OXPHOS, and ATP/AMP ratio in MDA-MB-231 and MCF7 BC cells. Opposite effects were obtained by SIRT6 silencing, which also blunted the expression of genes encoding for respiratory chain proteins, such as UQCRFS1, COX5B, NDUFB8, and UQCRC2, and increased AMPK activation in BC cells. In addition, SIRT6 overexpression increased, while SIRT6 silencing reduced, intracellular calcium concentration in MDA-MB-231 cells. Consistent with these findings, the heterozygous Sirt6 deletion reduced the expression of OXPHOS-related genes, the activity of respiratory complexes, and the ATP/AMP ratio in tumors isolated from MMTV-PyMT mice., Conclusions: Via its enzymatic activity, SIRT6 enhances PDH expression and activity, OXPHOS, ATP/AMP ratio, and intracellular calcium concentration, while reducing AMPK activation, in BC cells. Thus, overall, SIRT6 inhibition appears as a viable strategy for preventing or treating BC.

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit 1,2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet 3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Background: Older adults face radical changes in their social life during ageing, dealing with several age-related social adaptations. The aim of this review is to systematically explore the literature on social vulnerability (SV) and its association with functional decline activity of daily living (ADL)/instrumental activities of daily living (IADL) as an endpoint in older adults., Methods: We searched for relevant studies in three different databases: PubMed, Ovid Medline and PsychInfo. Inclusion criteria included: prospective cohort studies assessing SV correlation; studies in English, Italian, French and Spanish to the end of March 2018; a general population aged >65 years living in a community setting and/or studies including younger participants if the mean age was >65 years; and basic ADL and/or IADL by Katz and Lawton, respectively, as functional decline and clinical outcomes., Results: We identified 65 manuscripts that assessed the role of SV in functional decline. Our systematic analysis showed that 26, 36 and 19 studies observed a correlation between Basic Social Needs, Social Resources and Social Behaviour and Activity, respectively, and the onset of ADL/IADL functional decline. Twenty-six studies explored the correlation between General Social Resources and the onset of ADL/IADL functional decline., Conclusions: When examining a wide set of social variables, the "quality," rather than just structure, and "type" of social relationship represents the core feature of SV that predicts functional decline in older adults. By defining individual SV, its measurement and evaluation, we can plan effective social interventions aimed at preventing or delaying functional decline or death., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

Methods: This review is based on the material obtained via MEDLINE (PubMed), EMBASE, and Clinical Trials databases, from January 1980 until May 2019. The search term used was "Alzheimer's disease," combined with "cardiovascular disease," "hypertension," "dyslipidaemia," "diabetes mellitus," "atrial fibrillation," "coronary artery disease," "heart valve disease," and "heart failure." Out of the 1,328 papers initially retrieved, 431 duplicates and 216 records in languages other than English were removed. Among the 681 remaining studies, 98 were included in our research material on the basis of the following inclusion criteria: (a) the community-based studies; (b) using standardized diagnostic criteria; (c) reporting raw prevalence data; (d) with separate reported data for sex and age classes., Results: While AD and CVD alone may be considered deleterious to health, the study of their combination constitutes a clinical challenge. Further research will help to clarify the real impact of vascular factors on these diseases. It may be hypothesized that there are various mechanisms underlying the association between AD and CVD, the main ones being hypoperfusion and emboli, atherosclerosis, and the fact that, in both the heart and brain of AD patients, amyloid deposits may be present, thus causing damage to these organs., Conclusions: AD and CVD are frequently associated. Further studies are needed in order to understand the effect of CVD and its risk factors on AD in order to better comprehend the effects of subclinical and clinical CVD on the brain. Finally, we need to clarify the impact of the underlying hypothesized mechanisms of this association and to investigate gender issues., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Giacomo Tini et al.)

