Giovannella Baggio

Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans

Mitochondrial DNA (mtDNA) is characterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated polymorphisms whose combination defines groups of mtDNA types (haplogroups) that are currently used to reconstruct human evolution lineages. We used such inherited mtDNA markers to compare mtDNA population pools between a sample of individuals selected for successful aging and longevity (212 subjects older than 100 years and in good clinical condition) and a sample of 275 younger individuals (median age 38 years) carefully matched as to sex and geographic origin (northern and southern Italy). All nine haplogroups that are typical of Europeans were found in both samples, but male centenarians emerged in northern Italy as a particular sample: 1) mtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests); and 2) the frequency of the J haplogroup was notably higher in centenarians than in younger individuals (P=0.0052 by Fisher exact test). Since haplogroups are defined on the basis of inherited variants, these data show that mtDNA inherited variability could play a role in successful aging and longevity.—De Benedictis, G., Rose, G., Carrieri, G., De Luca, M., Falcone, E., Passarino, G., Bonafé, M., Monti, D., Baggio, G., Bertolini, S., Mari, D., Mattace, R., Franceschi, C. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J. 13, 1532–1536 (1999)

Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: Principal results of PHYLLIS - A randomized double-blind trial

Background and Purpose— The Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) tested whether (1) the angiotensin-converting enzyme (ACE) inhibitor fosinopril (20 mg per day) was more effective on carotid atherosclerosis progression than the diuretic hydrochlorothiazide (25 mg per day), (2) pravastatin (40 mg per day) was more effective than placebo when added to either hydrochlorothiazide or fosinopril, and (3) there were additive effects of ACE inhibitor and lipid-lowering therapies. Methods— A total of 508 hypertensive, hypercholesterolemic patients with asymptomatic carotid atherosclerosis were randomized to: (A) hydrochlorothiazide; (B) fosinopril; (C) hydrochlorothiazide plus pravastatin; and (D) fosinopril plus pravastatin, and followed up blindly for 2.6 years. B-Mode carotid scans were performed yearly by certified sonographers in 13 hospitals and read centrally. Corrections for drift were calculated from readings repeated at study end. Primary outcome was change in mean maximum intima-media thickness of far and near walls of common carotids and bifurcations bilaterally (CBMmax). Results— CBMmax significantly progressed (0.010±0.004 mm per year; P=0.01) in group A (hydrochlorothiazide alone) but not in groups B, C, and D. CBMmax changes in groups B, C, and D were significantly different from changes in group A. Changes in group A were concentrated at the bifurcations. “Clinic” and “ambulatory” blood pressure reductions were not significantly different between groups, but total and low-density lipoprotein cholesterol decreased by ≈1 mmol/L in groups C and D. Conclusions— Progression of carotid atherosclerosis occurred with hydrochlorothiazide but not with fosinopril. Progression could also be avoided by associating pravastatin with hydrochlorothiazide.

Systolic and pulse blood pressures (but not diastolic blood pressure and serum cholesterol) are associated with alterations in carotid intima-media thickness in the moderately hypercholesterolaemic hypertensive patients of the Plaque Hypertension Lipid Lowering Italian Study

