Publications by authors named "Cristina Giuliani"

56 Publications

Whole-genome sequencing analysis of semi-supercentenarians.

Elife 2021 May 4;10. Epub 2021 May 4.

Department of Medicine, Unit of Internal Medicine, University of Verona, Verona, Italy.

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.
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http://dx.doi.org/10.7554/eLife.57849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096429PMC
May 2021

Genetic history of Calabrian Greeks reveals ancient events and long term isolation in the Aspromonte area of Southern Italy.

Sci Rep 2021 Feb 4;11(1):3045. Epub 2021 Feb 4.

Department of Cultural Heritage, University of Bologna, Ravenna, Italy.

Calabrian Greeks are an enigmatic population that have preserved and evolved a unique variety of language, Greco, survived in the isolated Aspromonte mountain area of Southern Italy. To understand their genetic ancestry and explore possible effects of geographic and cultural isolation, we genome-wide genotyped a large set of South Italian samples including both communities that still speak Greco nowadays and those that lost the use of this language earlier in time. Comparisons with modern and ancient populations highlighted ancient, long-lasting genetic links with Eastern Mediterranean and Caucasian/Near-Eastern groups as ancestral sources of Southern Italians. Our results suggest that the Aspromonte communities might be interpreted as genetically drifted remnants that departed from such ancient genetic background as a consequence of long-term isolation. Specific patterns of population structuring and higher levels of genetic drift were indeed observed in these populations, reflecting geographic isolation amplified by cultural differences in the groups that still conserve the Greco language. Isolation and drift also affected the current genetic differentiation at specific gene pathways, prompting for future genome-wide association studies aimed at exploring trait-related loci that have drifted up in frequency in these isolated groups.
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http://dx.doi.org/10.1038/s41598-021-82591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862261PMC
February 2021

Analysis of human mitochondrial genome co-occurrence networks of Asian population at varying altitudes.

Sci Rep 2021 Jan 8;11(1):133. Epub 2021 Jan 8.

Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore, 453552, India.

Networks have been established as an extremely powerful framework to understand and predict the behavior of many large-scale complex systems. We studied network motifs, the basic structural elements of networks, to describe the possible role of co-occurrence of genomic variations behind high altitude adaptation in the Asian human population. Mitochondrial DNA (mtDNA) variations have been acclaimed as one of the key players in understanding the biological mechanisms behind adaptation to extreme conditions. To explore the cumulative effects of variations in the mitochondrial genome with the variation in the altitude, we investigated human mt-DNA sequences from the NCBI database at different altitudes under the co-occurrence motifs framework. Analysis of the co-occurrence motifs using similarity clustering revealed a clear distinction between lower and higher altitude regions. In addition, the previously known high altitude markers 3394 and 7697 (which are definitive sites of haplogroup M9a1a1c1b) were found to co-occur within their own gene complexes indicating the impact of intra-genic constraint on co-evolution of nucleotides. Furthermore, an ancestral 'RSRS50' variant 10,398 was found to co-occur only at higher altitudes supporting the fact that a separate route of colonization at these altitudes might have taken place. Overall, our analysis revealed the presence of co-occurrence interactions specific to high altitude at a whole mitochondrial genome level. This study, combined with the classical haplogroups analysis is useful in understanding the role of co-occurrence of mitochondrial variations in high altitude adaptation.
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http://dx.doi.org/10.1038/s41598-020-80271-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794584PMC
January 2021

Age-related DNA methylation changes are sex-specific: a comprehensive assessment.

Aging (Albany NY) 2020 12 3;12(23):24057-24080. Epub 2020 Dec 3.

Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky University, Nizhniy Novgorod, Russia.

The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in and genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.
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http://dx.doi.org/10.18632/aging.202251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762479PMC
December 2020

Investigating Mitonuclear Genetic Interactions Through Machine Learning: A Case Study on Cold Adaptation Genes in Human Populations From Different European Climate Regions.

Front Physiol 2020 11;11:575968. Epub 2020 Nov 11.

