Silvia Giovannini

Molecular inflammation: Underpinnings of aging and age-related diseases

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) upregulation of pro-inflammatory mediators (e.g., TNF-alpha, IL-1beta, IL-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-kappaB 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.

Sarcopenia as a risk factor for falls in elderly individuals: Results from the ilSIRENTE study

BACKGROUND & AIMS Sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the relationship between sarcopenia and 2-year risk of falls in a population of persons aged 80 years or older. METHODS Data are from the baseline and follow-up evaluations of the Aging and Longevity Study in the Sirente Geographic Area (ilSIRENTE Study) (n=260). According to the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia was diagnosed in presence of low muscle mass (mid-arm muscle circumference) plus either low muscle strength (hand grip) or low physical performance (4-m walking speed). The primary outcome measure was the incident falls during the follow-up period of 2 years. The relationship between sarcopenia and incident falls was estimated by deriving hazard ratios (HRs) from multiple logistic regression models considering the dependent variable of interest at least one fall during the follow-up period. RESULTS Sixty-six participants (25.4%) were identified as affected by sarcopenia. Eighteen out of 66 (27.3%) participants with sarcopenia and 19 out of 194 (9.8%) without sarcopenia reported incident falls during the two-year follow-up of the study (p<0.001). After adjusting for age, gender, cognitive impairment, ADL impairment, sensory impairments, BMI, depression, physical activity, cholesterol, stroke, diabetes, number of medications, and C-reactive protein, participants with sarcopenia had a higher risk of incident falls compared with non sarcopenic subjects (adjusted hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.25-8.29). CONCLUSIONS The present study suggests that sarcopenia - assessed using the EWGSOP algorithm - is highly prevalent among elderly persons without gender differences (25%). Sarcopenic participants were over three times more likely to fall during a follow-up period of 2 years relative to non sarcopenic individuals, regardless of age, gender and other confounding factors.

Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study

BACKGROUND AND AIMS sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the impact of sarcopenia on the risk of all-cause death in a population of frail older persons living in community. METHODS we analysed data from the Aging and Longevity Study, a prospective cohort study that collected data on all subjects aged 80 years and older residing in the Sirente geographic area (n = 364). The present analysis was conducted among those subjects who were between 80 and 85 years of age at the time of the baseline assessment (n = 197). The main outcome measure was all-cause mortality over 7-year follow-up. According to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, the diagnosis of sarcopenia required the documentation of low muscle mass and the documentation of either low muscle strength or low physical performance. Cox proportional regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals of death by the presence of sarcopenia. RESULTS using the EWGSOP-suggested criteria, 43 subjects with sarcopenia (21.8%) were identified. During the 7-year follow-up, 29 (67.4%) participants died among subjects with sarcopenia compared with 63 subjects (41.2%) without sarcopenia (P < 0.001). After adjusting for potential confounders including age, gender, education, activities of daily living (ADL) impairment, body mass index, hypertension, congestive heart failure, chronic obstructive pulmonary disease, number of diseases, TNF-α, participants with sarcopenia had a higher risk of death for all causes compared with non-sarcopenic subjects (HR: 2.32, 95% CI: 1.01-5.43). CONCLUSIONS our results obtained from a representative sample of very old and frail subjects show that sarcopenia is associated with mortality, independently of age and other clinical and functional variables.

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 x 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 (CyPD) 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.

Modulation of GH/IGF-1 axis: Potential strategies to counteract sarcopenia in older adults

Aging is associated with progressive decline of skeletal muscle mass and function. This condition, termed sarcopenia, is associated with several adverse outcomes, including loss of autonomy and mortality. Due to the high prevalence of sarcopenia, a deeper understanding of its pathophysiology and possible remedies represents a high public health priority. Evidence suggests the existence of a relationship between declining growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and age-related changes in body composition and physical function. Therefore, the age-dependent decline of GH and IGF-1 serum levels may promote frailty by contributing to the loss of muscle mass and strength. Preclinical studies showed that infusion of angiotensin II produced a marked reduction in body weight, accompanied by decreased serum and muscle levels of IGF-1. Conversely, overexpression of muscle-specific isoform of IGF-1 mitigates angiotensin II-induced muscle loss. Moreover, IGF-1 serum levels have been shown to increase following angiotensin converting enzyme inhibitors (ACEIs) treatment. Here we will review the most recent evidence regarding age-related changes of the GH/IGF-1 axis and its modulation by several interventions, including ACEIs which might represent a potential novel strategy to delay the onset and impede the progression of sarcopenia.

Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction.

TNF-alpha-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-alpha-triggered apoptosis. We investigated IL-15 signaling and the TNF-alpha-mediated pathway of apoptosis in the gastrocnemius muscle of Fischer344xBrown 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 a-chain decreased in senescent ad libitum (AL) fed rats, but were maintained in CR rodents. Elevations of TNF-alpha, 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-alpha-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.