Objective The Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS), is the first study in patients with hypertension (diastolic blood pressure (DBP) 95–115 mmHg; systolic blood pressure (SBP) 150–210 mmHg), moderate hypercholesterolaemia (LDL-cholesterol 4.14–5.17 mmol/l (160–200 mg/dl) and initial carotid artery alterations (maximum intima–media thickness (IMT) Tmax ⩾ 1.3 mm). The primary objective of PHYLLIS is investigating whether in these patients administration of an angiotensin converting enzyme inhibitor, fosinopril, and a statin, pravastatin, is more effective than administration of a diuretic and a lipid-lowering diet in retarding or regressing alterations in carotid IMT. While the study is in progress, baseline data are here reported to clarify the association of various risk factors with carotid IMT in these medium–high risk hypertensive patients. Methods Patients numbering 508 have been randomized to PHYLLIS by 13 peripheral units, in Italy. Age was (mean ± SD) 58.4 ± 6.7 years, males were 40.2%, current smokers 16.5%, means ± SD of serum total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglycerides concentrations were 6.79 ± 0.67, 4.69 ± 0.51, 1.37 ± 0.38, 1.59 ± 0.64 mmol/l (262.4 ± 25.8, 181.3 ± 19.8, 53.0 ± 14.6, 141.0 ± 56.7 mg/dl). Means ± SD of clinic sitting SBP/DBP were 159.8 ± 9.0/98.3 ± 4.2 mmHg. 483 of the 508 patients also had 24 h ambulatory BP monitoring, edited and read at a centralized unit (mean ± SD 24 h SBP/DBP averages 136.3 ± 14.1/84.0 ± 10.0 mmHg). Quantitative B-mode ultrasound (Biosound 2000 II 5A, Biosound, Indianapolis, Indiana, USA) recordings of carotid arteries were taken by certified sonographers in the peripheral units and tracings were all read at a central unit. CBMmax (mean IMT of eight sites at common carotids and bifurcations) was 1.21 ± 0.17; Mmax (mean of 12 sites also including internal carotids) 1.16 ± 0.17, and Tmax (single maximum) 1.85 ± 0.48 mm. Results Ambulatory SBP and pulse pressure (PP) (24 h, daytime, night-time averages) and their variability indices (24 h SD) were always significantly correlated with CBMmax and Mmax (P 0.01–0.001), and the correlations remained significant after adjustment for age, gender and smoking. No measurement of DBP was ever associated with any IMT measurement. Likewise, no lipid variable was found associated with any IMT measurement. Conclusions Baseline data from PHYLLIS indicate that in this population of hypertensive patients with moderate hypercholesterolaemia, SBP and PP are with age among the most significant factors associated with carotid artery alterations. However, the narrow range of inclusion LDL-cholesterol and DBP values may have obscured an additional role of these variables.

Gene/longevity association studies at four autosomal loci ( REN, THO, PARP, SOD2 )

The possibility that four loci (REN, THO, PARP, SOD2) are associated with longevity was explored by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). The markers (all located within the respective gene) were HUMREN4; HUMTHO1; HUMPARP (gt)845nt; SOD2(C/T)401nt. In order to reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns (small: S, and large: L, alleles). A significant loss of LL homozygous genotypes was found at the THO locus in male but not in female centenarians with respect to matched controls. On the other hand no significant difference was found between case/control genotypic frequencies at REN, PARP, SOD2 loci. The latter loci therefore do not affect inter-individual variability in life expectancy (at least in terms of qualitative variants associated with the tested markers). However, the data is consistent with an association between the THO locus and longevity.

Do men and women follow different trajectories to reach extreme longevity

Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.

Tooth loss in the elderly and its association with nutritional status, socio-economic and lifestyle factors

Objective. Tooth loss impacts on general health and is a risk factor for malnutrition, disability, loss of self-sufficiency, and deterioration in quality of life. The present study was carried out to evaluate the prevalence of edentulism and its association with social and lifestyle factors in a population of elderly Italians. Material and Methods. Dental, social, and disease conditions were evaluated in a large community-based cohort (3054) of elderly subjects (≥65 years) of both sexes in northern Italy. Logistic regression analyses with stepwise forward selection were performed to estimate the independent contribution of nutritional, socio-economic, and lifestyle variables to dental status. Adjusted ORs and 95% CI were estimated for variables significantly associated with edentulism. Results. The prevalence of edentulism was about 44.0%. It was more pronounced in females and it was twice as prevalent in the 90+ years age group. Among edentulous subjects, 17.5% wore no prostheses. Difficulties in chewing and in swallowing were reported by 47.6% and 13.7% of the subjects, respectively. Multivariate analysis indicates that edentulism was associated with age in both sexes. For women, independently associated risk factors were: years since menopause >23 (OR = 1.81; 95% CI: 1.37–2.40), number of children >3 (OR = 1.95; 95% CI: 1.36–2.80), and living alone (OR = 1.47; 95% CI: 1.15–1.88). For men, these were serum albumin <40 g/l (OR = 1.79; 95% CI: 1.22–2.63), current smoking (OR = 4.01; 95% CI: 2.59–6.20), and former smoking (OR = 3.42; 95% CI: 2.42–4.82). Conclusions. The prevalence of edentulism among the elderly Italian population studied was at the high end among Western countries, and higher in women than in men. In women, tooth loss correlated with aging, female events (pregnancies, menopausal status), and living alone. In men, aging and smoking are important determinants of edentulism, which is associated with the risk condition of hypoalbuminemia. Difficulty in chewing was associated with dentition type. In our study, the high prevalence of edentulous subjects without prostheses suggests a need for educational and social measures to improve patients’ attitudes to dental care and to encourage the use of prostheses among the elderly.

