Antonino Catalano

Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity

Longevity and aging are two sides of the same coin, as they both derive from the interaction between genetic and environmental factors. Aging is a complex, dynamic biological process characterized by continuous remodeling. One of the most recent theories on aging focuses on immune response, and takes into consideration the activation of subclinical, chronic low-grade inflammation which occurs with aging, named “inflammaging”. Long-lived people, especially centenarians, seem to cope with chronic subclinical inflammation through an anti-inflammatory response, called therefore “anti-inflammaging”. In the present review, we have focused our attention on the contrast between inflammaging and anti-inflammaging systems, by evaluating the role of cytokines and their impact on extreme longevity. Cytokines are the expression of a network involving genes, polymorphisms and environment, and are involved both in inflammation and anti-inflammation. We have described the role of IL-1, IL-2, IL-6, IL-12, IL-15, IL-18, IL-22, IL-23, TNF-α, IFN-γ as pro-inflammatory cytokines, of IL-1Ra, IL-4, IL-10, TGF-β1 as anti-inflammatory cytokines, and of lipoxin A4 and heat shock proteins as mediators of cytokines. We believe that if inflammaging is a key to understand aging, anti-inflammaging may be one of the secrets of longevity.

Improvement of Primary Dysmenorrhea Caused by a Single Oral Dose of Vitamin D: Results of a Randomized, Double-blind, Placebo-Controlled Study

P rimary dysmenorrhea is a common disorder characterized by painful uterine cramping, just before or during menstruation, in the absence of any pelvic pathologic conditions. It is frequently accompanied by other symptoms such as nausea, vomiting, diarrhea, asthenia, and insomnia. Primary dysmenorrhea affects almost half of menstruating women, often resulting in school and work absenteeism with major educational and economic consequences. An excessive uterine production of prostaglandins (PGs) is the pathogenetic trigger of dysmenorrhea. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the currently accepted drugs for the management of this disorder. Because the vitamin D receptor is widespread and the mitochondria l cytochrome P450 enzyme 25hydroxyvitamin D3 (25[OH]D)-1 -hydroxylase (1 OHase), which catalyzes the synthesis of 1 ,25dihydroxyvitamin D3 (1,25[OH]2D) from its precursor 25(OH)D, is expressed in the human uterus and in immune system cells, and because vitamin D reduces the synthesis of PGs, a beneficial effect of vitamin D in the uterus pathophysiology is possible. The aim of this prospective intervention study was to evaluate the effect of a single-loading oral dose of cholecalciferol (300 000 IU) on primary dysmenorrhea.

Neridronate Prevents Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

Today, androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, although it presents important complications such as osteoporosis. Neridronate, a relatively new bisphosphonate, is able to prevent bone loss in patients with prostate cancer during androgen ablation.

Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus

BACKGROUND Sclerostin is an osteocyte-derived inhibitor of the Wnt/β-catenin signaling pathway, which acts as a negative regulator of bone formation. Published data on sclerostin levels in type 1 diabetes mellitus (T1DM) are few. OBJECTIVE To evaluate gender differences in sclerostin serum levels and the association among sclerostin, bone mass, bone metabolism, and the main clinical characteristics of subjects with T1DM. DESIGN AND METHODS A total of 69 patients with T1DM (mean age, 33.7±8.1; 49% males) were enrolled in this cross-sectional study in a clinical research center. Bone mineral density was measured by phalangeal quantitative ultrasound (QUS); bone turnover markers (urinary pyridinoline, deoxypyridinoline (D-PYR), and urine hydroxyproline (OH-PRO) to evaluate bone resorption; serum bone alkaline phosphatase and BGP to evaluate bone formation) and sclerostin were assessed. RESULTS D-PYR and sclerostin were significantly higher in women when compared with men (P=0.04). A disease duration >15 years was associated with higher sclerostin levels (P=0.03). Bone turnover markers and QUS parameters were not correlated with sclerostin. A significant negative correlation was observed among QUS parameters, BMI, and OH-PRO. Sclerostin serum levels were correlated with homocysteine (r=-0.34, P=0.005) and vitamin B12 (r=-0.31, P=0.02). Generalized linear model showed that macroangiopathy was the only predictor of sclerostin serum levels (β=-11.8, 95% CI from -21.9 to -1.7; P=0.02). CONCLUSIONS Our data demonstrate that women with T1DM exhibit higher sclerostin levels than men and that circulating sclerostin is not associated with bone turnover markers and phalangeal QUS measurements. Macroangiopathy was associated with sclerostin levels.

