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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.

Recent longitudinal studies in dietary daily intake in human centenarians have shown that a satisfactory content of some micronutrients within the cells maintain several immune functions, a low grade of inflammation and preserve antioxidant activity. Micronutrients (zinc, copper, selenium) play a pivotal role in maintaining and reinforcing the performances of the immune and antioxidant systems as well as in affecting the complex network of the genes (nutrigenomic) with anti- and pro-inflammatory tasks. Genes of pro- and anti-inflammatory cytokines and some key regulators of trace elements homeostasis, such as Metallothioneins (MT), are involved in the susceptibility to major geriatric disease/disorders. Moreover, the genetic inter-individual variability may affect the nutrients’ absorption (nutrigenetic) with altered effects on inflammatory/immune response and antioxidant activity. The interaction between genetic factors and micronutrients (nutrigenomic and nutrigenetic approaches) may influence ageing and longevity because the micronutrients may become also toxic. This review reports the micronutrient–gene interactions in ageing and their impact on the healthy state with a focus on the method of protein–metal speciation analysis. The association between micronutrient–gene interactions and the protein–metal speciation analysis can give a complete picture for a personalized nutrient supplementation or chelation in order to reach healthy ageing and longevity.

Mitochondrial components, including mitochondrial DNA (mtDNA), when released extracellularly, can act as "damage-associated molecular pattern" (DAMP) agents and cause inflammation. As many elderly people are characterized by a low-grade, chronic inflammatory status defined "inflamm-aging," we evaluated if circulating mtDNA can contribute to this phenomenon. Eight hundred and thirty-one Caucasian subjects were enrolled in the study, including 429 siblings aged 90-104 (90+ siblings). mtDNA plasma levels increased gradually after the fifth decade of life. In 90+ subjects, mtDNA values of two members of the same sibling relationship were directly correlated, suggesting a role for familiar/genetic background in controlling the levels of circulating mtDNA. The subjects with the highest mtDNA plasma levels had the highest amounts of TNF-α, IL-6, RANTES, and IL-1ra; the subjects with the lowest mtDNA levels had the lowest levels of the same cytokines. In vitro stimulation of monocytes with mtDNA concentrations similar to the highest levels observed in vivo resulted in an increased production of TNF-α, suggesting that mtDNA can modulate the production of proinflammatory cytokines. Our findings therefore show that circulating mtDNA increases with age, and can significantly contribute to the maintenance of the low-grade, chronic inflammation observed in elderly people.

Background The proportion of European elderly is expected to increase to 30% in 2060. Combining dietary components may modulate many processes involved in ageing. So, it is likely that a healthful diet approach might have greater favourable impact on age-related decline than individual dietary components. This paper describes the design of a healthful diet intervention on inflammageing and its consequences in the elderly. Methods The NU-AGE study is a parallel randomized one-year trial in 1250 apparently healthy, independently living European participants aged 65–80 years. Participants are randomised into either the diet group or control group. Participants in the diet group received dietary advice aimed at meeting the nutritional requirements of the ageing population. Special attention was paid to nutrients that may be inadequate or limiting in diets of elderly, such as vitamin D, vitamin B12, and calcium. C-reactive protein is measured as primary outcome. Discussion The NU-AGE study is the first dietary intervention investigating the effect of a healthful diet providing targeted nutritional recommendations for optimal health and quality of life in apparently healthy European elderly. Results of this intervention will provide evidence on the effect of a healthful diet on the prevention of age related decline.

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.

Inflamm-ageing, defined as the chronic low-grade inflammation typical of ageing, seems to be the common biological factor responsible for the decline and the onset of disease in the elderly. The major age-related diseases share a common inflammatory pathogenesis, giving rise to the so-called 'diseasome of inflamm-ageing'. Main objective of this review is to provide a comprehensive view of the complex interactions responsible for inflamm-ageing, underlining its relationship with metaflammation and the role of senescent cells, gut microbiota and nutrition in determining when, where and how much this phenomenon impacts on the health status during human lifespan.The ageing process and the health status of elderly people may be improved by facing and slowing down inflamm-ageing. Among the inflammation modulators, gut microbiota and nutrition should be exploited as potential powerful tools to promote healthy ageing and to extend the lifespan in humans.The possibility to control inflamm-ageing represents a powerful tool to modulate and counteract the major age-related pathologies and it is urgent to clarify the shady areas of the complex mechanisms underpinning inflamm-ageing in order to carry out targeted therapeutic interventions towards an improvement of the health status in the elderly population.