Objectives: More than 60% of the new cancer diagnoses are currently made in older adults, a highly heterogeneous population. Reliable and time-saving tools to define older adults' prognosis are needed to inform the oncologist's decisions in routine clinical practice. We sought to define a multi-domain classification tool for the prediction of all-cause one-year mortality in a cohort of older adults with solid tumors., Materials and Methods: We conducted a single-centre, prospective study of patients with solid cancer aged 65 or older and with G8 score ≤ 14. All patients underwent a comprehensive geriatric assessment (CGA) before starting their surgical or medical treatment. One-year mortality was recorded. A CGA-based prediction tool of one-year mortality was developed and subsequently validated in two independent training and testing cohorts with a 70/30 split, respectively., Results: 162 patients were enrolled. Mean patient age was 78 ± 5.5 years. Forty-three percent of the patients were men. Colorectal and breast cancer were the most common diagnoses. The clinical variables selected for the development of the new classifier (MetaGENUA®) were: mini-nutritional assessment (MNA), instrumental day life activities (IADL), Cumulative Illness Rating Scale (CIRS), geriatric depression scale (GDS), age, and cancer stage. In our independent validation cohort, MetaGENUA® showed high specificity (0.86) and AUC = 0.71 (95% CI = 0.55-0.87)., Conclusions: MetaGENUA® predicts one-year mortality in older patients with cancer with high specificity. As such, MetaGENUA® is predicted to reveal as a useful tool to guide the oncologist's decisions in clinical practice., Competing Interests: Declaration of Competing Interest CG, GZ, LF, AN, PO, AB, and FM are inventors on a patent of a predictor of one-year mortality in older adults with cancer (MetaGENUA®) that was filed by the University of Genoa., (Copyright © 2019. Published by Elsevier Ltd.)

Background: As surgery remains the cornerstone of colorectal cancer (CRC) treatment, the number of older patients presented for colorectal resection is rapidly increasing. Nevertheless, the choice to operate an oldest-old patient still remain challenging and requires a careful assessment of risk to benefit ratio in order to guarantee appropriate surgical strategies and perioperative management., Case Presentation: A centenarian patient, acutely admitted to the emergency department, was diagnosed with an ileus caused by stenosing ascending colon cancer with abnormal distension of the right colon at high risk of perforation. Facing with this complex clinical scenario, a lateral decompressive cecostomy as alternative surgical procedure, was performed in local anesthesia in order to avoid the stressful event of an emergency surgery. Thereafter, the patient was admitted to the surgical ward and followed by a geriatrician who performed a comprehensive geriatric assessment (CGA) and daily clinical evaluations. This integrated plan of care was mainly focused on rehabilitation, nutritional interventions and therapeutic reconciliation, maximizing patient's clinical conditions and performance status. Then, the second surgical step, the radical colon surgery with curative intent and bowel continuity reestablishment was performed, demonstrating to be feasible and safety also in a very advanced age patient in term of prolonged survival and preservation of an adequate quality of life., Conclusions: This is the first case-report that illustrates a successful two step surgery for CRC in a centenarian patient thanks to a multidisciplinary based approach, overwhelming the mere concept of chronological age.

Alzheimer's disease (AD) is a disease caused by the complex interaction of multiple mechanisms, some of which are still not fully understood. To date, pharmacological treatments and supplementation of individual nutrients have been poorly effective in terms of the prevention and treatment of AD, while alternative strategies based on multimodal approaches (diet, exercise, and cognitive training) seem to be more promising. In this context, the focus on dietary patterns rather than on single food components could be more useful in preventing or counteracting the pathological processes typical of AD, thanks to the potential synergistic effects of various nutrients (neuronutrients). The aim of this narrative review is to summarize the currently existing preclinical and clinical evidence regarding the Mediterranean diet (MeDi), the Dietary Approaches to Stop Hypertension (DASH) diet, and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, which are three dietary patterns with well-known anti-inflammatory and antioxidant properties. Recently, they have been related to brain protection and AD prevention, perhaps thanks to their high content of neuroprotective bioactive compounds. Similarly, intermittent fasting (IF) or calorie restriction (CR) is emerging as interesting approaches that seem to promote hippocampal neurogenesis, activate adaptive stress response systems, and enhance neuronal plasticity, thus leading to motor and cognitive improvements in animal models of AD and hopefully also in human beings., Competing Interests: The authors have no relevant disclosures of potential conflicts of interest., (Copyright © 2019 Anna Laura Cremonini et al.)

