Roberto Antonicelli

A gender--dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity.

Current literature indicates that elevated IL‐6 serum levels are associated with diseases, disability and mortality in the elderly. In this paper, we studied the IL‐6 promoter genetic variability at –174 C/G locus and its effect on IL‐6 serum levels in a total of 700 people from 60 to 110 years of age, including 323 centenarians. We found that the proportion of homozygotes for the G allele at –174 locus decreases in centenarian males, but not in centenarian females. Moreover, we found that, only among males, homozygotes for the G allele at –174 locus have higher IL‐6 serum levels in comparison with carriers of the C allele. On the whole, our data suggest that those individuals who are genetically predisposed to produce high levels of IL‐6 during aging, i.e. –174 locus GG homozygous men, are disadvantaged for longevity.

Diagnostic potential of circulating miR-499-5p in elderly patients with acute non ST-elevation myocardial infarction

BACKGROUND Geriatric patients with acute non-ST elevation myocardial infarction (NSTEMI) can frequently present atypical symptoms and non-diagnostic electrocardiogram. The detection of modest cardiac troponin T (cTnT) elevation is challenging for physicians needing to routinely triage these patients. Unfortunately, non-coronary diseases, such as acute heart failure (CHF), may cause cTnT elevation. Circulating microRNAs (miRs) have emerged as biomarkers of MI. However, their diagnostic potential needs to be determined in elderly NSTEMI patients. METHODS 92 NSTEMI patients (82.6 ± 6.9 years old; complicated by CHF in 74% of cases) and 81 patients with acute CHF without AMI (81.3 ± 6.8 years old) were enrolled at presentation. A third group comprised 99 age-matched healthy control subjects (CTR). Plasma levels of miR-1, -21, -133a, -208a, -423-5p and -499-5p were analyzed. RESULTS MiR-1, -21 -133a and -423-5p showed a 3- to 10-fold increase and miR-499-5p exhibited >80-fold increase in acute NSTEMI patient vs. CTR. MiR-499-5p and -21 showed a significantly increased expression in NSTEMI vs. CHF. Interestingly, mir-499-5p was comparable to cTnT in discriminating NSTEMI vs. CTR and CHF patients. Its diagnostic accuracy was higher than conventional and hs-cTnT in differentiating NSTEMI (n=31) vs. acute CHF (n=32) patients with modest cTnT elevation at presentation (miR-499-5p AUC=0.86 vs. cTnT AUC=0.68 and vs. hs-cTnT AUC=0.70). CONCLUSIONS Circulating miR-499-5p is a sensitive biomarker of acute NSTEMI in the elderly, exhibiting a diagnostic accuracy superior to that of cTnT in patients with modest elevation at presentation.

Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging

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

Early Aggressive Versus Initially Conservative Treatment in Elderly Patients With Non–ST-Segment Elevation Acute Coronary Syndrome: A Randomized Controlled Trial

OBJECTIVES This study sought to determine the risk versus benefit ratio of an early aggressive (EA) approach in elderly patients with non-ST-segment elevation acute coronary syndromes (NSTEACS). BACKGROUND Elderly patients have been scarcely represented in trials comparing treatment strategies in NSTEACS. METHODS A total of 313 patients ≥ 75 years of age (mean 82 years) with NSTEACS within 48 h from qualifying symptoms were randomly allocated to an EA strategy (coronary angiography and, when indicated, revascularization within 72 h) or an initially conservative (IC) strategy (angiography and revascularization only for recurrent ischemia). The primary endpoint was the composite of death, myocardial infarction, disabling stroke, and repeat hospital stay for cardiovascular causes or severe bleeding within 1 year. RESULTS During admission, 88% of the patients in the EA group underwent angiography (55% revascularization), compared with 29% (23% revascularization) in the IC group. The primary outcome occurred in 43 patients (27.9%) in the EA group and 55 (34.6%) in the IC group (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.53 to 1.19; p = 0.26). The rates of mortality (HR: 0.87; 95% CI: 0.49 to 1.56), myocardial infarction (HR: 0.67; 95% CI: 0.33 to 1.36), and repeat hospital stay (HR: 0.81; 95% CI: 0.45 to 1.46) did not differ between groups. The primary endpoint was significantly reduced in patients with elevated troponin on admission (HR: 0.43; 95% CI: 0.23 to 0.80), but not in those with normal troponin (HR: 1.67; 95% CI: 0.75 to 3.70; p for interaction = 0.03). CONCLUSIONS The present study does not allow a definite conclusion about the benefit of an EA approach when applied systematically among elderly patients with NSTEACS. The finding of a significant interaction for the treatment effect according to troponin status at baseline should be confirmed in a larger size trial. (Italian Elderly ACS Study; NCT00510185).

MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling

In order to identify new markers of vascular cell senescence with potential in vivo implications, primary cultured endothelial cells, including human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), human coronary artery endothelial cells (HCAECs) and ex vivo circulating angiogenic cells (CACs), were analysed for microRNA (miR) expression. Among the 367 profiled miRs in HUVECs, miR-146a, miR-9, miR-204 and miR-367 showed the highest up-regulation in senescent cells. Their predicted target genes belong to nine common pathways, including Toll-like receptor signalling (TLR) that plays a pivotal role in inflammatory response, a key feature of senescence (inflammaging). MiR-146a was the most up-regulated miR in the validation analysis (>10-fold). Mimic and antagomir transfection confirmed TLR’s IL-1 receptor-associated kinase (IRAK1) protein modulation in both young and senescent cells. Significant correlations were observed among miR-146a expression and β-galactosidase expression, telomere length and telomerase activity. MiR-146a hyper-expression was also validated in senescent HAECs (>4-fold) and HCAECs (>30-fold). We recently showed that CACs from patients with chronic heart failure (CHF) presented a distinguishing feature of senescence. Therefore, we also included miR-146a expression determination in CACs from 37 CHF patients and 35 healthy control subjects (CTR) for this study. Interestingly, a 1,000-fold increased expression of miR-146a was observed in CACs of CHF patients compared to CTR, along with decreased expression of IRAK1 protein. Moreover, significant correlations among miR-146a expression, telomere length and telomerase activity were observed. Overall, our findings indicate that miR-146a is a marker of a senescence-associated pro-inflammatory status in vascular remodelling cells.

