Occupation, Literacy, Anthropometric Traits, and Life Expectancy of Italian Men Born 1900-1910: Evidence From Military Conscription Registers.

OBJECTIVE: The aim is to explore the role of anthropometric traits and sociodemographic characteristics on human survival. METHODS: Anthropometrics and sociodemographic data of 1944 conscripts born in the first decade of the 20th century in rural municipalities of Calabria (Southern Italy) who underwent medical examinations for military service were collected. Medical examinations were linked to individual survival data. RESULTS: Height and type of occupation influenced life expectancy. For taller men, the risk of mortality increases by about 20% when compared with men with middle height, while farmers exhibited a significant survival advantage compared to those with other working experiences. DISCUSSION: Height and type of occupation were associated with human mortality. These results are likely to be related to the effect of healthy dietary patterns and physical activity on life expectancy. Further studies are needed to understand to what extent these results obtained in a rural context can be generalized to other contexts.

Thymic function and survival at advance ages in nursing home residents from Southern Italy.

BACKGROUND: Immunosenescence is a complex process characterized by an age-related remodelling of immune system. The prominent effects of the immunosenescence process is the thymic involution and, consequently, the decreased numbers and functions of T cells. Since thymic involution results in a collapse of the T-cell receptor (TCR) repertoire, a reliable biomarker of its activity is represented by the quantification of signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels. Although it is reasonable to think that thymic function could play a crucial role on elderly survival, only a few studies investigated the relationship between an accurate measurement of human thymic function and survival at old ages. METHODS AND FINDINGS: By quantifying the amount sjTRECs by real-time polymerase chain reaction (PCR), the decrease in thymic output in 241 nursing home residents from Calabria (Southern Italy) was evaluated to investigate the relationship between thymic function and survival at old ages. We found that low sjTREC levels were associated with a significant increased risk of mortality at older ages. Nursing home residents with lower sjTREC exhibit a near 2-fold increase in mortality risk compared to those with sjTREC levels in a normal range. CONCLUSION: Thymic function failure is an independent predictor of mortality among elderly nursing home residents. sjTREC represents a biomarker of effective ageing as its blood levels could anticipate individuals at high risk of negative health outcomes. The identification of these subjects is crucial to manage older people's immune function and resilience, such as, for instance, to plan more efficient vaccinal campaigns in older populations.

An ELOVL2-Based Epigenetic Clock for Forensic Age Prediction: A Systematic Review.

The prediction of chronological age from methylation-based biomarkers represents one of the most promising applications in the field of forensic sciences. Age-prediction models developed so far are not easily applicable for forensic caseworkers. Among the several attempts to pursue this objective, the formulation of single-locus models might represent a good strategy. The present work aimed to develop an accurate single-locus model for age prediction exploiting ELOVL2, a gene for which epigenetic alterations are most highly correlated with age. We carried out a systematic review of different published pyrosequencing datasets in which methylation of the ELOVL2 promoter was analysed to formulate age prediction models. Nine of these, with available datasets involving 2298 participants, were selected. We found that irrespective of which model was adopted, a very strong relationship between ELOVL2 methylation levels and age exists. In particular, the model giving the best age-prediction accuracy was the gradient boosting regressor with a prediction error of about 5.5 years. The findings reported here strongly support the use of ELOVL2 for the formulation of a single-locus epigenetic model, but the inclusion of additional, non-redundant markers is a fundamental requirement to apply a molecular model to forensic applications with more robust results.

A new approach to broaden the range of eye colour identifiable by IrisPlex in DNA phenotyping.

IrisPlex system represents the most popular model for eye colour prediction. Based on six polymorphisms this model provides very accurate predictions that strongly depend on the definition of eye colour phenotypes. The aim of the present study was to introduce a new approach to improve eye colour prediction using the well-validated IrisPlex system. A sample of 238 individuals from a Southern Italian population was collected and for each of them a high-resolution image of eye was obtained. By quantifying eye colour variation into CIELAB space several clustering algorithms were applied for eye colour classification. Predictions with the IrisPlex model were obtained using eye colour categories defined by both visual inspection and clustering algorithms. IrisPlex system predicted blue and brown eye colour with high accuracy while it was inefficient in the prediction of intermediate eye colour. Clustering-based eye colour resulted in a significantly increased accuracy of the model especially for brown eyes. Our results confirm the validity of the IrisPlex system for forensic purposes. Although the quantitative approach here proposed for eye colour definition slightly improves its prediction accuracy, further research is still required to improve the model particularly for the intermediate eye colour prediction.