Objectives: Perioperative frailty assessment is still a challenge, especially in oncogeriatrics. We aimed at assessing the diagnostic accuracy of the 40 items Frailty Index (FI) as compared to the comprehensive geriatric assessment (CGA) for the prediction of one-year mortality and functional status after colorectal surgery in old-age subjects., Material and Methods: Ninety-nine consecutive patients aged 65 years or older who were candidate for elective gastrointestinal cancer surgery, with G8 score ≤ 14 were enrolled and subjected to CGA and to frailty stratification according to the 40-items FI. Long-term outcomes including one-year mortality and functional decline were collected., Results: Mean patient age was 80.3 ± 5.6 years. Colorectal cancer was the most common diagnosis. The most prevalent clinical phenotype was pre-frail. CGA and FI showed similar predictive accuracy in identifying one-year mortality after surgery and patient functional status. Our multivariate analysis indicated the pre-morbid functional status (IADL) and cancer stage as the most significant predictors of one-year mortality., Conclusions: This is the first study to investigate the prognostic accuracy of the 40-items FI as compared to CGA in a vulnerable octogenarian cancer population. Its results are consistent with patient functional status being a mediator of frailty and with both serving as intertwined markers of clinical vulnerability. In addition, according to our results, cancer and specific environmental stressors, such as surgery, are likely to affect the frailty trajectory., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy.

Major affective conditions including both unipolar (UD) and bipolar disorders (BD) are associated with significant disability throughout the life course. We aimed to investigate the most relevant socio-demographic/clinical differences between UD and BD subjects. Our sample included 180 inpatients, of which 82 (45.5%) participants were diagnosed with UD and 98 (54.5%) with BD. Relative to UD patients, BD individuals were more likely to report prior psychoactive medications, lifetime psychotic symptoms, nicotine abuse, a reduced ability to provide to their needs, gambling behavior, and fewer nonsuicidal self-harm episodes. Moreover, BD patients were more likely to report severe side effects related to medications, a younger age at illness onset and first hospitalization, higher illness episodes, and longer illness duration in years than UD subjects. In a multivariate logistic analysis accounting for age, gender, and socio-demographic characteristics, a significant positive contribution to bipolarity was found only for higher lifetime psychotic symptoms (β = 1.178; p ≤ .05) and number of illness episodes (β = .155; p ≤ .05). The present findings suggest that specific clinical factors may be used in order to better distinguish between UD and BD subgroups. Further studies are required to replicate these findings in larger samples., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Major affective conditions are associated with significant disability and psychosocial impairment. Whether specific socio-demographic and clinical characteristics may distinguish subgroups of patients in terms of prognosis and illness trajectories is a matter of debate., Methods: The sample of this naturalistic cohort study included 675 currently euthymic patients with major affective disorders of which 428 (63.4%) were diagnosed with unipolar and 247 (36.6%) with bipolar disorders., Results: Younger adults with a longer duration of untreated illness and residual inter-episodic symptoms were more likely to be single or divorced, students, with an earlier age of first treatment/hospitalization, longer duration of substance abuse and duration of illness than older patients who were, conversely, more likely to be widowed and retired. Multivariate analyses showed a significant positive contribution to age at illness onset by marital status, nonpsychiatric medications, substance abuse, psychiatric diagnosis (bipolar vs. unipolar), age at first treatment/hospitalization, duration of illness, and current age. According to a further analysis, we also found a significant positive contribution to duration of illness by marital status, educational level, positive history of psychiatric conditions in family, substance abuse, psychiatric diagnosis (bipolar vs. unipolar), age at illness onset, age at first treatment, and certain cardiovascular disorders., Conclusions: There are substantial socio-demographic and clinical differences that may help to distinguish specific subgroups of patients; however, additional studies are requested to replicate these results and further investigate the main factors underlying our findings., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims and Objectives: To assess the effects of a texture-modified food program for dysphagia on the nutritional, biochemical and functional profile in a cohort of institutionalised older people in Italy., Background: Dysphagic institutionalised older people, often also affected by dementia, are frequently exposed to malnutrition. Malnutrition in older people has negative effects on mortality, days of hospitalisation, infection, wound healing and risk of pressure injuries. Therefore, it is very important to prevent malnutrition in this frail population., Design: A pre-post study without a control group., Methods: The study included 479 dysphagic institutionalised older people from 20 nursing homes. Anthropometrical, biochemical, nutritional and functional parameters were collected retrospectively, 6 months before the study intervention, at time zero and, prospectively for 6 months after implementing the NUTRICARE food programme, for a total of nine evaluations. The NUTRICARE programme includes meals without nutritional supplementation, and personalised levels of density, viscosity, texture and particle size., Results: The total mean body mass index of our sample passed from 17.88-19.00; body weight averagely improved by 7.19%, as well as their nutritional and biochemical profiles. There was a progressive improvement of total protein and serum albumin values. Nutritional parameters (serum transferrin and lymphocytes) displayed similar changes. Plasma lymphocytes reached normal levels in 98.23% of the sample. Plasma creatinine levels remained steady throughout the study and within the normal range. No side effects were reported., Conclusion: The NUTRICARE food programme with a adequate proteins, calories, balanced nutritional and bromatological properties, and appropriate texture and palatability significantly improved the nutritional, biochemical and functional profile in a cohort of institutionalised dysphagic older people., Relevance to Clinical Practice: The introduction of a balanced nutritional programme, using high-quality natural ingredients, appropriate texture and palatability can significantly improve health and quality of life in dysphagic older people., (© 2017 John Wiley & Sons Ltd.)