Impact of telemonitoring at home on the management of elderly patients with congestive heart failure

We studied the effects of home telemonitoring in elderly patients with congestive heart failure (CHF) on mortality and rate of hospitalization, compliance with treatment, quality of life and costs of CHF management, by comparison with a group receiving usual care. Fifty-seven elderly CHF patients were randomized to standard care or to home telemonitoring-based care and followed for 12 months. In the subjects who were monitored, weekly reports on their clinical status were obtained and their management was modified accordingly. Home telemonitoring was associated with improvements in the composite endpoint of mortality and rate of hospitalizations (P = 0.006), a better compliance with therapy, more frequent use of beta-blockers and statins, lower total cholesterol level and a better reported health perception score. The improved results with home telemonitoring in CHF were probably due to better compliance and to closer monitoring of the patients.

The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death

AbstractA common arginine to proline polymorphism is harboured at codon 72 of the human p53 gene. In this investigation, we found that fibroblasts and lymphocytes isolated from arginine allele homozygote centenarians and sexagenarians (Arg+) undergo an oxidative-stress-induced apoptosis at a higher extent than cells obtained from proline allele carriers (Pro+). At variance, the difference in apoptosis susceptibility between Arg+ and Pro+ is not significant when cells from 30-year-old people are studied. Further, we found that Arg+ and Pro+ cells from centenarians differ in the constitutive levels of p53 protein and p53/MDM2 complex, as well as in the levels of oxidative stress-induced p53/Bcl-xL complex and mitochondria-localised p53. Consistently, all these differences are less evident in cells from 30-year-old people. Finally, we investigated the in vivo functional relevance of the p53 codon 72 genotype in a group of old patients (66–99 years of age) affected by acute myocardial ischaemia, a clinical condition in which in vivo cell death occurs. We found that Arg+ patients show increased levels of Troponin I and CK-MB, two serum markers that correlate with the extent of the ischaemic damage in comparison to Pro+ patients. In conclusion, these data suggest that p53 codon 72 polymorphism contributes to a genetically determined variability in apoptotic susceptibility among old people, which has a potentially relevant role in the context of an age-related pathologic condition, such as myocardial ischaemia.

Genetic analysis of Paraoxonase (PON1) locus reveals an increased frequency of Arg192 allele in centenarians

Human Paraoxonase (PON1) is a High-Density Lipoprotein (HDL)-associated esterase that hydrolyses lipo-peroxides. PON1 has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two polymorphisms have been extensively studied: a Leucine (L allele) to Methionine (M allele) substitution at codon 55, and a Glutamine (A allele) to Arginine (B allele) substitution at codon 192. We have examined these two aminoacidic changes in 579 people aged 20 to 65 years old, and 308 centenarians. We found that the percentage of carriers of the B allele at codon 192 (B+ individuals) is higher in centenarians than in controls (0.539 vs 0.447), moreover we found that among the B+ individuals, the phenomenon was due to an increase of people carrying M alleles at codon 55 locus. In conclusion, we propose that genetic variability at PON1 locus affects survival at extreme advanced age.

Leukocyte telomere shortening in elderly Type2DM patients with previous myocardial infarction.

OBJECTIVE We performed a cross-sectional study to examine the differences in leukocyte telomere length among three groups of subjects: patients with type 2 diabetes mellitus without history of previous myocardial infarction (Type2DM), patients with type 2 diabetes mellitus with evidence of previous myocardial infarction (Type2DM+MI), and healthy control subjects (CTR). The main objective of the present study is to investigate differences in telomere length between the studied groups of subjects, with the aim to clarify if telomere length could be a reliable marker associated with MI in Type2DM patients. Secondary end point is the identification of associations between leukocyte telomere length and selected variables related to glycemic control, pro-inflammatory status and lipidic profile. RESEARCH DESIGN AND METHODS A total of 272 elderly subjects, 103 Type2DM (mean age 70+/-4 years, 59% males), 65 Type2DM+MI (mean age 68+/-7 years, 68% males), and 104 CTR (mean age 69+/-7 years, 50% males) were studied. Telomere length, defined as T/S (Telomere-Single copy gene ratio), was determined in leukocytes by quantitative real-time polymerase chain reaction (real-time PCR)-based assay. Moreover, we assessed: (1) high sensitive C reactive protein (hsCRP), fibrinogen and plasminogen-activator inibitor-1 (PAI-1) as inflammatory markers; (2) fasting glucose, insulin, glycated haemoglobin (HbA1C) and waist-to-hip ratio as markers of glycemic control; (3) total-cholesterol, HDL-cholesterol and triglycerides as markers of lipidic profile, in all sample population. The use of statins and sulfonylurea, as well as the presence of some relevant diabetes complications (nephropathy and retinopathy) were also assessed. CONCLUSION Type2DM+MI elderly patients have leukocyte telomere lengths shorter than those of Type2DM (without MI) and healthy CTR. Moreover, glucose, HbA1C and waist-to-hip ratio, variables related to glycemic control, showed a significant inverse correlation with leukocyte telomeres length.

Leukocyte telomere length is associated with complications of type 2 diabetes mellitus.

Diabet. Med. 28, 1388–1394 (2011)