Clinical and Prognostic Implications of Estimating Glomerular Filtration Rate by Three Different Creatinine-Based Equations in Older Nursing Home Residents.

Background: According to the international literature, the percentage of nursing home (NH) residents with renal insufficiency is very high, ranging between 22 and 78%. Diminished kidney function represents a risk factor for drug overdosage, adverse drug reactions, end-stage renal disease, disability, morbidity, and mortality. Several studies suggested that screening for chronic kidney disease (CKD) in high-risk and older populations may represent a cost-effective approach to reducing progression to renal failure and CKD mortality. Objective: This study aimed (i) to investigate to what extent CKD may be staged interchangeably by three different creatinine-based estimated glomerular filtration rate (eGFR) equations in a sample of older adults living in long-term care facilities; (ii) to investigate factors explaining differences among eGFR equations; and (iii) to compare the predictivity of different creatinine-based eGFR equations with respect to all-cause mortality. Methods: A total of 522 residents aged 65 years and older participated in a prospective cohort study of 9 long-term care facilities in Calabria. eGFR was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Berlin initiative study (BIS), and full age spectrum (FAS) equations. Disability in at least one activity of daily living (ADL), depression, cognitive impairment, comorbidity, and malnutrition was considered in the analysis. Statistical analysis was carried out by Bland-Altman analysis, and 2-year mortality was investigated by Kaplan-Meier curves and Cox regression analysis. Results: Depending on the adopted equation, the prevalence of NH residents with impaired renal function (eGFR < 60 ml/min/1.73 m2) ranged between 58.2% for the CKD-EPI and 79.1% for the BIS1 equation. The average difference between BIS and FAS was nearly negligible (0.45 ml/min/1.73 m2), while a significant bias was detected between CKD-EPI and BIS and also between CKD-EPI and FAS (6.21 ml/min/1.73 m2 and 6.65 ml/min/1.73 m2, respectively). Although the eGFR study equations had comparable prognostic accuracy in terms of mortality risk, BIS and FAS were able to reclassify NH residents pertaining to a low-risk group with CKD-EPI, and this reclassification improves the discriminative capacity of CKD-EPI with respect to overall mortality. Conclusion: Despite the relatively good correlation between eGFRs calculated using all adopted equations, the findings in this study reported clearly demonstrated that CKD-EPI and BIS/FAS equations are not interchangeable to assess eGFR among older people and particularly in institutionalized and frail older subjects.

A Blood-Based Molecular Clock for Biological Age Estimation.

In the last decade, extensive efforts have been made to identify biomarkers of biological age. DNA methylation levels of ELOVL fatty acid elongase 2 (ELOVL2) and the signal joint T-cell receptor rearrangement excision circles (sjTRECs) represent the most promising candidates. Although these two non-redundant biomarkers echo important biological aspects of the ageing process in humans, a well-validated molecular clock exploiting these powerful candidates has not yet been formulated. The present study aimed to develop a more accurate molecular clock in a sample of 194 Italian individuals by re-analyzing the previously obtained EVOLV2 methylation data together with the amount of sjTRECs in the same blood samples. The proposed model showed a high prediction accuracy both in younger individuals with an error of about 2.5 years and in older subjects where a relatively low error was observed if compared with those reported in previously published studies. In conclusion, an easy, cost-effective and reliable model to measure the individual rate and the quality of aging in human population has been proposed. Further studies are required to validate the model and to extend its use in an applicative context.

A New Robust Epigenetic Model for Forensic Age Prediction.