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

Cold climates represent one of the major environmental challenges that anatomically modern humans faced during their dispersal out of Africa. The related adaptive traits have been achieved by modulation of thermogenesis and thermoregulation processes where nuclear (nuc) and mitochondrial (mt) genes play a major role. In human populations, mitonuclear genetic interactions are the result of both the peculiar genetic history of each human group and the different environments they have long occupied. This study aims to investigate mitonuclear genetic interactions by considering all the mitochondrial genes and 28 nuclear genes involved in brown adipose tissue metabolism, which have been previously hypothesized to be crucial for cold adaptation. For this purpose, we focused on three human populations (i.e., Finnish, British, and Central Italian people) of European ancestry from different biogeographical and climatic areas, and we used a machine learning approach to identify relevant nucDNA-mtDNA interactions that characterized each population. The obtained results are twofold: (i) at the methodological level, we demonstrated that a machine learning approach is able to detect patterns of genetic structure among human groups from different latitudes both at single genes and by considering combinations of mtDNA and nucDNA loci; (ii) at the biological level, the analysis identified population-specific nuclear genes and variants that likely play a relevant biological role in association with a mitochondrial gene (such as the "obesity gene" in Finnish people). Further studies are needed to fully elucidate the evolutionary dynamics (e.g., migration, admixture, and/or local adaptation) that shaped these nucDNA-mtDNA interactions and their functional role.
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http://dx.doi.org/10.3389/fphys.2020.575968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686538PMC
November 2020

Ecological Sensing Through Taste and Chemosensation Mediates Inflammation: A Biological Anthropological Approach.

Adv Nutr 2020 11;11(6):1671-1685

School of Anthropology and Museum Ethnography, University of Oxford, Oxford, United Kingdom.

Ecological sensing and inflammation have evolved to ensure optima between organism survival and reproductive success in different and changing environments. At the molecular level, ecological sensing consists of many types of receptors located in different tissues that orchestrate integrated responses (immune, neuroendocrine systems) to external and internal stimuli. This review describes emerging data on taste and chemosensory receptors, proposing them as broad ecological sensors and providing evidence that taste perception is shaped not only according to sense epitopes from nutrients but also in response to highly diverse external and internal stimuli. We apply a biological anthropological approach to examine how ecological sensing has been shaped by these stimuli through human evolution for complex interkingdom communication between a host and pathological and symbiotic bacteria, focusing on population-specific genetic diversity. We then focus on how these sensory receptors play a major role in inflammatory processes that form the basis of many modern common metabolic diseases such as obesity, type 2 diabetes, and aging. The impacts of human niche construction and cultural evolution in shaping environments are described with emphasis on consequent biological responsiveness.
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http://dx.doi.org/10.1093/advances/nmaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666896PMC
November 2020

Genomic history of the Italian population recapitulates key evolutionary dynamics of both Continental and Southern Europeans.

BMC Biol 2020 05 22;18(1):51. Epub 2020 May 22.

Interdepartmental Centre Alma Mater Research Institute on Global Challenges and Climate Change, University of Bologna, Bologna, Italy.

Background: The cline of human genetic diversity observable across Europe is recapitulated at a micro-geographic scale by variation within the Italian population. Besides resulting from extensive gene flow, this might be ascribable also to local adaptations to diverse ecological contexts evolved by people who anciently spread along the Italian Peninsula. Dissecting the evolutionary history of the ancestors of present-day Italians may thus improve the understanding of demographic and biological processes that contributed to shape the gene pool of European populations. However, previous SNP array-based studies failed to investigate the full spectrum of Italian variation, generally neglecting low-frequency genetic variants and examining a limited set of small effect size alleles, which may represent important determinants of population structure and complex adaptive traits. To overcome these issues, we analyzed 38 high-coverage whole-genome sequences representative of population clusters at the opposite ends of the cline of Italian variation, along with a large panel of modern and ancient Euro-Mediterranean genomes.

Results: We provided evidence for the early divergence of Italian groups dating back to the Late Glacial and for Neolithic and distinct Bronze Age migrations having further differentiated their gene pools. We inferred adaptive evolution at insulin-related loci in people from Italian regions with a temperate climate, while possible adaptations to pathogens and ultraviolet radiation were observed in Mediterranean Italians. Some of these adaptive events may also have secondarily modulated population disease or longevity predisposition.

Conclusions: We disentangled the contribution of multiple migratory and adaptive events in shaping the heterogeneous Italian genomic background, which exemplify population dynamics and gene-environment interactions that played significant roles also in the formation of the Continental and Southern European genomic landscapes.
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http://dx.doi.org/10.1186/s12915-020-00778-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243322PMC
May 2020

The Contextualized Genetics of Human Longevity: JACC Focus Seminar.

