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      Human insulin/IGF-1 and familial longevity at middle age

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          Abstract

          Recently, we have shown that compared to controls, long-lived familial nonagenarians (mean age: 93.4 years) from the Leiden Longevity Study displayed a lower mortality rate, and their middle-aged offspring displayed a lower prevalence of cardio-metabolic diseases, including diabetes mellitus. The evolutionarily conserved insulin/IGF-1 signaling (IIS) pathway has been implicated in longevity in model organisms, but its relevance for human longevity has generated much controversy. Here, we show that compared to their partners, the offspring of familial nonagenarians displayed similar non-fasted serum levels of IGF-1, IGFBP3 and insulin but lower non-fasted serum levels of glucose, indicating that familial longevity is associated with differences in insulin sensitivity.

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          Most cited references 23

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          Demography. Broken limits to life expectancy.

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            Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein.

            The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.
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              Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study.

              We conducted a sib pair study in very old subjects for the purpose of mapping longevity loci. In the present analysis, we explore whether our recruitment strategy has resulted in a population enriched for a heritable component for exceptional longevity. Our study includes families with at least two long-living siblings (men aged 89 years or above; women aged 91 years or above). Data were collected on date of birth and, if applicable, date of death of parents, brothers and sisters, offspring, and spouses of the long-living participants. Standardised mortality ratios (SMRs) compared with the general Dutch population, were calculated. The SMR for all siblings of the long-living participants was 0.66 (95% CI 0.60-0.73). A similar survival benefit was also observed in the parents (SMR=0.76, 95% CI 0.66-0.87) and in the offspring of the long-living subjects (SMR=0.65, 95% CI 0.51-0.80). The SMR of the spouses of the long-living subjects was 0.95 (95% CI 0.82-1.12). The familial clustering of extended survival is unlikely to be caused by ascertainment bias, because in all analyses the long-living participants were excluded. Moreover, it is also unlikely to be caused by environmental factors, because the spouses of the long-living participants had a mortality risk comparable with the general Dutch population, whereas they share the same environment. We conclude that our sample is genetically enriched for extreme survival.
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                Author and article information

                Journal
                Aging (Albany NY)
                ImpactJ
                Aging
                Impact Journals LLC
                1945-4589
                August 2009
                24 July 2009
                : 1
                : 8
                : 714-722
                Affiliations
                1 Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands
                2 Netherlands Consortium for Healthy Ageing (NCHA)
                3 Department of Clinical Chemistry, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands
                4 Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
                Author notes
                Correspondence: Diana van Heemst, PhD, Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, the Netherlands D.van_Heemst@ 123456lumc.nl
                Article
                2806046
                20157552
                Copyright: ©2009 Rozing 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 work is properly cited.

                Categories
                Research Article

                Cell biology

                igfbp3, familial longevity, glucose handling, igf-1, height

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