Forensic DNA phenotyping refers to an emerging field of forensic sciences aimed at the prediction of externally visible characteristics of unknown sample donors directly from biological materials. The aging process significantly affects most of the above characteristics making the development of a reliable method of age prediction very important. Today, the so-called "epigenetic clocks" represent the most accurate models for age prediction. Since they are technically not achievable in a typical forensic laboratory, forensic DNA technology has triggered efforts toward the simplification of these models. The present study aimed to build an epigenetic clock using a set of methylation markers of five different genes in a sample of the Italian population of different ages covering the whole span of adult life. In a sample of 330 subjects, 42 selected markers were analyzed with a machine learning approach for building a prediction model for age prediction. A ridge linear regression model including eight of the proposed markers was identified as the best performing model across a plethora of candidates. This model was tested on an independent sample of 83 subjects providing a median error of 4.5 years. In the present study, an epigenetic model for age prediction was validated in a sample of the Italian population. However, its applicability to advanced ages still represents the main limitation in forensic caseworks.

Inter-Individual Variability in Xenobiotic-Metabolizing Enzymes: Implications for Human Aging and Longevity.

Xenobiotic-metabolizing enzymes (XME) mediate the body's response to potentially harmful compounds of exogenous/endogenous origin to which individuals are exposed during their lifetime. Aging adversely affects such responses, making the elderly more susceptible to toxics. Of note, XME genetic variability was found to impact the ability to cope with xenobiotics and, consequently, disease predisposition. We hypothesized that the variability of these genes influencing the interaction with the exposome could affect the individual chance of becoming long-lived. We tested this hypothesis by screening a cohort of 1112 individuals aged 20-108 years for 35 variants in 23 XME genes. Four variants in different genes (CYP2B6/rs3745274-G/T, CYP3A5/rs776746-G/A, COMT/rs4680-G/A and ABCC2/rs2273697-G/A) differently impacted the longevity phenotype. In particular, the highest impact was observed in the age group 65-89 years, known to have the highest incidence of age-related diseases. In fact, genetic variability of these genes we found to account for 7.7% of the chance to survive beyond the age of 89 years. Results presented herein confirm that XME genes, by mediating the dynamic and the complex gene-environment interactions, can affect the possibility to reach advanced ages, pointing to them as novel genes for future studies on genetic determinants for age-related traits.

Cardiovascular risk profiling of long-lived people shows peculiar associations with mortality compared with younger individuals.

AIM: Centenarians represent a biological model of successful aging because they escaped/postponed most invalidating age-related diseases, such as cardiovascular diseases. The aim of the present study was to clarify whether a favorable cardiovascular risk profile increases the survival chances in long-lived people. METHODS: A total of 355 community-dwelling nonagenarians and centenarians living in Southern Italy were recruited in the study. Patients were classified as at low and high cardiovascular risk on the basis of serum cholesterol, diabetes, hypertension and smoking status. The relationship between cardiovascular risk factors and 10-year mortality was investigated by Cox regression analysis. Splines-based hazard ratio curves were also estimated for total cholesterol, low-density lipoprotein cholesterol, and systolic and diastolic blood pressure. RESULTS: Low levels of selected cardiovascular risk factors usually associated with lower mortality in adults do not increase survival chances among oldest-old individuals. In particular, after adjusting for age, sex, and cognitive, functional and nutritional status, serum cholesterol >200 mg/dL increased the survival chances during the follow-up period (hazard ratio 0.742, 95% CI 0.572-0.963). CONCLUSIONS: The present results showed that in nonagenarians and centenarians, the clinical and prognostic meaning associated with traditional cardiovascular risk factors is very different from younger populations. Consequently, considering the increase of this population segment, further studies are required to confirm these results and to translate them into clinical practice/primary care. Geriatr Gerontol Int 2019; 19: 165-170.

Uncoupling protein 4 (UCP4) gene variability in neurodegenerative disorders: further evidence of association in Frontotemporal dementia.