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.

Centenarians' offspring represent a suitable model to study age-dependent variables (e. g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay, total IGF-I, IGFBP-3, total IGF-II, insulin, glucose, HOMA2-B% and HOMA2-S% in 192 centenarians' offspring and 80 offspring-controls of which both parents died relatively young. Both groups were well-matched for age, gender and BMI with the centenarians' offspring. IGF-I bioactivity (p

The human model within MARK-AGE project contains innovative concepts.

A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers ("inflamm-ageing"). This status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation ("inflamm-ageing") will be discussed in this review in the context of its onset/progression leading to site-restricted and systemic effects. Moreover, some of the possible strategies and therapies to counteract the different sources of molecular mediators which lead to the age-related inflammatory phenotype will be presented.

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.

Background The proportion of European elderly is expected to increase to 30% in 2060. Combining dietary components may modulate many processes involved in ageing. So, it is likely that a healthful diet approach might have greater favourable impact on age-related decline than individual dietary components. This paper describes the design of a healthful diet intervention on inflammageing and its consequences in the elderly. Methods The NU-AGE study is a parallel randomized one-year trial in 1250 apparently healthy, independently living European participants aged 65–80 years. Participants are randomised into either the diet group or control group. Participants in the diet group received dietary advice aimed at meeting the nutritional requirements of the ageing population. Special attention was paid to nutrients that may be inadequate or limiting in diets of elderly, such as vitamin D, vitamin B12, and calcium. C-reactive protein is measured as primary outcome. Discussion The NU-AGE study is the first dietary intervention investigating the effect of a healthful diet providing targeted nutritional recommendations for optimal health and quality of life in apparently healthy European elderly. Results of this intervention will provide evidence on the effect of a healthful diet on the prevention of age related decline.

Being indicators of nutritional and functional status, anthropometric characters may have great prognostic significance for survival at extremely advanced ages. For ethical and practical reasons however it is advisable to use characters such as arm measurements easily measurable even in bedridden subjects. This study compares the influence of some upper arm measurements and of Body Mass Index (BMI) on survival of the 77 subjects aged 98 years and over (98 +) recruited within the MALVA project, one of the first Italian population-based studies on extremely old people. Adopting methods for multiple imputation of missing values, Gompertz regression models adjusted for gender and age were estimated for each anthropometric character or combination of characters, i.e. BMI; mid-upper arm circumference (MUAC) + elbow breadth (EB) + triceps skinfold thickness (TSF); corrected arm muscle area (CAMA). Being underweight and having a low CAMA and a low MUAC/high EB were positively associated with an increased risk of death, while no significant association was found with the condition of being overweight/obese and the triceps skinfold thickness. When anthropometric variables were included in regression models along with covariates relating to nutritional and functional status, BMI and MUAC, but not CAMA, emerged as protective factors. It is suggested that MUAC can be recommended in evaluating the health status of extremely old people and that measuring EB may help to estimate the non-boney component of the arm.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (

Aging is a complex biological phenomenon in which the deficiency of the nutritional state combined with the presence of chronic inflammation and oxidative stress contribute to the development of many age-related diseases. Under this profile, the free radicals produced by the oxidative stress lead to a damage of DNA, lipids and proteins with subsequent altered cellular homeostasis and integrity. In young-adult age, the cell has a complex efficient system to maintain a proper balance between the levels of free radicals and antioxidants ensuring the integrity of cellular components. In contrast, in old age this balance is poorly efficient compromising cellular homeostasis. Supplementation with Vitamin E can restore the balance and protect against the deteriorating effects of oxidative stress, progression of degenerative diseases, and aging. Experiments in cell cultures and in animals have clearly shown that Vitamin E has a pivotal role as antioxidant agent against the lipid peroxidation on cell membranes preserving the tissue cells from the oxidative damage. Such a role has been well documented in immune, endothelial, and brain cells from old animals describing how the Vitamin E works both at cytoplasmatic and nuclear levels with an influence on many genes related to the inflammatory/immune response. All these findings have supported a lot of clinical trials in old humans and in inflammatory age-related diseases with however contradictory and inconsistent results and even indicating a dangerous role of Vitamin E able to affect mortality. Various factors can contribute to all the discrepancies. Among them, the doses and the various isoforms of Vitamin E family (α,β,γ,δ tocopherols and the corresponding tocotrienols) used in different trials. However, the more plausible gap is the poor consideration of the Vitamin E-gene interactions that may open new roadmaps for a correct and personalized Vitamin E supplementation in aging and age-related diseases with satisfactory results in order to reach healthy aging and longevity. In this review, this peculiar nutrigenomic and/or nutrigenetic aspect is reported and discussed at the light of specific polymorphisms affecting the Vitamin E bioactivity.