J Am Coll Cardiol 2020 03;75(8):968-979

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy. Electronic address:

The genetics of human longevity has long been studied, and in this regard, centenarians represent a very informative model. Centenarians are characterized by 2 main features: 1) the capability to avoid or postpone the major age-related diseases; and 2) a high level of heterogeneity of their phenotype. The first suggests that longevity and resistance to diseases are mediated by shared mechanisms, the latter that many strategies can be used to become long lived, likely as a result of variable genome-environment interactions. The authors suggest that the complexity of genome-environment interactions must be considered within an evolutionary and ecological perspective and that the concept of "risk allele" is highly context dependent, changing with age, time, and geography. Genes involved in both longevity and cardiovascular diseases, taken as a paradigmatic example of age-related diseases, as well as other emerging topics in genetics of longevity, such as micro-ribonucleic acid (miRNA) genetics, polygenic risk scores, environmental pollutants, and somatic mutations are discussed.
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http://dx.doi.org/10.1016/j.jacc.2019.12.032DOI Listing
March 2020

Author Correction: Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes.

Sci Rep 2020 Feb 21;10(1):3554. Epub 2020 Feb 21.

Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036, Rende, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59859-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035314PMC
February 2020

One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project.

Geroscience 2020 04 24;42(2):687-701. Epub 2020 Jan 24.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Mediterranean diet has been proposed to promote healthy aging, but its effects on aging biomarkers have been poorly investigated. We evaluated the impact of a 1-year Mediterranean-like diet in a pilot study including 120 elderly healthy subjects from the NU-AGE study (60 Italians, 60 Poles) by measuring the changes in their epigenetic age, assessed by Horvath's clock. We observed a trend towards epigenetic rejuvenation of participants after nutritional intervention. The effect was statistically significant in the group of Polish females and in subjects who were epigenetically older at baseline. A genome-wide association study of epigenetic age changes after the intervention did not return significant (adjusted p value < 0.05) loci. However, we identified small-effect alleles (nominal p value < 10-4), mapping in genes enriched in pathways related to energy metabolism, regulation of cell cycle, and of immune functions. Together, these findings suggest that Mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.
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http://dx.doi.org/10.1007/s11357-019-00149-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205853PMC
April 2020

HPV DNA Associates With Breast Cancer Malignancy and It Is Transferred to Breast Cancer Stromal Cells by Extracellular Vesicles.

Front Oncol 2019 16;9:860. Epub 2019 Sep 16.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

A causal link between Human Papillomavirus (HPV) and breast cancer (BC) remains controversial. In spite of this, the observation that HPV DNA is over-represented in the Triple Negative (TN) BC has been reported. Here we remark the high prevalence of HPV DNA (44.4%) in aggressive BC subtypes (TN and HER2+) in a population of 273 Italian women and we convey the presence of HPV DNA in the epithelial and stromal compartments by . As previously reported, we also found that serum derived-extracellular vesicles (EVs) from BC affected patients contain HPV DNA. Interestingly, in one TNBC patient, the same HPV DNA type was detected in the serum-derived EVs, cervical and BC tissue samples. Then, we report that HPV DNA can be transferred by EVs to recipient BC stromal cells that show an activated phenotype (e.g., CD44, IL6 expression) and an enhanced capability to sustain mammospheres (MS) formation. These data suggest that HPV DNA vehiculated by EVs is a potential trigger for BC niche aggressiveness.
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http://dx.doi.org/10.3389/fonc.2019.00860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756191PMC
September 2019

Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes.

Sci Rep 2019 07 17;9(1):10395. Epub 2019 Jul 17.

Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036, Rende, Italy.

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate < 0.1) associated with mortality. Haplotype multivariate analysis revealed that patients carrying the G-C-C haplotype have an increased probability of survival, while an opposite effect was observed among subjects carrying the T-T-A haplotype. Our findings provide evidence that the EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients.
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http://dx.doi.org/10.1038/s41598-019-46894-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637129PMC
July 2019

Dissecting the Pre-Columbian Genomic Ancestry of Native Americans along the Andes-Amazonia Divide.

Mol Biol Evol 2019 06;36(6):1254-1269

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.

