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1.  Interleukin-6, C-Reactive Protein, Tumor Necrosis Factor-alpha as Predictors of Mortality in Frail, Community-Living Elderly Individuals 
Background
Aging is characterized by a chronic low-grade inflammation that has been found to be related to mortality risk in older persons.
Objectives
The aim of the present study was to investigate whether interleukin-6 (IL-6), C-reactive protein (CRP) and Tumor Necrosis Factor-alpha (TNF-α) protein levels predict all-cause mortality in a sample of older persons living in the community.
Design and Setting
Data are from the Aging and Longevity Study in the Sirente Geographic Area (ilSIRENTE Study), a prospective cohort study that collected information on individuals aged 80 years and older living in an Italian mountain community (n=362). The main outcome was the hazard ratio of death after four years of follow-up.
Participants and measurements
Participants were classified according to the median value of the 3 inflammatory markers (IL-6: 2.08 pg/mL; TNF-α: 1.43 pg/mL and CRP: 3.08 mg/L). In addition, a composite summary score of inflammation was created.
Results
A total of 150 deaths occurred during a 4-year follow-up. In the unadjusted model, high levels of each of the 3 markers were associated with increased mortality. After adjusting for potential confounders, high levels of IL-6 and CRP were associated with a significantly increased risk of death (HR, 2.18; 95% CI 1.29–3.69 and 2.58; 95% CI 1.52–4.40, respectively); whereas the association between TNF-α protein levels and mortality lost significance (1.26; 95% CI: 0.74 to 2.15). The composite summary score of inflammation was strongly associated with mortality, with the highest risk estimated for individuals with all three inflammatory markers above the median.
Conclusions
Low levels of inflammatory markers are associated with better survival in elderly, independently of age and other clinical and functional variables.
doi:10.1111/j.1532-5415.2011.03570.x
PMCID: PMC4321727  PMID: 21883115
Interleukin-6; C-Reactive Protein; TNF-alpha; Mortality; Frail Elderly
2.  EFFECTS OF ACE-INHIBITION ON IGF-1 AND IGFBP-3 CONCENTRATIONS IN OLDER ADULTS WITH HIGH CARDIOVASCULAR RISK PROFILE 
Objectives
The present study evaluates the effects of a 6-month treatment with an ACE-inhibitor (ie, fosinopril) on serum concentrations of total IGF-1 and IGF binding protein (IGFBP)-3 in older adults at high risk for cardiovascular disease.
Design
Data are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study, a double-blind, crossover, randomized, placebo-controlled trial.
Setting
Participants were recruited from the communities of Winston Salem, NC, and Greensboro, NC.
Participants
Subjects ≥55 years old with high cardiovascular disease risk profile.
Intervention
The intervention consisted of 6-month administration of fosinopril vs. placebo.
Measurements
Serum concentrations of total IGF-1 and IGFBP-3 were measured in 100 participants of the TRAIN study at baseline, 6-month and 12-month follow-up visits. Differences in total IGF-1 and IGFBP-3 concentrations were assessed using two-sided paired t-tests.
Results
The mean age of participants (47% women) was 66.5 (standard deviation 7.2) years. Serum concentrations of total IGF-1 were significantly higher after 6-month treatment with fosinopril compared to placebo (203.73 ng/mL vs 194.24 ng/mL; p=0.02): After ACE-inhibitor intervention, significantly higher serum IGFBP-3 concentrations compared to controls (4308.81 ng/mL vs 4086.93 ng/mL; p=0.03) were also reported.
Conclusions
A six-month treatment with fosinopril increases systemic levels of total IGF-1 and IGFBP-3 in older adults with high cardiovascular risk profile. This may represent a potential biological explanation to the beneficial effects of ACE-inhibition on stroke, ischemic heart disease and insulin resistance.
PMCID: PMC4311891  PMID: 20617288
Angiotensin Converting Enzyme inhibitor; Insulin like growth factor 1; Insulin like growth factor binding protein 3; older adults
3.  Late-life enalapril administration induces nitric oxide-dependent and independent metabolic adaptations in the rat skeletal muscle 
Age  2012;35(4):1061-1075.