Ongoing research suggests that mitochondrial dysfunction is a common hallmark in neurodegenerative diseases, pointing to mitochondrial uncoupling process as a critical player. We recently reported that rs9472817-C/G, an intronic variant of neuronal mitochondrial uncoupling protein-4 (UCP4/SLC25A27) gene affects the risk of late onset Alzheimer's disease (LOAD), and that the variant's effect is strongly dependent on APOE-ε4 status. Here, we extended our analysis to a cohort of 751 subjects including late-onset familial and sporadic cases of frontotemporal dementia (FTD; 213), Parkinson disease (PD;96), and 442 healthy controls. In all subgroups, carriers of APOE-ε4 allele were at higher risk of disease. Regarding the rs9472817, no association was detected in familial FTD and both subgroups of PD patients. In sporadic FTD, as in LOAD, we found that the C allele increased the risk of disease of about 1.51-fold in a dose-dependent manner (p=0.013) independently from that conferred by APOE-ε4. Expression quantitative trait loci (eQTL) data of different brain regions suggest that rs9472817 likely exerts its effect by a cis-regulatory mechanism involving modulation of UCP4. If validated, the involvement of UCP4 in both FTD and LOAD might indicate interesting shared etiological factors which might give future therapeutic clues.

The Impact of the Emerging Genomics Data on the Management of Agerelated Phenotypes in the Context of Cellular Senescence.

Before the last decade, attempts to identify the genetic factors involved in the susceptibility to age-related complex diseases such as cardiovascular disease, diabetes and cancer had very limited success. Recently, two important advancements have provided new opportunities to improve our knowledge in this field. Firstly, it has emerged the concept of studying the molecular mechanisms underlying the age related decline of the organism (such as cellular senescence), rather than the genetics of single disorders. In addition, advances in DNA technology have uncovered an incredible number of common susceptibility variants for several complex traits. Despite these progresses, the translation of these discoveries into clinical practice has been very difficult. To date, several attempts in translating genomics to medicine are being carried out to look for the best way by which genomic discoveries may improve our understanding of fundamental issues in the prediction and prevention of some complex diseases. The successful strategy seems to be testing simultaneously multiple susceptibility variants in combination with traditional risk factors. In fact, such approach showed that genetic factors substantially improve the prediction of complex diseases especially for coronary heart disease and prostate cancer, making possible appropriate behavioural and medical interventions. In the future, the identification of new genetic variants and their inclusion into current risk profile models will probably improve the discrimination power of these models for other complex diseases such as type 2 diabetes mellitus and breast cancer. On the other hand, for traits with low heritability, this improvement will probably be negligible, and this will urge further researches on the role played by traditional and newly discovered non-genetic risk factors.

Epidemiology and genetics of frontotemporal dementia: a door-to-door survey in southern Italy.

The objectives of this study were to estimate frontotemporal dementia (FTD) prevalence, identify FTD-related mutations, and correlate FTD phenotype with mutations in a southern Italian population. The study population consisted of subjects ≥ 50 years of age residing in the Community of Biv. on January 1, 2004, and a door-to-door 2-phase design was used. Genetic and biochemical analyses were done on samples collected from 32 patients. Prevalence rates were 0.6 for Alzheimer's disease, 0.4 for vascular dementia (VD), 3.5 for FTD, 0.2 for Parkinson dementia, and 1.2 for unspecified dementia. Three GRN (1 known and 2 novel) mutations with reduced plasma protein levels were found associated to 3 distinct phenotypes (behavioral, affective, and delirious type). We report an unusually high FTD prevalence in the investigated population, but a low prevalence of Alzheimer's disease. We confirm the heterogeneity of FTD phenotype associated with different GRN mutations.

Clinical manifestations of highly prevalent corticosteroid-binding globulin mutations in a village in southern Italy.