Extensive European and African admixture coupled with loss of Amerindian lineages makes the reconstruction of pre-Columbian history of Native Americans based on present-day genomes extremely challenging. Still open questions remain about the dispersals that occurred throughout the continent after the initial peopling from the Beringia, especially concerning the number and dynamics of diffusions into South America. Indeed, if environmental and historical factors contributed to shape distinct gene pools in the Andes and Amazonia, the origins of this East-West genetic structure and the extension of further interactions between populations residing along this divide are still not well understood. To this end, we generated new high-resolution genome-wide data for 229 individuals representative of one Central and ten South Amerindian ethnic groups from Mexico, Peru, Bolivia, and Argentina. Low levels of European and African admixture in the sampled individuals allowed the application of fine-scale haplotype-based methods and demographic modeling approaches. These analyses revealed highly specific Native American genetic ancestries and great intragroup homogeneity, along with limited traces of gene flow mainly from the Andes into Peruvian Amazonians. Substantial amount of genetic drift differentially experienced by the considered populations underlined distinct patterns of recent inbreeding or prolonged isolation. Overall, our results support the hypothesis that all non-Andean South Americans are compatible with descending from a common lineage, while we found low support for common Mesoamerican ancestors of both Andeans and other South American groups. These findings suggest extensive back-migrations into Central America from non-Andean sources or conceal distinct peopling events into the Southern Continent.
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http://dx.doi.org/10.1093/molbev/msz066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526910PMC
June 2019

The Genetic Variability of in Different Human Populations and Its Implications for Longevity.

Genes (Basel) 2019 03 15;10(3). Epub 2019 Mar 15.

Laboratory of Molecular Anthropology & Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, 40126 Bologna, Italy.

Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E () polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer's disease (AD) and cardiovascular disease (CVD). In this case, the available literature on and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of variation evolved.
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http://dx.doi.org/10.3390/genes10030222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471373PMC
March 2019

First evidence of association between past environmental exposure to dioxin and DNA methylation of CYP1A1 and IGF2 genes in present day Vietnamese population.

Environ Pollut 2018 Nov 17;242(Pt A):976-985. Epub 2018 Jul 17.

Medical Genetics Unit, S. Orsola Hospital, University of Bologna, Italy and European School of Genetic Medicine, Italy.

During the Vietnam War, the United States military sprayed over 74 million litres of Agent Orange (AO) to destroy forest cover as a counterinsurgency tactic in Vietnam, Laos and Cambodia. The main ingredient was contaminated by 2,3,7,8-tetrachlorodibenzo-paradioxin (TCDD). DNA methylation (DNAm) differences are potential biomarker of environmental toxicants exposure. The aim of this study was to perform a preliminary investigation of the DNAm levels from peripheral blood of the present-day Vietnamese population, including individuals whose parents, according to historical data, were exposed to AO/TCDD during the war. 94 individuals from heavily sprayed areas (cases) and 94 individuals from non-sprayed areas (controls) were studied, and historical data on alleged exposure of parents collected. 94 cases were analysed considering those whose father/parents participated in the war (N = 29) and considering the place of residence of both parents (64 living in sprayed areas versus 30 in non-contaminated areas). DNAm levels in CYP1A1 and IGF2 genes were measured (MALDI-TOF technology). The analyses showed that: 1) one CpG site in the CYP1A1 and one in the IGF2 gene showed significant differences in DNAm levels between cases and controls; 2) the CYP1A1 region resulted to be hypomethylated (in 9 out of 16 sites/units; p-val<0.01) in 29 individuals whose father/parents participated in the war in the spray zones; 3) we showed that the place of residence of both parents influenced methylation levels of the CYP1A1 and IGF2 genes (p-val<0.05). In conclusion this study indicates that past environmental exposure to dioxin (AO/TCDD) shapes the DNAm profile of CYP1A1 and that the place of living for parents in former spray zones influences DNAm of CYP1A1 and IGF2 genes. These results open the way to new applications of DNAm as potential biomarker(s) of past human exposure to dioxin.
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http://dx.doi.org/10.1016/j.envpol.2018.07.015DOI Listing
November 2018

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework.

Circ Res 2018 09;123(7):745-772

IRCCS, Institute of Neurological Sciences of Bologna, Italy (C.F.).

Human longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequences for biomedicine. The genetics of human longevity is still poorly understood despite several investigations that used different strategies and protocols. Here, we argue that such rather disappointing harvest is largely because of the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan seems to be the result of an intriguing mixture of gene-environment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological, and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status, and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as genome-wide association study and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as apolipoprotein E, Forkhead box O3, interleukin 6, insulin-like growth factor-1, chromosome 9p21, 5q33.3, and somatic mutations among others. The major results of this approach suggest that (1) the genetics of longevity is highly population specific; (2) small-effect alleles, pleiotropy, and the complex allele timing likely play a major role; (3) genetic risk factors are age specific and need to be integrated in the light of the geroscience perspective; (4) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the 3 genetics of human body, that is, nuclear, mitochondrial, and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.312562DOI Listing
September 2018

Impact of demography and population dynamics on the genetic architecture of human longevity.