Pre-frailty and risk of cardiovascular disease in elderly men and women: the Pro.V.A. study.

BACKGROUND Frailty is an important risk factor for cardiovascular disease (CVD), but the impact of early, potentially reversible stages of frailty on CVD risk is unknown. OBJECTIVES This study sought to ascertain whether pre-frailty can predict the onset of CVD in a cohort of community-dwelling, not disabled, elderly people. METHODS A sample of 1,567 participants age 65 to 96 years without frailty or disability at baseline was followed for 4.4 years. Pre-frailty was defined as the presence of 1 or 2 modified Fried criteria (unintentional weight loss, low physical activity level, weakness, exhaustion, and slow gait speed), and incident CVD as onset of coronary artery diseases, heart failure, stroke, peripheral artery disease, or CVD-related mortality. RESULTS During follow-up, 551 participants developed CVD. Compared with participants who did not become frail, those with 1 modified Fried criterion (p = 0.03) and those with 2 criteria (p = 0.001) had a significantly higher risk of CVD, even after adjusting for several potential confounders (traditional risk factors for CVD, inflammatory markers, and hemoglobin A1c levels). Low energy expenditure (p = 0.03), exhaustion (p = 0.01), and slow gait speed (p = 0.03) were significantly associated with the onset of CVD, whereas unintentional weight loss and weakness were not. CONCLUSIONS Our findings suggest that pre-frailty, which is potentially reversible, is independently associated with a higher risk of older adults developing CVD. Among the physical domains of pre-frailty, low gait speed seems to be the best predictor of future CVD.

Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians

The susceptibility to undergo apoptosis of fresh human peripheral blood mononuclear cells (PBMCs) from three groups of healthy donors of different ages: young people (19-40 years), old people (65-85 years) and centenarians was assessed. Apoptosis was induced by 2-deoxy-D-ribose (dRib), an agent which induces apoptosis in quiescent PBMCs by interfering with cell redox status and mitochondrial membrane potential (MMP). Our major finding is that an inverse correlation emerged between the age of the donors and the propensity of their PBMCs to undergo dRib-induced apoptosis. PBMCs from old people and centenarians also showed an increased resistance to dRib-induced glutathione depletion and a decreased tendency to lose MMP. The anti-apoptotic molecule Bcl-2 was similarly expressed in PBMCs from the three age groups. Moreover, the plasma level of the stable product of transglutaminase, epsilon(gamma-glutamyl)lysine isodipeptide, a marker of total body apoptotic rate, was decreased in centenarians compared to young and elderly people. On the whole, these findings suggest that physiological aging is characterised by a decreased tendency to undergo apoptosis, a phenomenon likely resulting from adaptation to lifelong exposure to damaging agents, such as reactive oxygen species, and may contribute to one of the major phenomena of immunosenescence, i.e. the progressive accumulation of memory/effector T cells.

DNA multiallelic systems reveal gene/longevity associations not detected by diallelic systems. The APOB locus

Abstract To identify possible genetic factors affecting human longevity we compared allele pools at two candidate loci for longevity between a sample of 143 centenarians (S) and a control sample of 158 individuals (C). The candidate loci were APOB and TPO, which code for apolipoprotein B and thyroid peroxidase, respectively. Both restriction fragment length (RFL) (XbaI2488 and EcoRI4154) and variable number of tandem repeat (VNTR) (3′APOB-VNTR) polymorphisms were analysed at the APOB locus; the TPO-VNTR polymorphism (intron 10) was analysed at the TPO locus. The main result of the investigation was that there is an association between the APOB locus and longevity that is revealed only when multiallelic polymorphisms are considered. In particular: (i) the frequency of 3′APOB-VNTR alleles with fewer than 35 repeats is significantly lower in cases than in controls; (ii) the linkage disequilibrium between the XbaI-RFLP and the EcoRI-RFLP is significantly different from 0 in cases but not in controls; (iii) the EcoRI-RFLP and XbaI-RFLP allele frequencies do not discriminate between cases and controls. The differences observed between case and control allele pools are specific to the APOB locus, since no significant difference was observed at the TPO locus.

The effect of cardiovascular and osteoarticular diseases on disability in older Italian men and women: Rationale, design, and sample characteristics of the Progetto Veneto Anziani (PRO.V.A.) study

OBJECTIVES: Describe the methodology and preliminary results of the Progetto Veneto Anziani (PRO.V.A.) Study, an observational study of the Italian population aged 65 and older