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We aimed to determine the effect of a Mediterranean-style diet, tailored to meet dietary recommendations for older adults, on blood pressure and arterial stiffness. In 12 months, randomized controlled trial (NU-AGE [New Dietary Strategies Addressing the Specific Needs of Elderly Population for Healthy Aging in Europe]), blood pressure was measured in 1294 healthy participants, aged 65 to 79 years, recruited from 5 European centers, and arterial stiffness in a subset of 225 participants. The intervention group received individually tailored standardized dietary advice and commercially available foods to increase adherence to a Mediterranean diet. The control group continued on their habitual diet and was provided with current national dietary guidance. In the 1142 participants who completed the trial (88.2%), after 1 year the intervention resulted in a significant reduction in systolic blood pressure (-5.5 mm Hg; 95% CI, -10.7 to -0.4; P=0.03), which was evident in males (-9.2 mm Hg, P=0.02) but not females (-3.1 mm Hg, P=0.37). The -1.7 mm Hg (95% CI, -4.3 to 0.9) decrease in diastolic pressure after intervention did not reach statistical significance. In a subset (n=225), augmentation index, a measure of arterial stiffness, was improved following intervention (-12.4; 95% CI, -24.4 to -0.5; P=0.04) with no change in pulse wave velocity. The intervention also resulted in an increase in 24-hour urinary potassium (8.8 mmol/L; 95% CI, 0.7-16.9; P=0.03) and in male participants (52%) a reduction in pulse pressure (-6.1 mm Hg; 95% CI, -12.0 to -0.2; P=0.04) and 24-hour urinary sodium (-27.1 mmol/L; 95% CI, -53.3 to -1.0; P=0.04). In conclusion, a Mediterranean-style diet is effective in improving cardiovascular health with clinically relevant reductions in blood pressure and arterial stiffness.

Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are the best example of healthy aging in humans as most of them have escaped or substantially delayed the onset of major age-related diseases. Within this scenario, the purpose of the present work was to understand if immune status is associated with survival and health status in centenarians. To this aim, 116 centenarians were concomitantly characterized for their immunological, health and functional status, and followed-up for five-year survival. On the basis of previous knowledge we focused on a core of fundamental and basic immune parameters (number of leukocytes, monocytes, total lymphocytes, CD3(+) T lymphocytes, CD4(+) helper T lymphocytes, CD8(+) cytotoxic T lymphocytes, CD19(+) B lymphocytes and plasma levels of IgM), and the most important findings can be summarized as follows: i. a hierarchical cluster analysis was able to define Cluster1 (88 centenarians) and Cluster2 (28 centenarians) characterized by low and high values of all these immune parameters, respectively; ii. centenarians of Cluster2 showed a statistically longer five-year survival and more favorable values of other important immune (naïve, activated/memory and effector/memory T cells) and metabolic (glycemia, insulin and HOMA-IR) parameters, in accord with previous observations that centenarians have a peculiar immune profile, a preserved insulin pathway and a lower incidence of type 2 diabetes; and iii. unexpectedly, parameters related to frailty, as well as functional and cognitive status, did not show any significant correlation with the immune clustering, despite being capable per se of predicting survival. In conclusion, high values of basic immunological parameters and important T cell subsets correlate with five-year survival in centenarians, independent of other phenotypic characteristics. This unexpected biological scenario is compatible with the general hypothesis that in centenarians a progressive disconnection and loss of biological coherence among the different functions of the body occur, where survival/mortality result from the failure of any of these domains which apparently follow an independent age-related trajectory.