Aging (Albany NY) 2018 Aug;10(8):1947-1963

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

The study of the genetics of longevity has been mainly addressed by GWASs that considered subjects from different populations to reach higher statistical power. The "price to pay" is that population-specific evolutionary histories and trade-offs were neglected in the investigation of gene-environment interactions. We propose a new "diachronic" approach that considers processes occurred at both evolutionary and lifespan timescales. We focused on a well-characterized population in terms of evolutionary history ( Italians) and we generated genome-wide data for 333 centenarians from the peninsula and 773 geographically-matched healthy individuals. Obtained results showed that: (i) centenarian genomes are enriched for an ancestral component likely shaped by pre-Neolithic migrations; (ii) centenarians born in Northern Italy unexpectedly clustered with controls from Central/Southern Italy suggesting that Neolithic and Bronze Age gene flow did not favor longevity in this population; (iii) local past adaptive events in response to pathogens and targeting arachidonic acid metabolism became favorable for longevity; (iv) lifelong changes in the frequency of several alleles revealed pleiotropy and trade-off mechanisms crucial for longevity. Therefore, we propose that demographic history and ancient/recent population dynamics need to be properly considered to identify genes involved in longevity, which can differ in different temporal/spatial settings.
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http://dx.doi.org/10.18632/aging.101515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128422PMC
August 2018

Inflammaging: a new immune-metabolic viewpoint for age-related diseases.

Nat Rev Endocrinol 2018 10;14(10):576-590

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Ageing and age-related diseases share some basic mechanistic pillars that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, a variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self) and nutrients and gut microbiota (quasi-self). A limited number of receptors, whose degeneracy allows them to recognize many signals and to activate the innate immune responses, sense these stimuli. In this situation, metaflammation (the metabolic inflammation accompanying metabolic diseases) is thought to be the form of chronic inflammation that is driven by nutrient excess or overnutrition; metaflammation is characterized by the same mechanisms underpinning inflammaging. The gut microbiota has a central role in both metaflammation and inflammaging owing to its ability to release inflammatory products, contribute to circadian rhythms and crosstalk with other organs and systems. We argue that chronic diseases are not only the result of ageing and inflammaging; these diseases also accelerate the ageing process and can be considered a manifestation of accelerated ageing. Finally, we propose the use of new biomarkers (DNA methylation, glycomics, metabolomics and lipidomics) that are capable of assessing biological versus chronological age in metabolic diseases.
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http://dx.doi.org/10.1038/s41574-018-0059-4DOI Listing
October 2018

To Seek or Not to Seek Advice: Talking About Romantic Issues During Emerging Adulthood.

Eur J Psychol 2018 Mar 12;14(1):125-142. Epub 2018 Mar 12.

Department of Psychology, CRIdee, Università Cattolica del Sacro Cuore, Milano, Italy.

The aim of the study was to explore whether and how emerging adults talk about their romantic relationships with their close others, especially their parents and friends, also considering gender differences. Data were collected via eight single-sex focus groups conducted with 50 Italian emerging adults (aged 18-25), and were analyzed using thematic analysis. Two main themes emerged. The first was labeled "to seek advice", which was divided into three subthemes: "I look for different points of view," "I treasure other people's words," and "I listen and then do it my own way." The second theme was "to not seek advice," which was divided into two subthemes: "I do not need comparison" and "I need to choose on my own." The findings revealed that close friends, more than parents, are important interlocutors for discussions on romantic relationships, and few gender differences were found. Furthermore, we can speculate that emerging adults' reasons for seeking advice or not could relate to their autonomy and relatedness needs.
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http://dx.doi.org/10.5964/ejop.v14i1.1454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973521PMC
March 2018

Psychological Well-Being, Multiple Identities, and Discrimination Among First and Second Generation Immigrant Muslims.

Eur J Psychol 2018 Mar 12;14(1):66-87. Epub 2018 Mar 12.

Department of Psychology, Università Cattolica del Sacro Cuore, Milano, Italy.

