Insulin/IGF-I-signaling pathway: An evolutionarily conserved mechanism of longevity from yeast to humans

University of Bologna, Bolonia, Emilia-Romagna, Italy
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 12/2003; 285(5):E1064-71. DOI: 10.1152/ajpendo.00296.2003
Source: PubMed


Although the underlying mechanisms of longevity are not fully understood, it is known that mutation in genes that share similarities with those in humans involved in the insulin/insulin-like growth factor I (IGF-I) signal response pathway can significantly extend life span in diverse species, including yeast, worms, fruit flies, and rodents. Intriguingly, the long-lived mutants, ranging from yeast to mice, share some important phenotypic characteristics, including reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-I plasma levels. Such genetic homologies and phenotypic similarities between insulin/IGF-I pathway mutants raise the possibility that the fundamental mechanism of aging may be evolutionarily conserved from yeast to mammals. Very recent findings also provide novel and intriguing evidence for the involvement of insulin and IGF-I in the control of aging and longevity in humans. In this study, we focus on how the insulin/IGF-I pathway controls yeast, nematode, fruit fly, and rodent life spans and how it is related to the aging process in humans to outline the prospect of a unifying mechanism in the genetics of longevity.

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    • "Reductions in IGF-I activity with age are associated with reductions in SkM size and function. However, reduced signalling through the IIS pathway is also associated with increased lifespan and healthspan in model organisms (Clancy et al., 2001; Holzenberger et al., 2002; Barbieri et al., 2003; Tatar et al., 2003; Giannakou & Partridge, 2007; Piper et al., 2008; Selman et al., 2008; Vallejo et al., 2009; Kenyon, 2011; Selman et al., 2011). "
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    ABSTRACT: Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 04/2015; 14(4):511-23. DOI:10.1111/acel.12342 · 6.34 Impact Factor
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    • "Insulin/IGF-1 signaling responds adaptively to metabolic states, including calorie restriction, intermittent fasting, exercise and stress (Lee et al., 2014). The insulin/IGF-1 signaling pathway is evolutionarily conserved and plays a regulating role in the rate of aging across the organisms from yeast to humans (Barbieri et al., 2003; Dupont and Holzenberger, 2003; Kenyon, 2011; Shimokawa et al., 2003). Calorie restriction and exercise reduce circulating IGF-1 levels (Anisimov et al., 2005), but may increase cellular sensitivity to IGF-1. "
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    ABSTRACT: The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. In this perspective article, we describe some of the signaling pathways relevant to cellular energy metabolism that are modulated by 'neurohormetic phytochemicals' (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders. Published by Elsevier Ltd.
    Neurochemistry International 04/2015; 89. DOI:10.1016/j.neuint.2015.03.009 · 3.09 Impact Factor
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    • "From invertebrates to vertebrates, the insulin/IGF-1-like signaling pathway (IIS) is evolutionary conservation and plays an important role in regulating animal development and pathology [1]–[4]. In vertebrates, phosphatidylinositol 3-kinase (PI3K) is activated to generate phosphatidylinositol 3, 4, 5-triphosphate (PIP3) when the cell membrane-localized IIS receptor is stimulated by insulin or IGF-1. "
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    ABSTRACT: DAF-16 target genes are employed as reporters of the insulin/IGF-1 like signal pathway (IIS), and this is notably true when Caenorhabditis elegans (C. elegans) is used to study the action of anti-aging compounds on IIS activity. However, some of these genes may not be specific to DAF-16, even if their expression levels are altered when DAF-16 is activated. Celecoxib was reported to extend the lifespan of C. elegans through activation of DAF-16. Our results confirmed the function of celecoxib on aging; however, we found that the expression of ins-7, a DAF-16 target gene, was abnormally regulated by celecoxib. ins-7 plays an important role in regulating aging, and its expression is suppressed in C. elegans when DAF-16 is activated. However, we found that celecoxib upregulated the expression of ins-7 in contrast to its role in DAF-16 activation. Our subsequent analysis indicated that the expression level of ins-7 in C. elegans was negatively regulated by DAF-16 activity. Additionally, its expression was also positively regulated by DAF-16-independent mechanisms, at least following external pharmacological intervention. Our study suggests that ins-7 is not a specific target gene of DAF-16, and should not be chosen as a reporter for IIS activity. This conclusion is important in the study of INSs on aging in C. elegans, especially under the circumstance of drug intervention.
    PLoS ONE 06/2014; 9(6):e100320. DOI:10.1371/journal.pone.0100320 · 3.23 Impact Factor
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