According to the findings of some recent studies, the centenarians' offspring appear to represent a promising model for research on longevity and healthy aging. This study compares the health status and the functional status of three groups of subjects: 1. individuals with two long-lived parents (one of whom centenarian), 2. individuals with only one long-lived (centenarian) parent, and 3. individuals with no long-lived parents. The goal is to verify whether the centenarians' offspring display any advantage over the offspring of both non-long-lived parents and to evaluate whether the longevity of the non centenarian parent provides a further advantage. A total of 374 subjects (mean age approximately 70 years) was examined. A threshold for longevity was established for non-centenarian parents through demographic data available for Italy (males surviving to at least 81 years of age and females to 87 years). The participants were assessed for their health and functional status by means of a standardized questionnaire and tests of physical performance. Data were analyzed using multivariate regression models adjusted for socio-demographic characteristics and risk factors for age-related pathologies. The results of the study show that centenarians' offspring have a better functional status, a reduced risk for several age-related pathologies and reduced drug consumption than the offspring of non-long-lived parents. In addition, the health status of centenarians' offspring does not appear to be influenced by the longevity of the second parent. It therefore seems possible to conclude that at ages around 70 years the genetic contribution to health status deriving from having one centenarian parent is not substantially improved if the other parent is also long-lived.

Factor structure analyses have revealed the presence of specific biological system markers in healthy humans and diseases. However, this type of approach in very old persons and in type 2 diabetes (T2DM) is lacking. A total sample of 2,137 Italians consisted of two groups: 1,604 healthy and 533 with T2DM. Age (years) was categorized as adults (≤65), old (66-85), oldest old (>85-98) and centenarians (≥99). Specific biomarkers of routine haematological and biochemical testing were tested across each age group. Exploratory factorial analysis (EFA) by principal component method with Varimax rotation was used to identify factors including related variables. Structural equation modelling (SEM) was applied to confirm factor solutions for each age group. EFA and SEM identified specific factor structures according to age in both groups. An age-associated reduction of factor structure was observed from adults to oldest old in the healthy group (explained variance 60.4% vs 50.3%) and from adults to old in the T2DM group (explained variance 57.4% vs 44.2%). Centenarians showed three-factor structure similar to those of adults (explained variance 58.4%). The inflammatory component became the major factor in old group and was the first one in T2DM. SEM analysis in healthy subjects suggested that the glucose levels had an important role in the oldest old. Factorial structure change during healthy ageing was associated with a decrease in complexity but showed an increase in variability and inflammation. Structural relationship changes observed in healthy subjects appeared earlier in diabetic patients and later in centenarians.

Virtual reality (VR) has been used as a complementary therapy for managing psychological and physical symptoms in cancer patients. In palliative care, the evidence about the use of VR is still inadequate. This study aims to assess the effect of an immersive VR-based intervention conducted at home on anxiety, depression, and pain over 4days and to evaluate the short-term effect of VR sessions on cancer-related symptomatology. Participants were advanced cancer patients assisted at home who were provided with a VR headset for 4days. On days one and four, anxiety and depression were measured by the Hospital Anxiety and Depression Scale (HADS) and pain by the Brief Pain Inventory (BPI). Before and after each VR session, symptoms were collected by the Edmonton Symptom Assessment Scale (ESAS). Participants wore a smart wristband measuring physiological signals associated with pain, anxiety, and depression. Fourteen patients (mean age 47.2±14.2years) were recruited. Anxiety, depression (HADS), and pain (BPI) did not change significantly between days one and four. However, the ESAS items related to pain, depression, anxiety, well-being, and shortness of breath collected immediately after the VR sessions showed a significant improvement (p

Chronic insomnia is the most common sleep disorder in the elderly population. From 9 to 50% of patients suffer of paradoxical insomnia, with the same symptoms and ailments, though characterized by normal sleep patterns. We have investigated the level of parameters related to stress in a group of post-menopausal female patients (age range 55-70 years) suffering by either objective or paradoxical insomnia, in particular we have measured 24-hours urinary cortisol, allostatic load index, Perceived Stress Scale (PSS) score, and, for the first time, mitokines (mitochondrial stress response molecules) such as FGF21, GDF15 and Humanin (HN). Results show that the two groups are different as far as sleep efficiency score, as expected, but not for stress parameters, that in some cases resulted within the normality range, although quite close to the top threshold (such as cortisol) or much higher with respect to normality ranges (such as PSS). Therefore, the consequences of paradoxical insomnia on the expression of these parameters are the same as objective insomnia. As far as the level of mitokines, we showed that FGF21 and HN in particular resulted altered (decreased and increased, respectively) with respect to control population, however with no difference between the two groups of patients.