CONTEXT: Corticosteroid-binding globulin (CBG) is the binding protein for cortisol. Rare kindreds with CBG mutations reducing CBG levels or altering binding affinity have been described, along with clinical manifestations encompassing fatigue, chronic pain, and hypotension. The largest kindred, exhibiting two mutations (null and Lyon) were Australian immigrants from Italy. OBJECTIVE: Our objective was to determine the prevalence of the null/Lyon mutations in the village where the original null/Lyon family emigrated and compare subjects with and without CBG mutations, without previous knowledge of their mutation status. DESIGN, SETTING, AND PARTICIPANTS: We conducted a survey field study that included 495 adult residents. MAIN OUTCOMES: We assessed clinical history, CBG mutation analysis, plasma CBG, salivary cortisol, body mass index, waist circumference, blood pressure, and the Krupp fatigue scale. RESULTS: Eighteen of 495 participants (3.6%, seven males and 11 females) had one of two function-altering CBG mutations. All were heterozygous for the null (n = 6) or Lyon mutations (n = 12). Of 12 Lyon participants (four males and eight females), eight (two males and six females) had chronic widespread pain and five osteoarthritis with associated pain (one male and four females). Of six null participants (three males and three females), three (one male and two females) had chronic pain and four osteoarthritis with associated pain (two males and two females). CONCLUSIONS: A high combined prevalence (3.6%) of these two CBG mutations was detected. The presence of either mutation conferred a propensity to chronic pain. In other communities, individuals with the same genetic background complain more of fatigue than pain, suggesting an environmental effect on the phenotype. These findings, combined with animal CBG gene knockout and human CBG single-nucleotide polymorphism haplotype studies, suggest that CBG influences the endocrine and neurobehavioral response to stress, including the development of pain/fatigue syndromes.

A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features.

We report a novel presenilin1 (PSEN1) gene mutation (I143 V) in a four-generation family with Alzheimer's disease. Clinical, molecular, and neuropathological examinations were performed on index patient; thirteen affected subjects were also identified. The index patient presented at 55 with personality changes, apathy, reduction of verbal fluency, and temporal and spatial disorientation. At 68, she showed visual hallucinations; blurred language, and rigidity. She became bedridden and died at 75. A novel mutation at codon 143 was found in PSEN1 gene, changing isoleucine to valine. The brain showed severe atrophy of the frontal and temporal lobes. Parenchymal amyloid-ß (Aß) deposits were abundant, diffuse to grey structures and contained Aß42, but very few Aß40. Amyloid angiopathy was absent. Neurofibrillary changes were severe. Our study confirms that PSEN1 mutations can be associated with unusual phenotypes. The peculiarity of the age at onset (not very early), the long course, and the frontal involvement, together with the rather complete absence of Aß40 and of amyloid angiopathy, widen the spectrum of PSEN1-linked phenotypes.

PSEN1 and PRNP gene mutations: co-occurrence makes onset very early in a family with FTD phenotype.

Prion protein (PRNP) gene mutations have recently been associated with clinical pictures resembling Frontotemporal dementia (FTD). We describe a novel seven extra-repeat insertional mutation in the PRNP gene in a family affected by early-onset autosomal dominant FTD previously reported as caused by a PSEN1 mutation in which there was inconsistency between clinical picture and genotype. Both mutations were pathogenic and showed a variable penetrance when present separately; when occurring together, the onset was very early, within the third decade of life. Genetic screening of the PRNP gene becomes of major importance in early onset autosomal dominant dementia.

Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia.

Intronic MAPT mutations altering exon 10 splicing lead mainly to an increase of 4Rtau. The objective of this study is to report clinical, genetic, and neuropathological data of an apparently sporadic early onset frontotemporal dementia (FTD) case associated with 2 novel intronic MAPT gene mutations IVS10+4A > C and IVS9-15T > C that increase 3Rtau. Methods and subjects used are clinical, neuroradiological, and neuropathological examination; molecular genetics of MAPT, PGRN, and other relevant genes. Exon 10 splicing tested with minigene constructs. Tau deposits detected by immunohistochemistry. Sarkosyl-insoluble and soluble tau investigated by immunoblotting. Two novel MAPT mutations IVS10+4A > C and the IVS9-15T > C transmitted by the unaffected parents were identified. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analyses on minigenes and in brain tissue showed that both mutations cause an increase of tau mRNA (messenger ribonucleic acid) transcripts lacking exon 10 only in the patient. Immunohistochemistry and immunoblotting of the patient's brain revealed tau deposits composed mostly of 3Rtau isoforms with a predominance of the shorter 3Rtau isoforms. The compound heterozygosity of the patient increasing 3Rtau seems to be responsible for the disease and furthermore suggests that sporadic cases can be caused by genetic mutations.

MAPT V363I variation in a sporadic case of frontotemporal dementia: variable penetrant mutation or rare polymorphism?