Background: The histopathological hallmarks in Alzheimer's disease (AD) include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. Glycoxidation plays a crucial role in AD pathogenesis, as pentosidine and Nε- carboxymethyl-lysine (CML), were detected in AD hallmarks, and in vivo cerebrospinal fluid (CSF). However, the definitive role of AGEs in the neuropathology of AD is inconclusive. The aim of this preliminary study was to assess the level of pentosidine in CSF of patients affected by neurological disorders, including probable AD, in order to assess the feasibility of AGEs detection in CSF and to explore pentosidine as a potential biomarker in AD., Methods: Twenty-five patients diagnosed with AD (NINCDS ADRDA criteria) and different neurological disorders were enrolled. Diabetic patients were excluded. Pentosidine, CML, amyloid β1-42 were assessed by high performance liquid chromatography (HPLC) by Odetti modified method,and by sandwich ELISA respectively., Results: Our data showed the presence of pentosidine in all CSF samples, a significant increase in CSF pentosidine levels with age (p<0.05) and a significant decreased concentration of pentosidine in four AD subjects (p<0.01), after normalization to CSF protein concentration., Conclusions: The study showed that AGEs concentration in CSF might benefit from age correction, at least for pentosidine, originally addressing a potential systemic age-dependent AGEs accumulation. The significant decrease of CSF pentosidine in AD, even in 4 patients, might conceive that different AGEs inform specific types of neurodegeneration, depending on oxidative stress levels, blood - brain barrier permeability, brain localization and systemic risk factors.