Background and aims: The prevalence of malnutrition is over 70% in advanced cancer patients and impacts negatively on survival and quality of life. Artificial nutrition can be integrated into a home palliative care program. This observational study aims to describe the criteria for identifying the cancer patients that could benefit from home artificial nutrition (HAN) and to evaluate its impact on survival and performance status. Methods: The selection criteria for patient's eligibility to HAN were: Karnofsky Performance Status (KPS) ≥40, life expectancy ≥6 weeks, inadequate caloric intake ± malnutrition, suitable psycho-physical conditions and informed consent. The access route for nutritional therapy (home parenteral nutrition, HPN; home enteral nutrition, HEN) was chosen according to the ESPEN Guidelines. The parameters considered were: primary site of the tumor; oral food intake; nutritional status; stage of cachexia; fluid, energy and protein supplied by HAN; survival. Results: From 1990 to 2019, 43,474 cancer patients were assisted at home in Bologna (Italy). HAN started in 969 patients (2.2% of total patients, 571 men and 398 women, mean age 65.7 ± 12.7 years): HPN in 629 patients (64.9%), with gastrointestinal obstruction as the main indication; HEN in 340 patients (35.1%), with dysphagia as the main indication. Considering the 890 deceased patients, the mean survival after the start of HAN was 18.3 weeks and 649 patients (72.9%) survived more than 6 weeks. The mean survival was higher in HEN (22.1 weeks) compared to HPN patients (16.1 weeks) (p < .001). After one month, KPS was unchanged in 649 (67.0%), increased in 232 (23.9%) and decreased in 88 patients (9.1%). The mean KPS increased in patients starting HAN in pre-cachexia and cachexia (p < .001). Cachexia and refractory cachexia at the entry were associated with a reduced survival [odds ratio: 1.5 and 2.3 respectively, p < .001 for both condition] respect to pre-cachexia. Conclusions: The selection criteria allow the identification of the patient who can take advantage of HAN. HAN can be effective in avoiding death from malnutrition in 73% of patients, and in maintaining or improving the KPS at one month in 90% of cases. The benefits provided by HAN on survival and performance status depend on the cachexia degree at the entry.

Aspartate-Glutamate Carrier 1 (AGC1) deficiency is a rare neurological disease caused by mutations in the solute carrier family 25, member 12 (SLC25A12) gene, encoding for the mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), a component of the malate&ndash, aspartate NADH shuttle (MAS), expressed in excitable tissues only. AGC1 deficiency patients are children showing severe hypotonia, arrested psychomotor development, seizures and global hypomyelination. While the effect of AGC1 deficiency in neurons and neuronal function has been deeply studied, little is known about oligodendrocytes and their precursors, the brain cells involved in myelination. Here we studied the effect of AGC1 down-regulation on oligodendrocyte precursor cells (OPCs), using both in vitro and in vivo mouse disease models. In the cell model, we showed that a reduced expression of AGC1 induces a deficit of OPC proliferation leading to their spontaneous and precocious differentiation into oligodendrocytes. Interestingly, this effect seems to be related to a dysregulation in the expression of trophic factors and receptors involved in OPC proliferation/differentiation, such as Platelet-Derived Growth Factor &alpha, (PDGF&alpha, ) and Transforming Growth Factor &beta, s (TGF&beta, s). We also confirmed the OPC reduction in vivo in AGC1-deficent mice, as well as a proliferation deficit in neurospheres from the Subventricular Zone (SVZ) of these animals, thus indicating that AGC1 reduction could affect the proliferation of different brain precursor cells. These data clearly show that AGC1 impairment alters myelination not only by acting on N-acetyl-aspartate production in neurons but also on OPC proliferation and suggest new potential therapeutic targets for the treatment of AGC1 deficiency.