The V363I mutation of the microtubule-associated protein tau gene has previously been associated with a case of primary progressive nonfluent aphasia with variable penetrance. Herein, we report the finding of the V363I variation in a sporadic early onset frontotemporal dementia patient and in several members of her family. The V363I variation was associated with frontotemporal dementia only in the proband which was also homozygous for the A allele of the progranulin single-nucleotide polymorphism rs9897526 and for methionine at codon 129 of the prion protein gene. The microtubule-associated protein tau V363I variation could be considered either an incomplete penetrant mutation or a rare polymorphism; although its pathogenicity has yet to be clearly demonstrated, modifier genetic factors seem to contribute to the pathogenic effects observed in the patient underlining the great complexity existing in neurodegenerative diseases and questioning so-called sporadic cases that can potentially be caused by gene mutation.

Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia.

A clinical and molecular overlap between Alzheimer's disease (AD) and frontotemporal dementia (FTD) has been reported. Presenilins have been associated with FTD or with FTD-like phenotype, while mutations in the MAPT gene have been linked to a clinical phenotype of AD. We performed a clinical and genetic examination in two FTD siblings and their family tree has been reconstructed. We identified a novel Val75Ala MAPT mutation in one patient and in the other the Arg62His Presenilin2 mutation. The DNA variations identified, defined mutations by frequency, per se are not causative of the disease. These mutations, possibly in association with other unknown environmental and genetic factors, may contribute to neurodegeneration. In this family, the disease might result from a genetically interconnected spectrum of altered pathways that could link most neurodegenerative disorders. Moreover, the novel mutation identified merits further functional studies that would contribute to the unravelling of such a complex field.

AbetaPP A713T mutation in late onset Alzheimer's disease with cerebrovascular lesions.

Mutations in the amyloid-beta protein precursor (AbetaPP) gene can cause autosomal dominant early-onset Alzheimer's disease, or Alzheimer's disease (AD) associated with cerebral amyloid angiopathy (CAA), cerebral hemorrhage, or both. We have previously reported that the AbetaPP A713T mutation is associated with AD and subcortical ischemic lesions at magnetic resonance imaging in a large family which neuropathology confirmed CAA, stroke, and AD lesions. The objective of this clinical and molecular study was to investigate AbetaPP gene mutations in 59 patients affected by AD with cerebrovascular lesions (CVLs) and a family history of dementia. We identified three affected subjects with the AbetaPP A713T mutation. Since the prevalence of this mutation worldwide is very low, a common founder could exist in southern Italy. The pathogenicity of this mutation was confirmed and the clinical AD phenotype with CVLs seems to be a distinctive feature in the southern Italian population. The identification of these patients suggests that genetic epidemiology in large cohorts of familial late onset AD with CVLs would increase the probability of identifying AbetaPP mutations.

Novel PSEN1 and PGRN mutations in early-onset familial frontotemporal dementia.

BACKGROUND: Frontotemporal dementia is a clinically and genetically heterogeneous syndrome. Mutations in two genes, Microtubule Associated Protein Tau (MAPT) and Progranulin (PGRN), and rarely Presenilin mutations, have been causally linked to this disorder. OBJECTIVE: To investigate the presence of PGRN, PSEN1, PSEN2 and APP mutations in a group of familial early-onset frontotemporal dementia (f-EOFTD) patients negative for MAPT gene mutations. SUBJECTS AND METHODS: We prospectively studied 17 unrelated subjects diagnosed with f-EOFTD (one case neuropathologically confirmed as FTD-Ub+). Among these subjects eight belonged to eight autosomal dominant families unrelated to each other, and nine had at least one first degree relative affected by dementia. RESULTS: We identified two novel heterozygous mutations in two unrelated patients, Cys139Arg in the PGRN gene and Val412Ile in the PSEN1 gene. CONCLUSIONS: Early-onset f-FTD remains a heterogeneous disorder from a genetic point of view. PGRN mutation frequency was low in our sample. The presence of a novel PSEN1 mutation suggests that presenilin molecular studies should be performed when screening for MAPT and PGRN genes is negative.