Recently, we showed that administration of the angiotensin-converting enzyme inhibitor enalapril to aged rats attenuated muscle strength decline and mitigated apoptosis in the gastrocnemius muscle. The aim of the present study was to investigate possible mechanisms underlying the muscle-protective effects of enalapril. We also sought to discern the effects of enalapril mediated by nitric oxide (NO) from those independent of this signaling molecule. Eighty-seven male Fischer 344 × Brown Norway rats were randomly assigned to receive enalapril (n = 23), the NO synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; n = 22), enalapril + l-NAME (n = 19), or placebo (n = 23) from 24 to 27 months of age. Experiments were performed on the tibialis anterior muscle. Total NOS activity and the expression of neuronal, endothelial, and inducible NOS isoforms (nNOS, eNOS, and iNOS) were determined to investigate the effects of enalapril on NO signaling. Transcript levels of tumor necrosis factor-alpha (TNF-α) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were assessed to explore actions of enalapril on inflammation and mitochondrial biogenesis, respectively. Protein expression of energy-sensing and insulin signaling mediators, including protein kinase B (Akt-1), phosphorylated Akt-1 (pAkt-1), mammalian target of rapamycin (mTOR), AMP-activated protein kinase subunit alpha (AMPKα), phosphorylated AMPKα (pAMPKα), and the glucose transporter GLUT-4, was also determined. Finally, the generation of hydrogen peroxide (H2O2) was quantified in subsarcolemmal (SSM) and intermyofibrillar (IFM) mitochondria. Enalapril increased total NOS activity, which was prevented by l-NAME co-administration. eNOS protein content was enhanced by enalapril, but not by enalapril + l-NAME. Gene expression of iNOS was down-regulated by enalapril either alone or in combination with l-NAME. In contrast, protein levels of nNOS were unaltered by treatments. The mRNA abundance of TNF-α was reduced by enalapril relative to placebo, with no differences among any other group. PCG-1α gene expression was unaffected by enalapril and lowered by enalapril + l-NAME. No differences in protein expression of Akt-1, pAkt-1, AMPKα, pAMPKα, or GLUT-4 were detected among groups. However, mTOR protein levels were increased by enalapril compared with placebo. Finally, all treatment groups displayed reduced SSM, but not IFM H2O2 production relative to placebo. Our data indicate that enalapril induces a number of metabolic adaptations in aged skeletal muscle. These effects result from the concerted modulation of NO and angiotensin II signaling, rather than from a dichotomous action of enalapril on the two pathways. Muscle protection by enalapril administered late in life appears to be primarily mediated by mitigation of oxidative stress and pro-inflammatory signaling.
doi:10.1007/s11357-012-9428-4
PMCID: PMC3705103  PMID: 22639176
Aging; Nitric oxide synthase (NOS) isoforms; Mitochondria; mTOR; Glucose tolerance; l-NAME; Inflammation; ACE inhibitors
4.  Molecular Inflammation: Underpinnings of Aging and Age-related Diseases 
Ageing research reviews  2008;8(1):18-30.
Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) up-regulation of pro-inflammatory mediators (e.g., TNF-α, IL-1β, 6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-κB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity.
doi:10.1016/j.arr.2008.07.002
PMCID: PMC3782993  PMID: 18692159
molecular inflammation; aging; calorie restriction; exercise; cytokines; oxidative stress; inflammatory diseases; age-related diseases; obesity; sarcopenia; dementia; atherosclerosis; cancer; osteoporosis
5.  Cu to Zn ratio, physical function, disability, and mortality risk in older elderly (ilSIRENTE study) 
Age  2011;34(3):539-552.