In this work we present a novel statistical approach to improve the assessment of the adherence to a 1-year nutritional intervention within the framework of the NU-AGE project. This was measured with a single adherence score based on 7-days food records, under limitations on the number of observations per subject and time frame of intervention. The results of the NU-AGE dietary intervention were summarized by variations of the NU-AGE index as described in the NU-AGE protocol. Food and nutrient intake of all participants was assessed by means of 7-days food records at recruitment and after 10 to 14 months of intervention (depending on the subject availability). Sixteen food groups and supplementations covering the dietary goals of the NU-AGE diet have been used to estimate the NU-AGE index before and after the intervention. The 7-days food record is a reliable tool to register food intakes, however, as with other tools used to assess lifestyle dietary compliance, it is affected by uncertainty in this estimation due to the possibility that the observed week is not fully representative of the entire intervention period. Also, due to logistic limitations, the effects of seasonality can never be completely removed. These variabilities, if not accounted for in the index estimation, will reduce the statistical power of the analyses. In this work we discuss a method to assess these uncertainties and thus improve the resulting NU-AGE index. The proposed method is based on Hierarchical Bayesian Models. This model explicitly includes country-specific averages of the NU-AGE index, index variation induced by the dietary intervention, and country based seasonality. This information is used to evaluate the NU-AGE index uncertainty and thus to estimate the "real" NU-AGE index for each subject, both before and after the intervention. These corrections reduce the possibility of misinterpreting measurement variability as real information, improving the power of the statistical tests that are performed with the resulting index. The results suggest that this method is able to reduce the short term and seasonal variability of the measured index in the context of multicenter dietary intervention trials. Using this method to estimate seasonality and variability would allow one to obtain better measurements from the subjects of a study, and be able to simplify the scheduling of diet assessments. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01754012.

Body composition (BC) is an emerging important factor for the characterization of metabolic status. The assessment of BC has been studied in various populations and diseases such as obesity, diabetes, endocrine diseases as well as physiological and paraphysiological conditions such as growth and aging processes, and physical training. A gold standard technique for the assessment of human BC at molecular level is represented by dual-energy X-ray absorptiometry (DXA), which is able to precisely assess the body mass (and areal bone mineral density-aBMD) on a regional and whole-body basis. For the first time, within the framework of the NU-AGE project, BC has been assessed by means of a whole-body DXA scan in 1121 sex-balanced free-living, apparently healthy older adults aged 65-79 years enrolled in 5 European countries (Italy, France, United Kingdom, Netherlands, and Poland). The aim of this analysis is to provide a complete profile of BC in healthy elderly participants from five European countries and to investigate country- and sex-related differences by state-of-the-art DXA technology. To compare BC data collected in different centers, specific indexes and ratios have been used. Non-parametric statistical tests showed sex-specific significant differences in certain BC parameters. In particular, women have higher fat mass (FM) (Fat/Lean mass ratio: by 67%, p < 2.2e-16) and lower lean mass (Lean Mass index: by -18%, p < 2.2e-16) than men. On the other hand, men have higher android FM than women (Android/gynoid FM ratio: by 56%, p < 2.2e-16). Interesting differences also emerged among countries. Polish elderly have higher FM (Fat/Lean mass ratio: by 52%, p < 2.2e-16) and lower lean mass (Skeletal Mass index: by -23%, p < 2.2e-16) than elderly from the other four countries. At variance, French elderly show lower FM (Fat/Lean mass ratio: by -34%, p < 2.2e-16) and higher lean mass (Skeletal Mass index: by 18%, p < 2.2e-16). Moreover, five BC profiles in women and six in men have been identified by a cluster analysis based on BC parameters. Finally, these data can serve as reference for normative average and variability of BC in the elderly populations across Europe.

