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      Low circulating IGF-I bioactivity is associated with human longevity: Findings in centenarians’ offspring

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          Abstract

          Centenarians’ offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay, total IGF-I, IGFBP-3, total IGF-II, insulin, glucose, HOMA2-B% and HOMA2-S% in 192 centenarians’ offspring and 80 offspring-controls of which both parents died relatively young. Both groups were well-matched for age, gender and BMI with the centenarians’ offspring. IGF-I bioactivity (p<0.01), total IGF-I (p<0.01) and the IGF-I/IGFBP-3 molar ratio (p<0.001) were significantly lower in centenarians’ offspring compared to offspring matched-controls. Serum insulin, glucose, HOMA2-B% and HOMA2-S% values were similar between both groups. In centenarians’ offspring IGF-I bioactivity was inversely associated to insulin sensitivity. In conclusion: 1) centenarians’ offspring had relatively lower circulating IGF-I bioactivity compared to offspring matched-controls; 2) IGF-I bioactivity in centenarians’ offspring was inversely related to insulin sensitivity. These data support a role of the IGF-I/insulin system in the modulation of human aging process.

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          Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

          In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.
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            Age-related changes in total and regional fat distribution.

            Aging is associated with progressive changes in total and regional fat distribution that have negative health consequences. Indeed, a preferential increase in abdominal fat, in particular visceral fat, combined with a decrease in lower body subcutaneous fat are commonly cited in the literature. These age-related changes in body composition can occur independent of changes in total adiposity, body weight or waist circumference, and represent a phenotype closely associated with increased morbidity and mortality risk. Tissues such as the heart, liver and skeletal muscle in the elderly have increased fat deposition, which increases risk for insulin resistance and cardiovascular disease. Furthermore, aging is associated with increased fat content within bone marrow, which exposes the elderly to fracture risk beyond that associated with low bone mineral density alone. Many of the age-associated body compositional changes cannot be detected by simple anthropometric measures alone, and the influence of gender, race or ethnicity, and physical activity patterns on these changes is unclear. This review will explore some of these age-related changes in total and regional fat distribution. Consideration will also be given to the strengths and limitations associated with some of the anthropometric methodologies employed for assessing these changes.
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              Evolutionary medicine: from dwarf model systems to healthy centenarians?

              Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                ImpactJ
                Aging (Albany NY)
                Impact Journals LLC
                1945-4589
                September 2012
                9 September 2012
                : 4
                : 9
                : 580-589
                Affiliations
                1 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
                2 IRCCS Istituto Auxologico Italiano, Milan, Italy
                3 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
                4 Geriatric Unit IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, Milan, Italy
                5 Dipartimento di Informatica, Sistemistica e Comunicazione, Universita' degli Studi di Milano Bicocca, Milan, Italy
                6 Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy
                7 C.I.G. Interdepartmental Center “L. Galvani”, University of Bologna, Bologna, Italy
                8 Department of Experimental Pathology, University of Bologna, Bologna, Italy
                Author notes
                Correspondence to: Giovanni Vitale, PhD; giovanni.vitale@ 123456unimi.it
                Article
                10.18632/aging.100484
                3492223
                22983440
                eb9c04bd-9127-4a0b-bac1-9056d946cdcf
                Copyright: © 2012 Vitale et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 28 June 2012
                : 8 September 2012
                Categories
                Research Paper

                Cell biology
                insulin receptors,longevity,igf-i receptors,centenarians,centenarians’ offspring,igf-i bioactivity

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