Sabrina Garasto

Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly

The human sirtuin 3 (SIRT3) gene encodes a putative mitochondrial NAD-dependent deacetylase (SIRT3) which belongs to the evolutionary conserved family of sirtuin 2 proteins. Studies in model organisms have demonstrated that SIR2 genes control lifespan, while no data are available regarding a possible role of SIRT3 in human longevity. By analysing the genotype-specific survival function relevant to the G477T marker of SIRT3, we found that in males the TT genotype increases (p=0.0272), while the GT genotype decreases (p=0.0391) survival in the elderly. Since SIRT3 lies in a chromosomal region (11p15.5) where four genes potentially associated with longevity are located (HRAS1, Insulin-like Growth Factor 2, Proinsulin, and Tyrosine Hydroxylase) we tested for linkage-disequilibrium between G477T alleles and alleles of the above genes. The disequilibrium was not significant in any case, thus suggesting that SIRT3 itself, or a gene strictly linked to SIRT3, may have a role in human longevity.

Regimen complexity and medication nonadherence in elderly patients

Objective: To assess whether the number of daily administrations of individual drugs, as a measure of regimen complexity, contributes to the profile of an elderly patient who adheres poorly to the prescribed therapy. Population: Six hundred ninety patients over 64 years who were consecutively admitted to 11 acute medical care and three long term/rehabilitation wards in Italy. Main outcome measure: Self-reported adherence to drugs taken at home before admission was measured by a single question assessment for each listed drug supplemented with a latter question about the circumstances of the missed administration. For cognitively impaired patients the question was put to patients’ relatives or caregivers. Methods: A structured multidimensional assessment was performed to identify nonadherence and its potential correlates. Correlates of nonadherence were identified by multivariable logistic regression. Results: We recorded 44 cases (6.4%) of nonadherence to at least one drug. Being assisted by foreign caregivers (OR 2.17; 95% CI 1.02–4.63) and the use of at least one multiple daily dosing drug (OR 2.99; 95% CI 1.24–7.17) were significant independent correlates of medication nonadherence, while age, selected indexes of frailty and the cumulative number of prescribed drugs were not. Conclusion: Regimen complexity and type of assistance are independent correlates of medication nonadherence.

Potentially inappropriate medications and functional decline in elderly hospitalized patients.

OBJECTIVES: To verify whether the use of potentially inappropriate medications (PIMs) is associated with loss of independence in elderly in‐patients by promoting adverse drug reactions (ADRs).

The allele (A)(-110) in the promoter region of the HSP70-1 gene is unfavorable to longevity in women.

Heat shock proteins (HSPs) are crucial for maintenance of cell homeostasis and survival both during and after various stresses. The capability to cope with stress is believed to affect the chance of health and survival at organismal level. We have investigated whether the gene pool relevant to the (A/C)-110 polymorphism in the promoter region of the HSP70-1 gene changes as the population ages and survival selection occurs. A total of 591 southern Italian subjects were enrolled in the study (263 males and 328 females; age range 18–109 years), free of clinically manifest diseases and with normal haemato-chemical parameters. A significant age-related decrease of the frequency of allele (A)-110 was observed in females. The probability ratio of 0.403 (95% confidence interval [0.163, 0.910]) computed by considering female centenarians as cases and young women (18–49 years old) as controls showed that the (A)-110 allele is unfavorable to longevity in females.

The study of APOA1, APOC3 and APOA4 variability in healthy ageing people reveals another paradox in the oldest old subjects

The genes coding for apolipoprotein A1 (APOA1), apolipoprotein C3 (APOC3) and apolipoprotein A4 (APOA4) are tandemly organised within a short region on chromosome 11q23‐q24. Polymorphisms of these genes have been extensively investigated in lipoprotein disorders and cardiovascular diseases, but poorly investigated in healthy ageing. The aim of this study was to describe possible modifications of the APOA1, APOC3, and APOA4 gene pool by cross‐sectional studies carried out in a healthy ageing population whose ages ranged from 18 to 109 years (800 subjects, 327 males and 473 females, free of clinically manifested disease, and with emato‐chemical parameters in the norm). APOA1‐MspI‐RFLP (−75 nt from the transcription starting site), APOC3‐SstI‐RFLP (3′UTR, 3238 nt), and APOA4‐HincII‐RFLP (Asp127/Ser127) were analysed according to age and sex. A significant age‐related variation of the APOA1 gene pool was observed in males. An analysis of the allele average effect exerted by APOA1‐MspI‐RFLP A/P alleles (Absence/Presence of the restriction site) on lipidemic parameters in 46–80 year old males showed that allele A decreased, while allele P significantly increased, serum LDL‐cholesterol. Unexpectedly, the P allele was over‐represented in the group of the oldest old subjects, thus giving evidence of another “genetic paradox of centenarians”.

Sex-specific longevity associations defined by Tyrosine Hydroxylase–Insulin–Insulin Growth Factor 2 haplotypes on the 11p15.5 chromosomal region

By studies in centenarians, it was recently found that an STR marker of the Tyrosine Hydroxylase (TH, 11p15.5) gene is associated with human longevity. The aim of the present study was to continue the exploration of the 11p15.5 chromosomal region in human longevity by analyzing two additional RFLP markers, which lie in the Insulin (INS) and Insulin Growth Factor 2 (IGF2) genes. Both the genes, which are localized downstream TH, are indeed good candidates in longevity, as ascertained on the basis of laboratory studies in experimental models. Neither INS nor IGF2 markers did reveal association with longevity. Nevertheless, linkage disequilibrium analyses showed sex-specific longevity associations defined by both TH-INS and TH-IGF2 haplotypes. On the whole, the results reinforce the involvement of the chromosomal region spanning from TH to IGF2 loci in controlling the longevity phenotype in humans.