Background: The Mediterranean diet (MD) is widely recommended for the prevention of chronic disease, but evidence for a beneficial effect on bone health is lacking. Objective: The aim of this study was to examine the effect of a Mediterranean-like dietary pattern [NU-AGE (New Dietary Strategies Addressing the Specific Needs of the Elderly Population for Healthy Aging in Europe)] on indexes of inflammation with a number of secondary endpoints, including bone mineral density (BMD) and biomarkers of bone and collagen degradation in a 1-y multicenter randomized controlled trial (RCT; NU-AGE) in elderly Europeans. Design: An RCT was undertaken across 5 European centers. Subjects in the intervention group consumed the NU-AGE diet for 1 y by receiving individually tailored dietary advice, coupled with supplies of foods including whole-grain pasta, olive oil, and a vitamin D3 supplement (10 µg/d). Participants in the control group were provided with leaflets on healthy eating available in their country. Results: A total of 1294 participants (mean ± SD age: 70.9 ±4.0 y; 44% male) were recruited to the study and 1142 completed the 1-y trial. The Mediterranean-like dietary pattern had no effect on BMD (site-specific or whole-body); the inclusion of compliance to the intervention in the statistical model did not change the findings. There was also no effect of the intervention on the urinary biomarkers free pyridinoline or free deoxypyridinoline. Serum 25-hydroxyvitamin D significantly increased and parathyroid hormone decreased (P < 0.001) in the MD compared with the control group. Subgroup analysis of individuals with osteoporosis at baseline (site-specific BMD T-score ≤ −2.5 SDs) showed that the MD attenuated the expected decline in femoral neck BMD (n = 24 and 30 in MD and control groups, respectively; P = 0.04) but had no effect on lumbar spine or whole-body BMD. Conclusions: A 1-y intervention of the Mediterranean-like diet together with vitamin D3 supplements (10 µg/d) had no effect on BMD in the normal age-related range, but it significantly reduced the rate of loss of bone at the femoral neck in individuals with osteoporosis. The NU-AGE trial is registered at clinicaltrials.gov as NCT01754012.

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm- aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act.

We investigated the anticancer effect of EGCG treatment on a breast carcinoma cell line resistant to tamoxifen (MCF-7Tam cells). As there are no reports about the molecular mechanisms implicated in EGCG treatment of tamoxifen resistant breast carcinoma cells, we studied the effects of EGCG treatment on three plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein (MRP1), P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). EGCG treatment (10-100 μg/ml for 24-72 hours) caused cell growth inhibition and dose-dependent apoptosis: after 100 μg/ml EGCG treatment for 24 hours, Bax expression increased and Bcl2 expression decreased (p

Objective: The lifelong exposure to a variety of stressors activates a plethora of defense mechanisms, including the hypothalamic-pituitary-adrenal axis which releases neuropeptides affecting the immune responses. Here, we report data on the capability of monocytes from young subjects and centenarians to migrate towards chemotactic stimuli (formyl-methionyl-leucyl-phenylalanine, f-MLP; adrenocorticotropic hormone, ACTH, and corticotrophin-releasing hormone, CRH). Plasma levels of ACTH, CRH and cortisol were measured as an index of ongoing stress response. Methods: Monocyte chemotaxis towards f-MLP (10–8M), ACTH(1–24) (10–14 and 10–8M) and CRH (10–14 and 10–8M) was evaluated in vitro in young subjects (n = 8, age range 25–35 years) and centenarians (n = 9, age >100 years) and expressed as chemotactic index. In 9 young subjects and 6 centenarians, plasma levels of cortisol, ACTH and CRH were measured. Results: Monocyte chemotaxis towards f-MLP, ACTH(1–24) and CRH (10–8M) was well preserved in centenarians, except when the lowest concentration of CRH was used. CRH, ACTH and cortisol plasma levels were significantly higher in centenarians than in young subjects. Conclusions: The capability of monocytes from centenarians to respond to chemotactic neuropeptides is well preserved. The decreased responsiveness to the lowest concentration of CRH might be due to downregulation of CRH receptors or to defects in the intracellular signal transduction pathway. The high plasma levels of cortisol, CRH and ACTH in centenarians indicate an activation of the entire stress axis, likely counteracting the systemic inflammatory process occurring with age. This activation fits with the hypothesis that lifelong low-intensity stressors activate ancient, hormetic defense mechanisms, favoring healthy aging and longevity.

