Papers by Claudio Franceschi
Mechanisms of Ageing and Development, 2003
In the present investigation we analysed Interleukin 6 (IL-6) in vitro production by Epstein Á/Ba... more In the present investigation we analysed Interleukin 6 (IL-6) in vitro production by Epstein Á/Barr virus (EBV)-immortalized B lymphocytes established from 43 subjects, 15 young people and 28 elderly people, including 18 centenarians, after 3, 6, 9, 24, 48 and 72 h of culture. The subjects were genotypized for the C to G transition at nucleotide (/174 of IL-6 gene promoter ((/174 C/G) and were classified as C allele carriers (C'/) and non-carriers (C(/). We found that: (i) the interindividual difference in in vitro IL-6 production was wider in elderly individuals in respect to young individuals, leading to different coefficient of variation in the two groups; (ii) the (/174 C/G polymorphism had an age-related effect on IL-6 in vitro production. Only among C(/ people, cells from elderly subjects produced significant higher level of IL-6 than cells from young subjects. These data are consistent with our previous results regarding the IL-6 serum levels in a large group of people of different age, including centenarians. Thus, the EBVimmortalized B lymphocytes can be considered a useful in vitro model for studying the genetic control of IL-6 production and its changes with age.
Nutrients, 2020
Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present... more Background and Aim: A state of chronic, subclinical inflammation known as inflammaging is present in elderly people and represents a risk factor for all age-related diseases. Dietary supplementation with ad hoc fortified foods seems an appealing strategy to counteract inflammaging. The purpose of this study was to test the efficacy of elderly-tailored fortified milk on inflammaging and different health parameters. Methods: A double-blind randomized cross-over study was performed on forty-eight volunteers aged 63–80 years. The fortified milk was enriched with ω-3 polyunsaturated fatty acids (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA), vitamins (25-hydroxyvitamin D, E, C, B6, B9, B12), and trace elements (zinc, selenium). The two intervention periods lasted for 12 weeks, with a 16-week washout intermission. Results: Compared to placebo, the consumption of fortified milk increased the circulating levels of different micronutrients, including vitamins and the ω-3 index of er...
Mechanisms of Ageing and Development, 2015
MARK-AGE aims at the identification of biomarkers of human aging capable of discriminating betwee... more MARK-AGE aims at the identification of biomarkers of human aging capable of discriminating between the chronological age and the effective functional status of the organism. To achieve this, given the structure of the collected data, a proper statistical analysis has to be performed, as the structure of the data are non trivial and the number of features under study is near to the number of subjects used, requiring special care to avoid overfitting. Here we described some of the possible strategies suitable for this analysis. We also include a description of the main techniques used, to explain and justify the selected strategies. Among other possibilities, we suggest to model and analyze the data with a three step strategy:
Mechanisms of Ageing and Development, 2006
Several alterations in immune function and a concomitant progressive increase in pro-inflammatory... more 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.
Nutrients, Jan 9, 2015
Aging is considered the major risk factor for cancer, one of the most important mortality causes ... more 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 inv...
Aging, 2013
Genetic association studies of age-related, chronic human diseases often suffer from a lack of po... more Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed /genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed...
BioMed Research International, 2014
Usually the genetics of human longevity is restricted to the nuclear genome (nDNA). However it is... more Usually the genetics of human longevity is restricted to the nuclear genome (nDNA). However it is well known that the nDNA interacts with a physically and functionally separated genome, the mitochondrial DNA (mtDNA) that, even if limited in length and number of genes encoded, plays a major role in the ageing process. The complex interplay between nDNA/mtDNA and the environment is most likely involved in phenomena such as ageing and longevity. To this scenario we have to add another level of complexity represented by the microbiota, that is, the whole set of bacteria present in the different part of our body with their whole set of genes. In particular, several studies investigated the role of gut microbiota (GM) modifications in ageing and longevity and an age-related GM signature was found. In this view, human being must be considered as “metaorganism” and a more holistic approach is necessary to grasp the complex dynamics of the interaction between the environment and nDNA-mtDNA-G...
Handbook on Immunosenescence
The function of immune system depends on a subtle and well tuned network of humoral mediators, co... more The function of immune system depends on a subtle and well tuned network of humoral mediators, collectively called cytokines, responsible for differentiation, proliferation and survival of lymphoid cells. They include colony stimulating factors, and cytokines such as interferons and tumor necrosis factors (TNFs). These molecules constitute a complex network: cytokines, such as IL-2, have a particular importance for the proliferation and differentiation of T, B, and NK cells. IL-2 and IL-10 lead to an increased production of IgM, ...
PLoS ONE, 2013
The aging phenotype in humans has been thoroughly studied but a detailed metabolic profiling capa... more 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 1 H-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 centenarians, elderly, and young individuals. With 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 characteristic of their extreme aging phenotype. Our data in centenarians support promotion of 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 result 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 pcresol 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.
Neuroimmunomodulation, 2008
At present, individuals can live up to 80–120 years, a time much longer than that of our ancestor... more 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 ...
Neurochemistry International, 1998
Adenosine has profound effects on immune cells and has been implicated in the intrathymic apoptot... more Adenosine has profound effects on immune cells and has been implicated in the intrathymic apoptotic deletion of T-cells during development. In order to characterize adenosine effects on quiescent peripheral blood mononuclear cells (PBMC), we have evaluated the ability of the previously characterized adenosine receptor agonist 2-chloro-adenosine (2CA; Ceruti, Barbieri et al., 1997) and of the antineoplastic drug 2-chloro-2′-deoxy-adenosine (2CdA, cladribine) to trigger apoptosis of PBMC. Apoptosis was assessed by morphological changes, DNA fragmentation by agarose gel electrophoresis and appearance of hypodiploid DNA peak by flow cytometry. 2CA (10 μM) and 2CdA (1 μM) induced apoptosis in human PBMC, which are
Mediators of Inflammation, 2014
T2DM is today considered as world-wide health problem, with complications responsible of an enhan... more T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for the 55.6%. Patients with A/A and A/G TLR4 genotypes showed significant differences in complication’s prevalence. In particular, AG carriers had higher risk prevalence for neuropathy (P=0.026), lower limb arteriopathy (P=0.013), and the major cardiovascular pathologies (P=0.017). Their cumulative ris...
Mechanisms of Ageing and Development, 2014
The Journal of Immunology, 2007
A progressive, systemic, and low-grade proinflammatory status is one of the major characteristics... more A progressive, systemic, and low-grade proinflammatory status is one of the major characteristics of immunosenescence. Emerging data suggest a possible contribution of CMV, known to chronically infect a large proportion of humans, lifelong from newborns to centenarians. To test this hypothesis, we evaluated functional T cell responses to two CMV immunogenic proteins, pp65 and IE-1, in 65 chronically infected subjects aged 25–100 years. PBMC were stimulated with mixtures of peptides spanning the entire sequence of both proteins, and Ag specificity and magnitude of intracellular IFN-γ- and TNF-α-positive cells were then analyzed within both CD4+ and CD8+ T cells. Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN-γ induced in T cells by both Ags was seven t...
International Reviews of Immunology, 1995
Free Radical Research, 2006
Experimental Gerontology, 2014
Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are... more 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.
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Papers by Claudio Franceschi