Given the growing number of Muslim immigrants in Western countries, there is a need for research focusing on their psychological well-being and correlates. The present study investigated whether perceived discrimination is associated with depression and satisfaction with migration through the mediating role of several identity dimensions (ethnic, national, and religious) among 204 first and second generation adult Muslim immigrants living in Italy. They participated in structured interviews, and a multi-group path analysis model was conducted using Mplus. While the impact of perceived discrimination on psychological well-being was modest for first generation Muslims, in the case of second generation Muslims perceived discrimination was directly associated with lower psychological well-being (higher depression and lower satisfaction with the migration decision) and indirectly associated with satisfaction with migration through the mediation of national and religious identity. The higher the levels of discrimination that second generation Muslims perceived, the weaker their national (host country) identity and the greater their religious identification. In turn, national and religious identities were associated with respectively higher and lower levels of satisfaction regarding their migration decision. The findings showed clear differences between first and second generation immigrant groups, revealing that perceived discrimination represents an obstacle to integration processes more for second generation immigrants than for first generations.
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http://dx.doi.org/10.5964/ejop.v14i1.1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973518PMC
March 2018

Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.

J Gerontol A Biol Sci Med Sci 2019 01;74(1):1-8

DIMES-Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, Bologna, Italy.

The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8,823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria, we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally, we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt-signaling pathways in the aging of human liver.
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http://dx.doi.org/10.1093/gerona/gly048DOI Listing
January 2019

Genes associated with Type 2 Diabetes and vascular complications.

Aging (Albany NY) 2018 02;10(2):178-196

Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy.

Type 2 Diabetes (T2D) is a chronic disease associated with a number of micro- and macrovascular complications that increase the morbidity and mortality of patients. The risk of diabetic complications has a strong genetic component. To this end, we sought to evaluate the association of 40 single nucleotide polymorphisms (SNPs) in 21 candidate genes with T2D and its vascular complications in 503 T2D patients and 580 healthy controls. The genes were chosen because previously reported to be associated with T2D complications and/or with the aging process. We replicated the association of T2D risk with I rs4402960 and detected novel associations with rs2735940 and rs2736098. The addition of these SNPs to a model including traditional risk factors slightly improved risk prediction. After stratification of patients according to the presence/absence of vascular complications, we found significant associations of variants in the , , and genes with diabetic retinopathy and nephropathy. Additionally, a variant in the gene was found associated with macrovascular complications. Notably, these genes are involved in some way in mitochondrial biology and reactive oxygen species regulation. Hence, our findings strongly suggest a potential link between mitochondrial oxidative homeostasis and individual predisposition to diabetic vascular complications.
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http://dx.doi.org/10.18632/aging.101375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842840PMC
February 2018

Muslim Immigrant Men's and Women's Attitudes Towards Intimate Partner Violence.

Eur J Psychol 2017 Nov 30;13(4):688-707. Epub 2017 Nov 30.

Department of Psychology, Università Cattolica del Sacro Cuore, Milano, Italy.

This study aims to study the attitudes towards Intimate Partner Violence (IPV) in a group of Muslim immigrants. To this end, six focus-groups were conducted involving 42 first-generation Muslim immigrants (21 males and 21 females) from Pakistan, Egypt and Morocco. Focus groups transcripts were then analyzed using the software ATLAS.ti. Irrespectively of nationality, couples replicate relational models learnt in their country of origin, implying a rigid gender-based role division. Women are considered less socially competent if compared to men and therefore in need of protection. Divorce is possible only in case of severe danger: women have to stand beside their husbands and maintain family unity. Even though they are not directly related to IPV, these factors may be key in determining its onset and perpetration. With regards to ethnic background, Pakistani interviewees not only seem to acknowledge the possible occurrence of violence within couple relationships, they also accept it as a mean to regulate socially dysfunctional behaviors. Both Moroccan males and females denounce the impact of post migration stressors as potential triggers of IPV. The distance from one's family of origin in migration is perceived as problematic by both men and women, however, while males' distance from their kin might make them feel overwhelmed with family responsibilities and give way to deviant behaviors, women suffer from the lack of support and protection by their extended family. Implications for practice are also discussed.
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http://dx.doi.org/10.5964/ejop.v13i4.1411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763457PMC
November 2017

Lactase persistence in Tunisia as a result of admixture with other Mediterranean populations.

Genes Nutr 2017 24;12:20. Epub 2017 Aug 24.

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences (BiGeA), University of Bologna, 40126 Bologna, Italy.

Background: The ability to digest lactose after weaning, namely, lactase persistence (LP), is encoded by polymorphisms in the gene and varies widely in frequency among different human populations. Although, evolution of LP-related genetic variants was investigated in many groups of Sub-Saharan African, Middle Eastern, and European ancestry, only few studies have focused on populations from North Africa and no data are especially available from the Tunisian one. For this reason, there is an urgent need to investigate the frequency patterns at these loci in Tunisia since this adaptive trait is implicated in health.