Aging is considered the major risk factor for cancer, one of the most important mortality causes in the western world. Inflammaging, a state of chronic, low-level systemic inflammation, is a pervasive feature of human aging. Chronic inflammation increases cancer risk and affects all cancer stages, triggering the initial genetic mutation or epigenetic mechanism, promoting cancer initiation, progression and metastatic diffusion. Thus, inflammaging is a strong candidate to connect age and cancer. A corollary of this hypothesis is that interventions aiming to decrease inflammaging should protect against cancer, as well as most/all age-related diseases. Epidemiological data are concordant in suggesting that the Mediterranean Diet (MD) decreases the risk of a variety of cancers but the underpinning mechanism(s) is (are) still unclear. Here we review data indicating that the MD (as a whole diet or single bioactive nutrients typical of the MD) modulates multiple interconnected processes involved in carcinogenesis and inflammatory response such as free radical production, NF-κB activation and expression of inflammatory mediators, and the eicosanoids pathway. Particular attention is devoted to the capability of MD to affect the balance between pro- and anti-inflammaging as well as to emerging topics such as maintenance of gut microbiota (GM) homeostasis and epigenetic modulation of oncogenesis through specific microRNAs.

OBJECTIVES: To assess the impact of a personalized diet, with or without addition of VSL#3 preparation, on biomarkers of inflammation, nutrition, oxidative stress and intestinal microbiota in 62 healthy persons aged 65-85 years. DESIGN: Open label, randomized, multicenter study. PRIMARY ENDPOINT: High-sensitivity C-reactive protein. SETTING: Community. INTERVENTIONS: Eight week web-based dietary advice (RISTOMED platform) alone or with supplementation of VSL#3 (2 capsules per day). The RISTOMED diet was optimized to reduce inflammation and oxidative stress. MEASUREMENTS: Blood and stool samples were collected on days 1 and 56. RESULTS: Diet alone reduced ESR (p = 0.02), plasma levels of cholesterol (p < 0.01) and glucose (p = 0.03). Addition of VSL#3 reduced ESR (p = 0.05) and improved folate (p = 0.007), vitamin B12 (p = 0.001) and homocysteine (p < 0.001) plasma levels. Neither intervention demonstrated any further effects on inflammation. Subgroup analysis showed 40 participants without signs of low-grade inflammation (hsCRP

As centenarians well represent the model of healthy aging, there are many important implications in revealing the underlying molecular mechanisms behind such successful aging. By combining NMR metabonomics and shot-gun lipidomics in serum we analyzed metabolome and lipidome composition of a group of centenarians with respect to elderly individuals. Specifically, NMR metabonomics profiling of serum revealed that centenarians are characterized by a metabolic phenotype distinct from that of elderly subjects, in particular regarding amino acids and lipid species. Shot- gun lipidomics approach displays unique changes in lipids biosynthesis in centenarians, with 41 differently abundant lipid species with respect to elderly subjects. These findings reveal phospho/sphingolipids as putative markers and biological modulators of healthy aging, in humans. Considering the particular actions of these metabolites, these data are suggestive of a better counteractive antioxidant capacity and a well-developed membrane lipid remodelling process in the healthy aging phenotype.