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.

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.

8 a Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy 9 b CIG—Interdepartmental Centre L. Galvani, University of Bologna, Bologna, Italy 10 c Physics and Astronomy Department, University of Bologna, Bologna, Italy 11 d Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy 12 e Immunosenescence Unit, Department of Pathobiology and Biomedical Methodologies, University of Palermo, Palermo, Italy 13 f Geriatric Unit IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, University of Milan, Italy 14 g Department of Clinical Sciences and Community Health, University of Milan, Italy 15 h Experimental Laboratory of Immuno-rheumatology, IRCCS Istituto Auxologico Italiano, Milan, Italy 16 i Department of Clinical and Experimental Biomedical Sciences, University of Florence, Florence, Italy 17

Circulating microRNAs (miRs) have been investigated as diagnostic/prognostic biomarkers in human diseases. However, little is known about their expression throughout the aging process. Eleven healthy individuals aged 20, 80 and 100 years underwent miR plasma profiling. The validation cohort consisted of 111 healthy adults (CTR) aged 20-105 years and included 30 centenarians. In addition, 34 patients with cardiovascular disease (CVD) and 15 healthy centenarian offspring (CO) were enrolled. An exploratory factorial analysis grouped the miRs into three main factors: factor 1 primarily higher in 20-year-old subjects, but these differences did not reach statistical significance, factor 2 primarily higher in octogenarians and factor 3 primarily higher in centenarians. MiR-21, the most highly expressed miR of factors 2 and 3, was further validated, confirming the differences in the age groups. MiR-21 expression was higher in the CVD patients and lower in the CO compared to the age-matched CTR. MiR-21 was correlated with C-reactive protein and fibrinogen levels. TGF-β signaling was the predicted common pathway targeted by miRs of factors 2 and 3. TGF-βR2 mRNA, a validated miR-21 target, showed the highest expression in the leukocytes from a subset of the octogenarians. Our findings suggest that miR-21 may be a new biomarker of inflammation.

In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity. In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.

Human aging and longevity are complex and multi-factorial traits that result from a combination of environmental, genetic, epigenetic and stochastic factors, each contributing to the overall phenotype. The multi-factorial process of aging acts at different levels of complexity, from molecule to cell, from organ to organ systems and finally to organism, giving rise to the dynamic "aging mosaic". At present, an increasing amount of experimental data on genetics, genomics, proteomics and other -omics are available thanks to new high-throughput technologies but a comprehensive model for the study of human aging and longevity is still lacking. Systems biology represents a strategy to integrate and quantify the existing knowledge from different sources into predictive models, to be later tested and then implemented with new experimental data for validation and refinement in a recursive process. The ultimate goal is to compact the new acquired knowledge into a single picture, ideally able to characterize the phenotype at systemic/organism level. In this review we will briefly discuss the aging phenotype in a systems biology perspective, showing four specific examples at different levels of complexity, from a systemic process (inflammation) to a cascade-process pathways (coagulation) and from cellular organelle (proteasome) to single gene-network (PON-1), which could also represent targets for anti-aging strategies.