A growing body of evidence claims there is a pivotal role of heat temperatures and summer hot spells in the pathogenesis of exceeding morbidity and mortality among older people. The European well-known "2003 killer hot summer" has boosted many epidemiological and clinical investigations to clarify the pathogenetic correlation between hot spells and elderly mortality with new acquirements in terms of pathophysiology, preventive measures, and therapeutic approaches. However, a quite controversial issue arises: overall elderly mortality is higher in the cold winter compared with summer. The progressive development of preventive, therapeutic, and environmental measures, if targeted with promptness, has generally proven effective in coping with heat temperature, restraining elderly mortality. However, few investigations have been performed dealing with cold, with pioneeristic as well as simplistic approaches, without any conclusiveness or effectiveness in terms of prevention or therapy. Data from recent literature enlist various clinical and environmental approaches in counteracting cold-related mortality in elderly, but lack evidence-based results; a recent European collaborative study reported cold-related elderly mortality as non-negligible, deserving the growing attention of public authorities. We conducted a 4-year survey among 6 different nursing homes located in a seaside city of northern Italy so as to collect epidemiological data on stressful weather spells and elderly mortality. Our results showed that overall elderly mortality in the cold season displayed as significantly high rates as in summer, and the monthly deaths per year of observation showed higher rates in the cold season, addressing it as the most prevalent time period related to mortality in older people. Thus, research in the field is mandatory so as to draw a broader conceptual framework for the stratification of specific population risk profiling and the assessment of adequate preventive and therapeutic measures. To the present knowledge, the lack of pathophysiological understanding, the missing evidence-based data in coping with cold weather-related elderly mortality, together with policy makers' misconceptions is mounting the controversy on this emerging clinical issue., (2010 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Osteoporosis, a multifactorial and progressive skeletal metabolic disease, is characterized by low-mass density and structural deterioration of bone micro-architecture that leads to enhanced bone fragility and increased susceptibility to fractures. Recently, it has been proposed that age-related bone loss could be correlated with the glycoxidative process. The aim of the present study was to investigate the in vitro effects of pentosidine, a glycoxidative end product, on human osteoblasts (HOb). The mineralization rate, the specific bone markers (alkaline phosphatase [ALP], collagen Ialpha1 [COL Ialpha1], osteocalcin [BGP]), and the human receptor for advanced glycation end products (RAGE) gene expression have been evaluated. Pentosidine incubation of HOb caused a significant decrease in ALP, Col Ialpha1, and RAGE mRNA levels, but only the RAGE gene expression decreased with no dose dependency. Moreover, pentosidine incubation of osteoblasts hampered the formation of bone nodules. No effect was observed on BGP gene expression under all experimental conditions. Our data gives further support to a detrimental effect of AGEs on bone that leads to functional alterations of osteoblasts. This study addresses a crucial role of protein glycoxidation in the bone mineralization process. AGEs formation and accumulation in bone may be one of the first pathogenetic steps of bone remodeling in aging and in age-related diseases, leading to enhanced bone mass loss.

The purpose of the present study was to evaluate the direct effects of advanced glycation end products (AGEs) on beta-cells by their exposure to a glycated serum to estimate the cellular viability and the related insulin secretion. Glycation of fetal calf serum was obtained by incubation with 50 mol/L ribose at 37 degrees C for 7 days; at the end of this incubation period, the pentosidine content ranged between 15 and 16 x 10(5) pmol/L. HIT-T15 cells, a pancreatic islet cell line, were grown and cultured for 5 days in Roswell Park Memorial Institute (RPMI) medium containing either not glycated (NGS) or glycated (GS) fetal calf serum. Cellular oxidative stress (ie, thiobarbituric acid-reactive substances) was assessed by high-performance liquid chromatography. Cellular viability was evaluated by detection of proliferation, cell necrosis, and cell apoptosis rate. The insulin secretion and the related intracellular content were evaluated by enzyme-linked immunosorbent assay. The present study reported, after 5 days of exposure to the glycation environment, a moderately reduced cellular proliferation (-20.44% +/- 2.92%) with a corresponding increase of cell necrosis (+67.7% +/- 1.56%) and cell apoptosis (+39.83% +/- 2.92%) rate in comparison with the untreated cells. Oxidative intracellular stress was higher in GS conditions compared with the NGS ones (+293.3% +/- 87.53%). Insulin release from GS-treated HIT-T15 cells was lower than that of NGS-treated cells both when cells were stimulated with low glucose concentration (2.8 mmol/L, -30.3% +/- 4.91%) or when they were challenged with high glucose concentration (16.7 mmol/L, -29.2% +/- 5.82%). Incubation of HIT-T15 cells with glycated serum also caused a significant decrease of insulin intracellular content (-44.47% +/- 9.98%). Thus, AGEs were shown to exert toxic effects on insulin-secreting cells. Chronically high intracellular oxidative stress, due to accumulation of AGEs, affects the insulin secretion machinery. The present data suggest a pivotal role of the non-enzymatic glycation process in the onset and progression of diabetes during aging and a direct adverse effect of a glycated environment on the pancreatic islet cells.