With aging, an increased prevalence of a clustering of metabolic abnormalities has been observed. These abnormalities include obesity, dyslipidemia, hypertension, and insulin resistance and are collectively known as metabolic syndrome (MetS), a low-grade, systemic, inflammatory condition associated with an increased risk of cardiovascular disease, diabetes, and other adverse health outcomes. A number of studies have demonstrated that centenarians’ offspring have a significant survival advantage and a lower risk of developing the most important age-related diseases. They therefore represent one of the best models with which to study the familiar component of human longevity. The aim of this study was to determine if the offspring of centenarians (n = 265 subjects) showed a different prevalence of MetS in comparison to the offspring of non-long-lived parents (controls, n = 101 subjects). In addition, we assessed whether centenarians’ offspring showed particular features of MetS and a distinct regulation of circulating adipokines, cytokines, and metabolic mediators. Although the prevalence of MetS was quite similar both in the offspring of centenarians and the controls, MetS-affected centenarians’ offspring seemed healthier, more functionally fit, and had lower resistin levels. MetS prevalence did not change in centenarians’ offspring across resistin, IGF-1, and resistin/IGF-1 ratio tertiles. On the other hand, in controls, MetS prevalence strongly increased across resistin tertiles and in the third resistin/IGF-1 ratio tertile, indicating a dramatic increase in MetS prevalence when the ratio between these two factors is unbalanced, with high levels of resistin and low levels of IGF-1.

The aging phenotype in humans has been thoroughly studied but a detailed metabolic profiling capable of shading light on the underpinning biological processes of longevity is still missing. Here using a combined metabonomics approach compromising holistic 1H-NMR profiling and targeted MS approaches, we report for the first time the metabolic phenotype of longevity in a well characterized human aging cohort compromising mostly female’s centenarian, elderly, and young individuals. Within increasing age targeted MS profiling of blood serum displayed a marked decrease in tryptophan concentration, while an unique alteration of specific glycerophospholipids and sphingolipids are seen in the longevity phenotype.We hypothesized that the overall lipidome changes specific to longevity putatively reflect centenarians’ unique capacity to adapt/respond to the accumulating oxidative and chronic inflammatory conditions characteristics of their extreme aging phenotype. Our data in centenarians support promotion of a cellular detoxification mechanisms through specific modulation of the arachidonic acid metabolic cascade as we underpinned increased concentration of 8,9-EpETrE, suggesting enhanced cytochrome P450 (CYP) enzyme activity. Such effective mechanism might results in the activation of an anti-oxidative response, as displayed by decreased circulating levels of 9-HODE, and 9-oxoODE, markers of lipid peroxidation and oxidative products of linoleic acid. Lastly, we also revealed that the longevity process deeply affects the structure and composition of the human gut microbiota as shown by the increased extrection of phenylacetylglutamine (PAG) and p-cresol sulfate (PCS) in urine of centenarians. Together, our novel approach in this representative Italian longevity cohort support the hypothesis that a complex remodeling of lipid, amino acid metabolism, and of gut microbiota functionality are key regulatory processes marking exceptional longevity in humans.

In literature, some of the main factors defining the quality of aging are related to the inflammatory status (IS), oxidative stress (OX) and gut microbiota (GM) alterations. These elements may increase prevalence of age-related anorexia associated to a reduction of food intakes and a decrease of physical activity too. RISTOMED held under the EU-7FP, aimed at the evaluation of the effects on IS-OX-GM in the presence of an (e)-diet in an Elderly Population (65-80 yrs).The study was aimed to compare a e-diet elaborated with a new web platform, alone or implemented by 3 different nutraceutic components: Argan oil, probiotic VSL#3 and the AISA 5203-L extract. In order to evaluate the effects of the intervention, the following measurements and questionnaires have been considered within the protocol: Anthropometric data, handgrip, and Short Physical Performance Battery (SPPB), International Physical Activity Questionnaires (IPAQ), SF-36v2(PCS-MCS), Food Frequency Questionnaire (FFQ),among others. All the data and the results of this panel of questionnaires in Bordeaux, Berlin and Rome showed that in all the 4 arms of the 139 men and women enrolled there was an improvement in terms of quality of life. In a cluster of 44 subjects characterized by a low-grade inflammation with higher levels of CRP, ESR, fibrinogen, IL-6 and TNF-a, the e-diet induced a decrease of CRP in the group with the higher inflammation values, whereby AISA 5203-L amplified this protective effect. The e-diet alone decreased the oxidative stress with no further effect of the products. Cholesterol, triglycerides and glucose parameters were also improved by e-diet with a further effect of Argan oil was associated with a progress of these parameters when they were altered at the baseline. VSL#3 decreased homocysteine level, a vascular risk factor. On the basis of the results an improvement of mood was observed in all groups and an improvement of mental component SF36 was observed following the diet and the diet implemented by AISA 5203-L.