Methods: Forty SNPs covering the genes and including the two functional variants - 13,910 C > T and - 22,018 G > A were genotyped in 117 Tunisian individuals using the Sequenom Mass Array technology. The observed nucleotide and haplotype patterns of variation were then compared with those of several African, European, and Mediterranean human groups for which comparable data were publicly available. Admixture analysis on a 5 Mb genomic region surrounding the loci was also performed by extracting genotypes from a previously generated genome-wide dataset in order to deepen the reconstruction of the evolutionary history of these loci.

Results: We found that lactase non-persistence (LNP)-related alleles and haplotypes were predominantly present in the examined population. A clear differentiation between Tunisian, African, and North European/North Italian samples was found, while the Tunisian population showed more genetic affinity to Central and South Italian groups.

Conclusions: Our study provided a first report of LP-associated alleles and haplotypes in the Tunisian population. We highlighted a gradient followed by LP diffusion from Europe to North Africa. Based on the rich historic background of Tunisia, we suggest that this adaptive trait was introduced in that geographic region by a relatively recent gene flow.
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http://dx.doi.org/10.1186/s12263-017-0573-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571577PMC
August 2017

Multiple selective events at the PRDM16 functional pathway shaped adaptation of western European populations to different climate conditions.

J Anthropol Sci 2017 12 10;95:235-247. Epub 2017 Jul 10.

Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, 40126, Italy; Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, 40126, Italy.

Several studies highlighted the role of climate in shaping many human evolutionary processes. This occurred even in relatively recent times, having affected various human phenotypic traits, among which metabolic processes that orchestrate absorption and accumulation of substances to maintain energy homeostasis, that is critical for the survival of individuals in high energy-expenditure environments. To date, most researches have focalized on detection of climatic influence on SNPs' frequency in populations exposed to extreme environmental conditions or by comparing variation patterns between populations from different continents. In this study, we instead explored the genetic background of distinct western European human groups at loci involved in nutritional and thermoregulation processes, to test whether patterns of differential local adaptation to environmental conditions could be appreciated also at a lower geographical scale. Taking advantage from the 1000 Genomes Project data, genetic information for 21 genes involved in nutritional and thermoregulation processes was analysed for three western European populations. The applied Anthropological Genetics methods pointed to appreciable differentiation between the examined groups especially for the PRDM16 gene. Moreover, several neutrality tests suggested that balancing selection has acted on different regions of the gene in people from Great Britain, as well as that more recent positive selection could have also targeted some PRDM16 SNPs in Finn and Italian populations. These series of adaptive footprints are plausibly related to climate variability in both ancient and relatively recent times. Since this locus is involved in thermoregulation mechanisms and adipogenesis, local adaptations mediated by a pathway related to the brown adipose tissue activity could have evolved in response to changing cold temperature exposures of such populations.
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http://dx.doi.org/10.4436/JASS.95011DOI Listing
December 2017

A bio-cultural approach to the study of food choice: The contribution of taste genetics, population and culture.

Appetite 2017 07 31;114:240-247. Epub 2017 Mar 31.

Department of Biological, Geological and Environmental Sciences (BiGeA), Laboratory of Molecular Anthropology and Centre for Genome Biology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy.

The study of food choice, one of the most complex human traits, requires an integrated approach that takes into account environmental, socio-cultural and biological diversity. We recruited 183 volunteers from four geo-linguistic groups and highly diversified in terms of both genetic background and food habits from whom we collected genotypes and phenotypes tightly linked to taste perception. We confirmed previous genetic associations, in particular with stevioside perception, and noted significant differences in food consumption: in particular, broccoli, mustard and beer consumption scores were significantly higher (Adjusted P = 0.02, Adjusted P < 0.0001 and Adjusted P = 0.01, respectively) in North Europeans, when compared to the other groups. Licorice and Parmesan cheese showed lower consumption and liking scores in the Sri Lankan group (Adjusted P = 0.001 and Adjusted P < 0.001, respectively). We also highlighted how rs860170 (TAS2R16) strongly differentiated populations and was associated to salicin bitterness perception. Identifying genetic variants on chemosensory receptors that vary across populations and show associations with taste perception and food habits represents a step towards a better comprehension of this complex trait, aimed at improving the individual health status. This is the first study that concurrently explores the contribution of genetics, population diversity and cultural aspects in taste perception and food consumption.
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http://dx.doi.org/10.1016/j.appet.2017.03.046DOI Listing
July 2017

The epigenetic landscape of age-related diseases: the geroscience perspective.