Interleukin-6, C-Reactive Protein, and Tumor Necrosis Factor-Alpha as Predictors of Mortality in Frail, Community-Living Elderly Individuals

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 older persons living in the community.

Effect of Proinflammatory Gene Polymorphisms on the Risk of Alzheimer's Disease

Background: A number of studies associate Alzheimers disease (AD) with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute-phase proteins. Objective: In this study we evaluated the distribution of a set of functionally important polymorphisms of genes encoding prototypical inflammatory molecules in individuals with AD. We also investigated whether a synergistic effect of these proinflammatory gene polymorphisms on the risk of AD could be hypothesized. Methods: In a genetic association study that included 533 AD patients and 713 controls, the following gene polymorphisms were analyzed: C-reactive protein (CRP) 1059 G/C, interleukin 6 (IL6) -174 G/C, interleukin 1β (IL1B) -31 T/C, tumor necrosis factor α (TNF-α) -308 G/A, macrophage migration inhibitory factor (MIF) -173 G/C, monocyte chemoattractant protein 1 (CCL2) -2518 A/G, intercellular adhesion molecule 1 (ICAM1) 469 E/K, E-selectin (SELE) Ser128Arg, macrophage inflammatory protein 1α (CCL3) -906 T/A, matrix metalloproteinase 3 (MMP3) -1171 5A/6A and matrix metalloproteinase 9 (MMP9) -1562 C/T. Results: We found that IL6, IL1B, CCL2, CCL3, SELE, ICAM1, MMP3, and MMP9 gene polymorphisms were significantly and independently associated with AD. The association remained significant even after the Bonferroni correction. We also found that these proinflammatory polymorphisms were associated with different levels of risk for AD, depending on the number of high-risk genotypes concomitantly carried by a given individual. Conclusion: Proinflammatory genotypes might influence the development and progression of AD exerting a potential synergistic effect.

Myeloperoxidase Levels and Mortality in Frail Community-Living Elderly Individuals

BACKGROUND Elevated systemic levels of myeloperoxidase (MPO) have been associated with unfavourable clinical outcomes. In the present study, we evaluate the impact of MPO, a pro-oxidant enzyme that catalyzes the initiation of lipid peroxidation and affects nitric oxide levels, on the risk of all-cause mortality in a large population of frail octogenarians and nonagenarians living in community. METHODS We analyzed data from the Aging and Longevity Study in the Sirente Geographic Area (ilSIRENTE Study), a prospective cohort study that collected data on all individuals aged 80 years and older living in a mountain community (n = 363). The main outcome measure was the risk of death after 4 years of follow-up. Participants were divided into three groups based on MPO tertiles: lower tertile < or = 61.5 microg/L (n = 120), intermediate tertile 61.6-140.6 microg/L (n = 120), and higher tertile > or = 140.7 microg/L (n = 123). RESULTS A total of 150 deaths occurred during 4-years follow-up. The mean MPO level was 170.8 + or - 177.5 microg/L among those who died compared with 135.4 + or - 142.4 microg/L among survivors (p = .03). Individuals in the highest MPO tertile had higher risk of mortality (40% [60/123]) compared with those in the lower tertile (26% [39/120]). After adjusting for potential confounders, compared with participants in the lower tertile, those in the higher tertile had a hazard ratio for mortality of 1.97 (95% confidence interval: 1.02-3.80). CONCLUSION Our results obtained from a representative sample of very old and frail elderly individuals expand the knowledge that low levels of MPO are associated with better survival.

Interaction between GSTM1 genotype and IL-6 on mortality in older adults: results from the ilSIRENTE study

BACKGROUND AND AIMS The inflammatory process is related to oxidative stress and inflammation was proven to be a strong determinant of the aging process and to ultimately lead to death. The aim of the present study was to assess if, in a population of older adults, the effect of antioxidant genes GSTM1 and GSTT1 genotypes on mortality may differ depending on levels of inflammation. METHODS Data are from 353 older persons aged ≥80 years enrolled in the ilSIRENTE study. Study population was divided into two groups computed based on the median value of serum IL-6 (low IL-6, n=177 and high IL-6, n=176). All participants were followed up for 48 months. RESULTS Mean age of study participants was 85.8 years (Standard Deviation 4.8), 235 (66.6%) were women. Overall 48/177 participant (27.1%) in the low IL-6 group died during the study period, compared with 97/176 (55.1%) in the high IL-6 group (p<0.001). After adjusting for potential confounders, GSTM1 wildtype had no effect on mortality in the low IL-6 group (RR=1.07; 95% CI 0.46-2.47), but it was associated with a significant lower mortality rate in the high IL-6 level (RR=0.33; 95% CI 0.15-0.69). Testing the interaction between IL-6 and GSTM1 genotype, we found a significant result (p=0.02). No significant effect of GSTT1 genotype on mortality was shown in participants with low and high IL-6 level. CONCLUSION GSTM1 wildtype is associated with reduced mortality among older adults with high levels of inflammation, but not among those with low levels of inflammation.