How many animal models are adequate to study human aging? Aging is an adaptive process performed by an integrated panel of evolutionarily selected mechanisms aimed at maintaining soma integrity. The possibility of extrapolating results from animal models to human beings has to be addressed in an ecological context. Model systems fit basic requirements of scientific research, and experimental animals show a series of advantages for the study of aging and longevity in humans. However, animal models have intrinsic constraints because they are artificial: Humans are not inbred and live in different conditions from both an environmental and a socio-anthropological-cultural point of view. Even if research on aging and longevity has been performed primarily in model systems such as yeast, worms, and flies, results obtained in humans are not only of basic importance but are also largely unexpected, probably because of the peculiar characteristics of humans (protected environment, culture, economic conditions, stochasticity). In some cases, studies in animal models or humans have led to analogous results, largely because basic mechanisms involved in aging have been conserved throughout evolution. In other cases, results are different or even opposite, as is described in this chapter. Animal models are often not sufficiently adequate for the study of human longevity, but their usefulness in achieving knowledge at different levels (molecular, cellular, physiological, behavioral) is unquestionable. Thus, it seems that the concomitant and integrated use of ad hoc models, also comparing different species, together with new in silico and high throughput strategies, will be the general framework within which studies on human aging and longevity should be performed to accelerate the identification of new determinants of healthy aging and longevity.

Background: The aging phenotype in humans is very heterogeneous and can be described as a complex mosaic resulting from the interaction of a variety of environmental, stochastic and genetic-epigenetic variables. Therefore, each old person must be considered as a singleton, and consequently the definition of ‘aging phenotype’ is very difficult. Objective: We discuss the phenotype of centenarians, the best example of successful aging, as well as other models exploited to study human aging and longevity, such as families enriched in long-living subjects, twins and cohorts of unrelated subjects. Methods: A critical review of literature available until March 2008. Conclusions: No single model can be considered the gold standard for the study of aging and longevity, instead the combination of results obtained from different models must be considered in order to better understand these complex phenomena. We propose that a systems biology concept such as that of ‘bow-tie’ architecture, useful for managing informa...

A large part of the aging phenotype, including immunosenescence, is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status we proposed to call inflammaging. Within this perspective, healthy aging and longevity are likely the result not only of a lower propensity to mount inflammatory responses but also of efficient anti-inflammatory networks, which in normal aging fail to fully neutralize the inflammatory processes consequent to the lifelong antigenic burden and exposure to damaging agents. Such a global imbalance can be a major driving force for frailty and common age-related pathologies, and should be addressed and studied within an evolutionary-based systems biology perspective. Evidence in favor of this conceptualization largely derives from studies in humans. We thus propose that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.

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.

Many epidemiological data indicate the presence of a strong familial component of longevity that is largely determined by genetics, and a number of possible associations between longevity and allelic variants of genes have been described. A breakthrough strategy to get insight into the genetics of longevity is the study of centenarians, the best example of successful ageing. We review the main results regarding nuclear genes as well as the mitochondrial genome, focusing on the investigations performed on Italian centenarians, compared to those from other countries. These studies produced interesting results on many putative "longevity genes". Nevertheless, many discrepancies are reported, likely due to the population-specific interactions between gene pools and environment. New approaches, including large-scale studies using high-throughput techniques, are urgently needed to overcome the limits of traditional association studies performed on a limited number of polymorphisms in order to make substantial progress to disentangle the genetics of a trait as complex as human longevity.

Several alterations in immune function and a concomitant progressive increase in pro-inflammatory status are the major characteristics of ageing process. Cytokines play a key role during ageing acting both in regulatory communication among cells and in effector activity during an immune response. The impact of age on intracellular Type 1 (IFN-gamma and TNF-alpha) and Type 2 (IL-4) cytokines, after stimulation with PMA/ionomycin, was determined in three CD4+ T subsets, i.e. CD95- CD28+ (virgin), CD95+ CD28+ (activated/memory), and CD95+ CD28- (effector/memory) from 47 subjects aged between 21 and 99 years. The percentage of IFN-gamma positive cells significantly decreased in virgin CD4+ subset both in old and nonagenarian subjects, as well as in activated/memory T cells from old in comparison with young subjects. The percentage of TNF-alpha positive cells significantly decreased in activated/memory CD4+ subset from old people. Regarding Type 2 cytokines, IL-4 positive cells significantly increased in activated/memory CD4+ subset from nonagenarians. On the whole our data indicate that: (1) different Type 1 and Type 2 cytokine-positive CD4+ T subsets are differently affected by ageing process; (2) activated/memory T cells appear to be the most affected subset; (3) a shift towards an increased role of Type 2 cytokines and a diminished role of Type 1 cytokines emerges with ageing.