The topic is focused on human immune system and its remodelling during aging and the concomitant low grade inflammation that could favour the onset of age-associated pathologies

At present, individuals can live up to 80–120 years, a time much longer than that of our ancestors, as a consequence of the improvements in life conditions and medical care. Thus, the human immune system has to cope with a lifelong and evolutionarily unpredicted exposure to a variety of antigens, which are at the basis of profound age-related changes globally indicated as immunosenescence, a multifaceted phenomenon that increases morbidity and mortality due to infections and age-related pathologies. The major changes occurring during immunosenescence are the result of the accumulation of cellular, molecular defects and involutive phenomena (such as thymic involution) occurring concomitantly to a hyperstimulation of both innate and adaptive immunity (accumulation of expanded clones of memory and effector T cells, shrinkage of the T cell receptor repertoire, progressive activation of macrophages), and resulting in a low-grade, chronic state of inflammation defined as inflammaging. It is unknown whether inflammaging, which represents a risk factor for most age-related pathologies, is a cause or rather an effect of the aging process. In this complex scenario, the role of genetic background likely represents a fundamental variable to attain successful aging and longevity. Accordingly, centenarians seem to be equipped with gene variants that allow them to optimize the balance between pro- and anti-inflammatory molecules, and thus to minimize the effects of the lifelong exposure to environmental insults and stressors. The remarkable features of the genetics of aging and longevity are reviewed, stressing the unexpected and unusual results obtained regarding such a postreproductive type of genetics.

Immunosenescence is characterized by three main aspects: (i) the shrinkage of the T cell repertoire and the accumulation of oligoclonal expansions (megaclones) of memory/effector cells directed toward ubiquitary infectious agents; (ii) the involution of the thymus and the exhaustion of naive T cells; and (iii) a chronic inflammatory status called inflamm-aging. We present here possible strategies to counteract these main aspects of immunosenescence in humans with particular attention to the reduction of antigenic load by pathogens, such as CMV, and the normalization of intestinal microflora, the possible utilization of IL-7 to reverse thymic involution, the purging of megaclones, the forced expression of CD28 on T lymphocytes, the reduction of inflamm-aging and the administration of nutrients such as vitamin D. Possible drawbacks of all these strategies are discussed. Finally, the complexity of a rejuvenation approach is stressed, with particular attention to the inhibitory role played by the "old microenvironment" on the performance of progenitor cells, the best candidate to counteract the decline in regenerative potential characteristic of organs and tissues from old organisms.

Immunosenescence features, such as thymic involution, alteration of T-cell repertoire, autoimmunity and accumulation of memory/effector T cells, may be the result, at least in part, of a zinc deficiency, which is often observed during ageing. Zinc, as essential trace element, affects the immune system function and it is an important regulator of apoptosis of immune cells. In this study we addressed the question whether zinc supplementation in vitro at physiological doses can affect spontaneous and oxidative stress-induced apoptosis in peripheral blood mononuclear cells from subjects of three different age groups: young (mean age 28 years), old (mean age 72 years) and nonagenarians. We studied different parameters related to apoptosis (phosphatydilserine exposure, mitochondrial membrane potential, caspase 3 cleavage) and we found that zinc, while decreasing spontaneous apoptosis, can increase oxidative stress-induced apoptosis in an age-related fashion, being this effect more evident in nonagenarians than in old or young subjects. In particular, zinc can increase late apoptosis/necrosis, a phenomenon that could trigger unnecessary inflammation in vivo. We surmise that these age-associated alterations in susceptibility to apoptosis may be due to a different effect of zinc on T cell subsets, that are altered in very old people, and finally that the zinc deficiency, which is often observed in aged subjects, could be a compensatory mechanism to counteract the inflammatory status of the elderly.