The Genetics of Human Longevity

Capri, Miriam; Salvioli, Stefano; Sevini, Federica; Valensin, Silvana; Celani, Laura; Monti, Daniela; Pawelec, Graham; Benedictis, G. De; Gonos, Efstathios S.; Franceschi, Claudio

doi:10.1196/annals.1354.033

Cited by 129 publications

(57 citation statements)

References 57 publications

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“…These factors, which may include parasite GPI, mammalian insulin or IGF, and mosquito NO and ILPs, may function synergistically along a dose-response continuum or they may act antagonistically so that the resource-intensive physiologies of reproduction and immunity are coordinately fine-tuned to maximize the benefits of blood feeding. Further, in mammals and nematodes, a second evolutionarily conserved growth factor signaling pathway regulated by the transforming growth factor (TGF)-βs, a large superfamily of proteins that includes growth factors and immunomodulatory cytokines, extensively intersects the insulin signaling pathway to regulate aging, oxidative stress, and immunity [69][70][71][72][73]. Like the insulin signaling pathway, the TGF-β signaling pathway regulates the NO-dependent immune response in An.…”

Section: Insulin Signaling and Its Impact On Malaria Transmissionmentioning

confidence: 99%

The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

Luckhart

Riehle

2007

Developmental & Comparative Immunology

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As revealed over the past twenty years, the insulin signaling cascade plays a central role in regulating immune and oxidative stress responses that affect the life spans of mammals and two model invertebrates, the nematode Caenorhabitis elegans and the fruit fly Drosophila melanogaster. In mosquitoes, insulin signaling regulates key steps in egg maturation and immunity and likely affects aging, although the latter has yet to be examined in detail. Reproduction, immunity and aging critically influence the capacity of mosquitoes to effectively transmit malaria parasites. Current work has demonstrated that molecules from the invading parasite and the blood meal elicit functional responses in female mosquitoes that are regulated through the insulin signaling pathway or by crosstalk with interacting pathways. Defining the details of these regulatory interactions presents significant challenges for future research, but will increase our understanding of mosquito/malaria parasite transmission and of the conservation of insulin signaling as a key regulatory nexus in animal biology. Keywordsinsulin; Anopheles; Plasmodium; mosquito; malaria; aging; oxidative stress; innate immunity; nitric oxide; transforming growth factor; β In all well-studied metazoans, metabolism, growth, and longevity are coordinately regulated via a nexus that involves signaling cascades activated by insulin and insulin-like growth factors (IGF). Although these pathways differ in downstream physiological effects and some of their signaling proteins, the proteins themselves and their scaffolding interactions are largely conserved among model organisms ( Fig. 1), particularly in the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse Mus musculus. This review will examine our current understanding of how the insulin and IGF signaling cascades (ISC) regulate immunity in these diverse model organisms. In addition, we will explore how recent Correspondence to: Shirley Luckhart. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Key targets of daf-16 regulation include genes for mitochondrial manganese superoxide dismutase (MnSOD) and glutathione S-transferase, which are closely linked to aging in C. elegans and other organisms, and genes for numerous C-type lectins, which play critical roles in cell adhesion and pathogen recognition [5]. Downregulation of these gene targets in daf-16 mutants would be predicted to enhance oxidative stress, which has been linked directly to aging in C. elegans [6,7], and decrease pathogen recognition [8]. Conversely, rescue of downregulated MnSOD...

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Section: Insulin Signaling and Its Impact On Malaria Transmissionmentioning

confidence: 99%

The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

Luckhart

Riehle

2007

Developmental & Comparative Immunology

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“…1 Unfortunately, such relationships are generally difficult to study. The investigation of all-cause mortality data can provide insight into the phenotypic pleiotropy or significant associations between a systemic disease and another condition.…”

Section: Introductionmentioning

confidence: 99%

Mortality in primary open-angle glaucoma: ‘two cupped discs and a funeral’

Hewitt

Sanfilippo

Ring

et al. 2009

Eye

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Purpose The aim of this study was to investigate the causes of mortality in individuals with open-angle glaucoma (OAG). Methods All-cause mortality data from the Registry of Births, Deaths and Marriages for the Australian state of Tasmania, for all people who were at least 40 years of age at the time of death, were classified using International Classification of Diseases-10 guidelines. This information was cross-referenced to identify participants in the Glaucoma Inheritance Study in Tasmania (GIST) who had died. Contingency tables were used for crude analysis and then models were constructed, adjusting for age at death as well as gender. Results Between 1996 and 2005, a total of 33 879 deaths were recorded. Data were unavailable for 4868 (14.4%) people. The mean age at death for the study sample was 78.4 ± 11.5 (range 41-109) years. Of those cases known to have OAG by their participation in GIST (n ¼ 2409), full mortality data were available for 741 (92.0%). Following adjustment for the age at death and male gender, the odds ratio for death due to ischaemic heart disease in people with OAG compared to the general population not known to have OAG was significant (OR ¼ 1.30, 95% CI: 1.08-1.56; P ¼ 0.006). Crude analysis revealed that there were significantly fewer people with OAG who died due to metastatic cancer (Po0.001); however, this did not remain significant following adjustment for age and gender. Conclusion The pathoaetiological relationship between OAG and ischaemic heart disease is unclear and requires further investigation. Increased awareness of the association between cardiovascular disease and OAG is warranted.

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“…Both of these genes and the majority of other potential findings that have emerged during the past decade (de Magalhães et al 2009a, b;Capri et al 2006Capri et al , 2008Pawlikowska et al 2009;Bonafè and Olivieri 2009;Singh et al 2007) are related mainly to inflammation, stress response or lipid and glucose metabolism.…”

Section: Introductionmentioning

confidence: 99%

Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes

Spazzafumo

Olivieri

Abbatecola

et al. 2011

AGE

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Factor structure analyses have revealed the presence of specific biological system markers in healthy humans and diseases. However, this type of approach in very old persons and in type 2 diabetes (T2DM) is lacking. A total sample of 2,137 Italians consisted of two groups: 1,604 healthy and 533 with T2DM. Age (years) was categorized as adults (≤65), old (66-85), oldest old (>85-98) and centenarians (≥99). Specific biomarkers of routine haematological and biochemical testing were tested across each age group. Exploratory factorial analysis (EFA) by principal component method with Varimax rotation was used to identify factors including related variables. Structural equation modelling (SEM) was applied to confirm factor solutions for each age group. EFA and SEM identified specific factor structures according to age in both groups. An age-associated reduction of factor structure was observed from adults to oldest old in the healthy group (explained variance 60.4% vs 50.3%) and from adults to old in the T2DM group AGE

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The Genetics of Human Longevity

Cited by 129 publications

References 57 publications

The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

Mortality in primary open-angle glaucoma: ‘two cupped discs and a funeral’

Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes

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