Effect of long-term treatment with raloxifene on mammary density in postmenopausal women.

Objective: To evaluate in a group of postmenopausal women the effects of long-term raloxifene treatment on breast density using a digitized analysis of mammograms and on insulinlike growth factor-1 (IGF-1), insulinlike growth factor binding protein-3 (IGFBP-3), and sex hormone-binding globulin (SHBG) plasma levels. Design: Seventy healthy postmenopausal women with normal body weight were enrolled in this study and were divided into two groups based on their bone status, evaluated by dual-energy x-ray at the lumbar spine (L2-4). Fifty women (chronological age 52.4 ± 4.1 y, menopausal age 42.1 ± 3.9 y), in whom the L2-4 T score was less than −2.5 SD, were treated with raloxifene HCl 60 mg/day orally for 2 years. The other 20 women (chronological age 53.6 ± 3.5 y, age at menopause 43.1 ± 3.6 y), in whom the L2-4 T score ranged between −1 and −2.5 SD, were enrolled as controls. All 70 women received calcium (1 g/d orally) and cholecalciferol (880 UI/d orally) supplementation. Moreover, all women followed a normocaloric and personalized diet. All women had mammography at baseline and after 2 years of therapy. The mammographic images on traditional support (radiography) were acquired by using a film scanner and were then elaborated by means of ad hoc software. Moreover, assessments of IGF-1, IGFBP-3, and SHBG plasma levels were obtained at baseline and after 24 months. Results: After 24 months of therapy, there was a significant variation in the raloxifene-treated group with respect to baseline in the distribution of gray classes of radiographic images. In particular, an attenuation of graphic trace with a reduction of the areas with the lowest and most elevated gray classes was observed. In the control group, no significant variations of graphic traces were observed. Moreover, raloxifene treatment significantly reduced IGF-1 and increased IGFBP-3 and SHBG plasma levels at 24 months. During follow-up, IGF-1, IGFPB-3, and SHBG levels did not change significantly in the control group. Conclusions: Long-term treatment with raloxifene in a population of postmenopausal women is able to reduce breast density. Such an effect could perhaps explain the reduction in the incidence of mammary carcinoma observed in the Multiple Outcomes of Raloxifene Evaluation study probably due to the direct antiestrogenic activity of raloxifene on mammalian tissue and/or its indirect activity increasing SHBG levels or modifying the IGF-1/IGFBP-3 ratio.

Zoledronic acid acutely increases sclerostin serum levels in women with postmenopausal osteoporosis.

CONTEXT Sclerostin is a circulating inhibitor of the Wnt-signaling pathway produced by osteocytes, which acts as a negative regulator of bone formation. Effects of zoledronic acid on sclerostin serum levels in postmenopausal osteoporosis are unknown. OBJECTIVE The purpose of this study was to evaluate sclerostin serum levels after zoledronic acid administration and correlate variations with bone turnover markers. DESIGN AND SETTING We conducted a prospective intervention study in an ambulatory care setting. PARTICIPANTS AND INTERVENTION Forty women (mean age 62.6 ± 4.9 years) with postmenopausal osteoporosis were enrolled in this study and randomized into 2 groups to receive zoledronic acid (5 mg) or placebo. MAIN OUTCOMES MEASURES At baseline and then at 2, 7, 30, and 360 days after zoledronic acid or placebo administration, serum levels of sclerostin, bone-specific alkaline phosphatase (BSAP), as a bone formation marker, and serum C-telopeptide of type 1 collagen (CTX), as a bone resorption marker, were measured. RESULTS Sclerostin serum levels increased by day 2, reached a peak at day 7 (3-fold baseline, P < .001), and then decreased at day 30 and returned near to baseline after 360 days in the zoledronic acid group. Both CTX and BSAP were reduced, and a significant negative correlation was observed between the percentage changes of sclerostin and the variation in BSAP and CTX at all time points in the zoledronic acid group (P < .05). No changes were observed in the placebo group. CONCLUSIONS Our data demonstrate that zoledronic acid increases sclerostin serum levels and that sclerostin could play a role in coupling bone resorption to bone formation.