Several lines of evidence suggest that both advanced glycation end products (AGEs) and oxidation processes play key roles in the physiology of aging and age-related pathologies, leading to irreversible proteins modifications in both tissues and the extracellular matrix. Such an accelerated accumulation of these modifications has been reported to be present in several age-related chronic diseases, such as atherosclerosis, diabetes, arthritis, and neurodegenerative diseases. The current literature reveals that the specific inhibition of AGEs may constitute an innovative therapeutic goal. In experimental animals, the use of sartans significantly reduces blood pressure and kidney pentosidine content, improving both histologic renal damage and proteinuria. In this study, 12 subjects who were affected by diabetes mellitus and hypertension were subjected to oral antihypertensive therapy with valsartan (class of sartans) with timed sampling of plasma and urine pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), malondialdehyde, and isoprostanes levels, respectively, at baseline and after both 3 and 6 months, with parallel ongoing evaluation of glycemic control and blood pressure levels. Valsartan elicited a good antihypertensive effect with a 30% decrease in plasma pentosidine levels (P < .05) after 3 months of therapy, followed by a slight increase after 6 months. Urinary pentosidine concentrations exhibited a 40% decrease after 3 months (215 +/- 19 vs 129 +/- 23 nmol/24 h) and a further significant reduction after 6 months of therapy (105 +/- 24 nmol/24 h). Plasma CML levels showed a progressive decrease after 3 months (23.15 +/- 3.215 vs 19.88 +/- 1.684 micromol/mL) and achieved a further slight reduction after 6 months of therapy (19.48 +/- 1.339 micromol/mL); for urinary CML, a statistically significant reduction was gained after the sixth month of therapy (48.51 +/- 5.70 vs 30.30 +/- 2.77 micromol/24 h after 3 months and 27.02 +/- 4.13 micromol/24 h after 6 months; F = 7.62, P < .005). Plasma and urinary concentrations of malondialdehyde were slightly modified by valsartan treatment; the mean levels after both 3 and 6 months did not significantly differ from baseline. Urinary 15-F2t-isoprostanes (2.96 +/- 0.45 ng/24 h) levels displayed a progressive decrease after both 3 (2.27 +/- 0.31 ng/24 h) and 6 months (1.70 +/- 0.23 ng/24 h) with statistical significance achieved only at the end of the study (P < .05). The present data suggest interesting in vivo antiglycation and antioxidation effects of this angiotensin II receptor antagonist with reductions in plasma and urinary pentosidine, plasma CML, and urinary isoprostanes levels. The present study supports an antagonistic role of valsartan in the production of AGEs precursors through the chelation of transition metals and an antioxidant activity that scavenges reactive oxygen species. This property of valsartan may broaden the scope of newly developed pharmacologic inhibitors of advanced glycoxidation.

It is well known that bone mass density decreases with age. Age-related bone mass loss is ascribed to several factors. Nonenzymatic glycation has been proposed as a new potential factor in the loss of bone during aging. In this study we evaluated the concentration of pentosidine, an advanced glycation end product, in cortical and trabecular bone and in the plasma of subjects undergoing orthopedic surgery. The relationship between these parameters and a clinical index of osteoporosis was also studied. Samples of bone and plasma of 104 nondiabetic subjects (74 women and 30 men), 72 +/- 1 years old, were studied. Pentosidine was determined by HPLC after decalcification and hydrolysis. The radiologic Singh index was evaluated blindly by orthopedic surgeons to provide the degree of osteoporosis. Pentosidine concentration of cortical bone shows a significant exponential increase with age (r = 0.610, P < 0.001). This increase, however, is not seen in the trabecular bone, which is characterized by a large spread in the data. Interestingly the concentration of cortical pentosidine is also related to the Singh score (r(s) = -0.274, P < 0.01). Plasma pentosidine has a significant exponential correlation with age (r = +0.339, P < 0.001) and a linear correlation with the cortical bone pentosidine (r = +0.248, P < 0.05). This study demonstrates that pentosidine increases exponentially in cortical bone during aging, and is thus a good biomarker for the degree of bone mass density loss. The trabecular bone concentration of pentosidine is more variable, probably because of the turnover rate and the local environment; plasma pentosidine might provide information on the bone turnover rate.