The major changes occurring life long in the human immune system are here described. The progressive inflammatory status which is established during aging together with the progressive susceptibility to infectious diseases are discussed in the frame of the genetic variant influence. Finally, the possibility to counteract the susceptibility to infections by coping with or slowing down immunosenescence, using different molecules or strategies, is argued

Within the scenario of an increasing life expectancy worldwide it is mandatory to identify determinants of healthy aging. Centenarian offspring (CO) is one of the most informative model to identify trajectories of healthy aging and their determinants (genetic and environmental), being representative of elderly in their 70th whose lifestyle can be still modified to attain a better health. This study is the first comprehensive investigation of the health status of 267 CO (mean age: 70.2 years) and adopts the innovative approach of comparing CO with 107 age‐matched offspring of non‐long‐lived parents (hereafter indicated as NCO controls), recruited according to strict inclusion demographic criteria of Italian population. We adopted a multidimensional approach which integrates functional and cognitive assessment together with epidemiological and clinical data, including pro‐ and anti‐inflammatory cytokines and adipokines, lipid profile, and insulin resistance. CO have a lower prevalence of stroke, cerebral thrombosis‐hemorrhage, hypertension, hypercholesterolemia, and other minor diseases, lower BMI and waist circumference, a better functional and cognitive status and lower plasma level of FT4 compared to NCO controls. We conclude that a multidimensional approach is a reliable strategy to identify the health status of elderly at an age when interventions to modify their health trajectory are feasible.

The health status of the oldest old, the fastest increasing population segment worldwide, progressively becomes more heterogeneous, and this peculiarity represents a major obstacle to their classification. We compared the effectiveness of four previously proposed criteria (Franceschi et al., 2000; Evert et al., 2003; Gondo et al., 2006; Andersen-Ranberg et al., 2001) in 1160 phenotypically fully characterized Italian siblings of 90 years of age and older (90+, mean age: 93 years; age range: 90-106 years) belonging to 552 sib-ships, recruited in Northern, Central and Southern Italy within the EU-funded project GEHA, followed for a six-year-survival. Main findings were: (i) "healthy" subjects varied within a large range, i.e. 5.2% (Gondo), 8.7% (Evert), 17.7% (Franceschi), and 28.5% (Andersen-Ranberg); (ii) Central Italy subjects showed better health than those from Northern and Southern Italy; (iii) mortality risk was correlated with health status independently of geographical areas; and (iv) 90+ males, although fewer in number, were healthier than females, but with no survival advantage. In conclusion, we identified a modified version of Andersen-Ranberg criteria, based on the concomitant assessment of two basic domains (cognitive, SMMSE; physical, ADL), called "Simple Model of Functional Status" (SMFS), as the most effective proxy to distinguish healthy from not-healthy subjects. This model showed that health status was correlated within sib-ships, suggesting a familial/genetic component. The health status of the oldest old, the fastest increasing population segment worldwide, progressively becomes more heterogeneous, and this peculiarity represents a major obstacle to their classification. We compared the effectiveness of four previously proposed criteria (Franceschi et al., 2000; Evert et al., 2003; Gondo et al., 2006; Andersen-Ranberg et al., 2001) in 1160 phenotypically fully characterized Italian siblings of 90 years of age and older (90+, mean age: 93 years; age range: 90-106 years) belonging to 552 sib-ships, recruited in Northern, Central and Southern Italy within the EU-funded project GEHA, followed for a six-year-survival. Main findings were: (i) "healthy" subjects varied within a large range, i.e. 5.2% (Gondo), 8.7% (Evert), 17.7% (Franceschi), and 28.5% (Andersen-Ranberg); (ii) Central Italy subjects showed better health than those from Northern and Southern Italy; (iii) mortality risk was correlated with health status independently of geographical areas; and (iv) 90+ males, although fewer in number, were healthier than females, but with no survival advantage. In conclusion, we identified a modified version of Andersen-Ranberg criteria, based on the concomitant assessment of two basic domains (cognitive, SMMSE; physical, ADL), called "Simple Model of Functional Status" (SMFS), as the most effective proxy to distinguish healthy from not-healthy subjects. This model showed that health status was correlated within sib-ships, suggesting a familial/genetic component.