Associations between copper to zinc ratio (CZr) and mortality have suggested CZr as a biomarker of aging. Nevertheless, very limited data exist on the association between serum CZr and physical or functional status of very old people. We examined the relationship between serum CZr and physical performance, muscle strength, functional status, and survival from the ilSIRENTE Study: a longitudinal study of persons aged 80 years or older (n = 346). An adjusted linear regression model was subsequently performed to calculate the regression coefficients of the associations between baseline physical and functional measures (dependent variable) with CZr or “Cu and Zn” alone taking also into account the influence of other relevant factors, including hematological (albumin, cholesterol, and urea) and inflammatory biomarkers (IL-6 and CRP) that were significantly different across CZr tertiles. CZr showed significant and stronger relationships than Cu or Zn alone with all baseline physical and functional measures in models that did not include adjustments for inflammatory parameters. CZr was also associated with physical decline, measured as “SPPB% decline” at 2 years of follow-up and mortality at 4 years of follow-up. Subjects in the high CZr tertile had a higher risk of death with an adjusted hazard ratio of 1.92 (95% CI, 1.12–3.29; p = 0.02). In conclusion, we have confirmed the role of CZr as a predictor of mortality, whereas the role of CZr as a biomarker or predictor of physical or functional performance seems to be the consequence of its strict relationships with inflammatory parameters. In this context, further investigations need to be carried out.
doi:10.1007/s11357-011-9252-2
PMCID: PMC3337923  PMID: 21544579
Cu to Zn ratio; Physical function; Disability; Mortality; Aging
7.  Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction 
TNF-α-mediated apoptosis is enhanced in aged rodent muscles, suggesting that this pathway may be involved in sarcopenia. Interleukin-15 (IL-15), a muscle-derived anabolic cytokine, mitigates muscle wasting and apoptosis in cachectic rats. This effect is thought to occur through inhibition of TNF-α-triggered apoptosis. We investigated IL-15 signaling and the TNF-α-mediated pathway of apoptosis in the gastrocnemius muscle of Fischer344×Brown Norway rats across the ages of 8, 18, 29 and 37 months, in relation to life-long calorie restriction (CR, 40% calorie intake reduction). Aging caused loss of muscle mass and increased apoptotic DNA fragmentation, which were mitigated by CR. Protein levels of IL-15 and mRNA abundance of IL-15 receptor α-chain decreased in senescent ad libitum (AL) fed rats, but were maintained in CR rodents. Elevations of TNF-α, TNF-receptor 1, cleaved caspase-8 and -3 were observed at advanced age in AL rats. These changes were prevented or mitigated by CR. Our results indicate that aging is associated with decreased IL-15 signaling in rat gastrocnemius muscle, which may contribute to sarcopenia partly through enhanced TNF-α-mediated apoptosis. Preservation of IL-15 signaling by CR may therefore represent a further mechanism contributing to the anti-aging effect of this dietary intervention in skeletal muscle.
doi:10.1016/j.mad.2008.12.008
PMCID: PMC2768529  PMID: 19396981
sarcopenia; interleukin-15; tumor necrosis factor-α; calorie restriction; apoptosis
8.  Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle 
Mitochondria-mediated apoptosis represents a central process driving age-related muscle loss. However, the temporal relation between mitochondrial apoptotic signaling and sarcopenia as well as the regulation of release of pro-apoptotic factors from the mitochondria has not been elucidated. In this study, we investigated mitochondrial apoptotic signaling in skeletal muscle of rats across a wide age range. We also investigated whether mitochondrial-driven apoptosis was accompanied by changes in the expression of Bcl-2 proteins and components of the mitochondrial permeability transition pore (mPTP). Analyses were performed on gastrocnemius muscle of 8-, 18-, 29- and 37- month-old male Fischer344×Brown Norway rats (9 per group). Muscle weight declined progressively with advancing age, concomitant with increased apoptotic DNA fragmentation. Cytosolic and nuclear levels of apoptosis inducing factor (AIF) and endonuclease G (EndoG) increased in old and senescent animals. In contrast, cytosolic levels of cytochrome c were unchanged with age. Mitochondrial Bcl-2, Bax and Bid increased dramatically in 37-month-old rats, with no changes in the Bax/Bcl-2 ratio in any of the age groups. Finally, expression of cyclophilin D was enhanced at very old age. Our findings indicate that the mitochondrial caspase-independent apoptotic pathway may play a more prominent role in skeletal muscle loss than caspase-mediated apoptosis.
doi:10.1016/j.mad.2008.05.005
PMCID: PMC2585824  PMID: 18579179
sarcopenia; apoptosis; permeability transition pore; AIF; endonuclease G

Results 1-8 (8)