Fracture Risk in Type 2 Diabetes: Current Perspectives and Gender Differences

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of osteoporotic fractures, resulting in disabilities and increased mortality. The pathophysiological mechanisms linking diabetes to osteoporosis have not been fully explained, but alterations in bone structure and quality are well described in diabetic subjects, likely due to a combination of different factors. Insulin deficiency and dysfunction, obesity and hyperinsulinemia, altered level of oestrogen, leptin, and adiponectin as well as diabetes-related complications, especially peripheral neuropathy, orthostatic hypotension, or reduced vision due to retinopathy may all be associated with an impairment in bone metabolism and with the increased risk of fractures. Finally, medications commonly used in the treatment of T2DM may have an impact on bone metabolism and on fracture risk, particularly in postmenopausal women. When considering the impact of hypoglycaemic drugs on bone, it is important to balance their potential direct effects on bone quality with the risk of falling-related fractures due to the associated hypoglycaemic risk. In this review, experimental and clinical evidence connecting bone metabolism and fracture risk to T2DM is discussed, with particular emphasis on hypoglycaemic treatments and gender-specific implications.

Hepatic osteodystrophy: Does the osteoprotegerin/receptor activator of nuclear factor-kB ligand systemplay a role?

Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease (CLD). Recently, two new cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor-kB ligand (RANKL), have been implicated in the pathogenesis of post-menopausal osteoporosis and other metabolic bone diseases. Therefore, the aim of our study was to evaluate bone metabolism, bone mineral density (BMD) and OPG/RANKL system in 65 male patients with CLD and in 65 healthy controls. Our patients showed lower BMD values than controls both at lumbar and femoral levels. Moreover, they had an unbalanced bone turnover with an increased resorption phase, as shown by high levels of urinary deoxypyridinoline and a decreased formation phase, as shown by the slightly, but significant, low levels of bone-alkaline phosphatase. Patients showed lower plasma levels of free-testosterone than controls and higher—although not significantly so—plasma levels of 17 β-estradiol. Furthermore, patients with CLD had higher levels of sex hormone-binding globulin and OPG, and lower levels of 25-hydroxyvitamin D (25-HOD)and IGF-I than the control group, while RANKL levels were similar in the two groups. In conclusion, our data do not confirm the hypothesis that the OPG/RANKL system could exert a key role in the pathogenesis of hepatic osteodystrophy, but rather that the observed increase in OPG levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption.

Phalangeal quantitative ultrasound and metabolic control in pre-menopausal women with type 1 diabetes mellitus.

Background: Several studies have reported increased fracture risk in Type 1 diabetes mellitus (T1 DM). Quantitative Ultrasound (QUS) provides information on the structure and elastic properties of bone, which are important determinants of fracture risk, along with bone mineral density. Aim: To study phalangeal sites by QUS, examine bone turnover markers and analyze association between these factors with metabolic control in a population of pre-menopausal women with T1 DM. Material and methods: Thirty-five T1 DM pre-menopausal women (mean age 34.5±6.8 yr) attending the Diabetic Outpatients Clinic in the Department of Internal Medicine, University of Messina, were consecutively enrolled and divided into two groups, taking into account the mean value of glycated hemoglobin in the last three years. Twenty healthy age-matched women served as controls. Phalangeal ultrasound measurements [Amplitude Dependent Speed of Sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), T-Score, Z-Score] were performed using a DBM Sonic Bone Profiler. Osteocalcin and deoxypyridinoline served as markers of bone formation and bone resorption, respectively. Results: T1 DM women with poor metabolic control showed lower phalangeal QUS values compared to healthy controls (p<0.01) and T1 DM women with good metabolic control (p<0.05). No significant differences in QUS measurements were detected between T1DM women with good metabolic control and healthy controls. Lower bone formation and increased bone resorption, although not statistically significant, were observed in patients with poor metabolic control in comparison to patients with good metabolic control. Conclusions: Poor metabolic control may worsen the quality of bone in T1 DM. Phalangeal QUS could be considered as a tool to screen T1 DM women for osteoporosis in pre-menopausal age.

Hypocalcemia: a sometimes overlooked cause of heart failure in the elderly

Heart failure, a common condition affecting older patients, is associated with increased hospitalization and mortality rates among geriatric patients. We describe the case of an 86-year-old woman with moderate renal failure, who presented pulmonary edema and severe myocardial dysfunction due to hypocalcemia. Renal failure, but also the combination of additional factors, may have contributed to hypocalcemia, including vitamin D deficiency, loop diuretics and glucocorticoid therapy — which alone can give rise to sodium retention and calciuresis, and worsens hypocalcemia. Although in animal experiments hypocalcemia has been shown to lead to cardiac decompensation, heart failure from hypocalcemia is quite rare in clinical practice. Calcium plays a key role in cardiac muscle contraction and metabolism. It is recommended that physicians check serum calcium levels in the elderly, as hypocalcemia is a reversible cause of heart failure.