Biogerontology 2017 08 28;18(4):549-559. Epub 2017 Mar 28.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via San Giacomo 12, Bologna, 40126, Italy.

In this review, we summarize current knowledge regarding the epigenetics of age-related diseases, focusing on those studies that have described DNA methylation landscape in cardio-vascular diseases, musculoskeletal function and frailty. We stress the importance of adopting the conceptual framework of "geroscience", which starts from the observation that advanced age is the major risk factor for several of these pathologies and aims at identifying the mechanistic links between aging and age-related diseases. DNA methylation undergoes a profound remodeling during aging, which includes global hypomethylation of the genome, hypermethylation at specific loci and an increase in inter-individual variation and in stochastic changes of DNA methylation values. These epigenetic modifications can be an important contributor to the development of age-related diseases, but our understanding on the complex relationship between the epigenetic signatures of aging and age-related disease is still poor. The most relevant results in this field come from the use of the so called "epigenetics clocks" in cohorts of subjects affected by age-related diseases. We report these studies in final section of this review.
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http://dx.doi.org/10.1007/s10522-017-9695-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514215PMC
August 2017

Assessing the combined effect of extremely low-frequency magnetic field exposure and oxidative stress on LINE-1 promoter methylation in human neural cells.

Radiat Environ Biophys 2017 05 3;56(2):193-200. Epub 2017 Mar 3.

Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, via Selmi 3, 40126, Bologna, Italy.

Extremely low frequency magnetic fields (ELF-MF) have been classified as "possibly carcinogenic", but their genotoxic effects are still unclear. Recent findings indicate that epigenetic mechanisms contribute to the genome dysfunction and it is well known that they are affected by environmental factors. To our knowledge, to date the question of whether exposure to ELF-MF can influence epigenetic modifications has been poorly addressed. In this paper, we investigated whether exposure to ELF-MF alone and in combination with oxidative stress (OS) can affect DNA methylation, which is one of the most often studied epigenetic modification. To this end, we analyzed the DNA methylation levels of the 5'untranslated region (5'UTR) of long interspersed nuclear element-1s (LINE-1 or L1), which are commonly used to evaluate the global genome methylation level. Human neural cells (BE(2)C) were exposed for 24 and 48 h to extremely low frequency pulsed magnetic field (PMF; 50 Hz, 1 mT) in combination with OS. The methylation levels of CpGs located in L1 5'UTR region were measured by MassARRAY EpiTYPER. The results indicate that exposures to the single agents PMF and OS induced weak decreases and increases of DNA methylation levels at different CpGs. However, the combined exposure to PMF and OS lead to significant decrease of DNA methylation levels at different CpG sites. Most of the changes were transient, suggesting that cells can restore homeostatic DNA methylation patterns. The results are discussed and future research directions outlined.
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http://dx.doi.org/10.1007/s00411-017-0683-8DOI Listing
May 2017

Centenarians as extreme phenotypes: An ecological perspective to get insight into the relationship between the genetics of longevity and age-associated diseases.

Mech Ageing Dev 2017 07 27;165(Pt B):195-201. Epub 2017 Feb 27.

Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy; Interdepartmental Center "L. Galvani" (CIG), University of Bologna, Bologna, Italy.

In this review, we address the genetic continuum between aging and age-related diseases, with particular attention to the ecological perspective. We describe the connections between genes that promote longevity and genes associated with age-related diseases considering tradeoff mechanisms in which the same genetic variants could have different effects according to the tissue considered and could be involved in several biological pathways. Then we describe mechanisms of antagonistic pleiotropy, focusing on the complex interplay between genetic variants and environmental changes (internal or external). We sustain the use of centenarians as "super-controls" for the study of the major age-related diseases, starting from the concept that the maximization of the phenotypic differences in the considered cohort, achieved by selecting the most divergent phenotypes, could be useful for increasing the significant differences observed in the genetic association study. We describe the potential impact of the population genetic variability in the study of human longevity and the possible contribution of the past selective pressures in shaping the current genomic background of individuals. In conclusion, we illustrate recent findings emerged from whole-genome sequencing of long-lived individuals and future perspectives for interpreting the huge amount of genetic data that will be generated in the next future.
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http://dx.doi.org/10.1016/j.mad.2017.02.007DOI Listing
July 2017