Does a retrograde response in human aging and longevity exist

The retrograde response (RR) is a compensatory mechanism by which mutant strains of yeast are able to cope with mitochondrial DNA (mtDNA) impairments by up-regulating the expression of the stress-responder nuclear genes and significantly increasing lifespan. Starting from the observation that both mtDNA variability and Tyrosine hydroxylase (THO, stress-responder gene) variability are correlated with human longevity, we asked ourselves whether mechanisms similar to RR may exist in humans. As a first investigative step we have analyzed the distribution of the mtDNA inherited variants (haplogroups) according to THO genotypes in three sample groups of increasing ages (20-49 years; 50-80 years; centenarians). We found that the mtDNA haplogroups and the THO genotypes are associated randomly in the first group, while in the second group, and particularly in the centenarians, a non-random association is observed between the mtDNA and nuclear DNA variability. Moreover, in centenarians the U haplogroup is over-represented (p=0.012) in subjects carrying the THO genotype unfavorable to longevity. On the whole these findings are in line with the hypothesis that longevity requires particular interactions between mtDNA and nuclear DNA and do not exclude the possibility that an RR has been maintained throughout evolution and it is present in higher organisms.

Prognostic significance of the short physical performance battery in older patients discharged from acute care hospitals.

We investigated the prognostic role of the Short Physical Performance Battery (SPPB) in elderly patients discharged from the acute care hospital. Our series consisted of 506 patients aged 70 years or more enrolled in a multicenter collaborative observational study. We considered three main outcomes: 1-year survival after discharge, functional decline, and hospitalization during follow-up. Independent predictors/correlates of the outcomes were investigated by Cox regression or logistic regression analysis when appropriate. The diagnostic accuracy of SPPB in relation to study outcomes was investigated by receiver operating characteristic (ROC) curve. SPPB score was associated with reduced mortality (hazard ratio [HR]=0.86, 95% confidence interval [CI] 0.78-0.95). When the analysis was adjusted for functional status at discharge, such an association was still near significant only for SPPB values >8 (HR=0.51; 95% CI 0.30-1.05). An SPPB score<5 could identify patients who died during follow-up with fair sensitivity (0.66), specificity (0.62), and area under the ROC curve (0.66). SPPB also qualified as independent correlate of functional decline (odds ratio [OR]=0.82; 95% CI 0.70-0.96), but not of rehospitalization or combined end-point death or rehospitalization. An SPPB score <5 could identify patients experiencing functional decline during follow-up with lower sensitivity (0.60), but higher specificity (0.69), and area under the ROC curve (0.69) with respect to mortality. In conclusion, SPPB can be considered a valid instrument to identify patients at major risk of functional decline and death after discharge from acute care hospital. However, it could more efficiently target patients at risk of functional decline than those at risk of death.

Targeting inflammation to slow or delay functional decline: where are we?

The role of inflammation in the pathophysiology of chronic age-related diseases is increasingly recognized, and inflammation could represent the common pathway linking diseases and disability. Thus, targeting inflammation could represent a useful strategy at preventing or delaying functional decline. In this paper we review recent evidence suggesting that selected drugs, such as statins, fibrates, angiotensin converting enzyme-inhibitors and angiotensin receptor blockers, and physical exercise may be able to contrast functional decline by blunting inflammation. Results from randomized trials investigating the effects of physical activity programs on inflammation and functional decline is still limited, and further investigations are warranted.

Geriatric Conditions and Adverse Drug Reactions in Elderly Hospitalized Patients

OBJECTIVES To investigate the relationship between clinical conditions typically observed in the geriatric patients (geriatric conditions) and adverse drug reactions in older patients admitted to acute care hospitals. DESIGN AND SETTING Prospective observational study conducted in 11 acute care medical wards throughout Italy. PARTICIPANTS Five hundred six patients aged 65 years or older consecutively admitted to participating wards. MEASUREMENTS The outcome of the study was the occurrence of any adverse drug reactions during the hospital stay. Geriatric conditions considered in the analysis were basic activities of daily living, history of falls, slow walking speed, malnutrition, dementia, depression, 1 or more unplanned admissions in the previous 3 months, history of stroke, unintentional weight loss, and exhaustion. The relationship between risk factors and outcomes was assessed using logistic regression. RESULTS Female gender (odds ratio [OR] 2.29; 95% confidence interval [CI] 1.18-4.45) and number of medications taken during hospitalization (OR 1.12; 95% CI 1.06-1.18), but not individual Geriatric conditions, were associated with the outcome after correction for potential confounders. However, the simultaneous presence of history of falls and dependency in at least 1 activities of daily living (OR 2.18; 95% CI 1.13-4.19) was associated with adverse drug reactions during stay. CONCLUSION The simultaneous presence of history of falls and dependency in at least one activity of daily living defines a condition of particular vulnerability of elderly hospitalized patients to adverse drug reactions. Physicians should be aware of this high-risk condition when prescribing new drugs to disabled older people.