Promoting longevity by maintaining metabolic and proliferative homeostasis - PubMed (original) (raw)

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Promoting longevity by maintaining metabolic and proliferative homeostasis

Lifen Wang et al. J Exp Biol. 2014.

Abstract

Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster. The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality. Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine.

Keywords: Aging; Drosophila; Homeostasis.

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Figures

Fig. 1.

Fig. 1.

Summary of endocrine interactions regulating metabolic and proliferative homeostasis in Drosophila. Tissue systems and endocrine signals that mediate specific responses to dietary changes and stress to maintain homeostasis in the adult animal are summarized. Drosophila insulin-like peptides (Dilps) play a central role in the regulation of metabolic and proliferative homeostasis in flies by coordinating multiple metabolic and regenerative responses to nutritional and stress conditions. This includes regulation of metabolic activity in the fat body, survival in hemocytes, and regeneration in the intestinal epithelium. Dilps secreted from peripheral tissues (Dilp6 in the fat body and Dilp3 in the intestine) control metabolic and proliferative activity locally, and may interact with insulin-producing cells (IPCs) in the brain to regulate the expression and secretion of brain-derived Dilps. Secretion of brain-derived Dilps is also regulated by stress signals (Jun-N-terminal kinase, JNK) and by fat-body-derived hormones such as Unpaired2 (Upd2). 4E-BP, eukaryotic translation initiation factor 4E binding protein; Foxo, Forkhead box protein O; InR, insulin receptor; Slif, slimfast.

Fig. 2.

Fig. 2.

Relationship between insulin signaling activity and stress/innate immune signaling in the control of homeostasis and lifespan. Stress signaling through Jun-N-terminal kinase (JNK) and innate immune signaling though NFkB can inhibit insulin signaling activity both systemically and locally. This antagonism between stress and insulin signaling influences both metabolic and proliferative tissue homeostasis in flies, significantly impacting lifespan (Biteau et al., 2010; Karpac et al., 2011). In conditions in which insulin signaling is high and JNK signaling is low (for example, in conditions of abundant nutrient intake in wild-types or in genetic conditions optimizing insulin signaling), longevity (black line) is low. When insulin signaling is moderately reduced or JNK signaling is activated (under calorie restriction or in genetic conditions leading to moderate increases of JNK or reduced insulin signaling capacity), tissue and metabolic homeostasis are maximized, increasing lifespan. When JNK is chronically or excessively activated (in conditions of stress or inflammation), or when insulin signaling is strongly impaired (strong loss-of-function mutations in insulin signaling components), lifespan declines again.

Fig. 3.

Fig. 3.

Control of tissue regeneration in the Drosophila intestine. (A) The intestinal stem cell lineage in Drosophila. In response to stress, intestinal stem cells (ISCs) divide asymmetrically to give rise to a new ISC and an enteroblast (EB), which differentiates into either an enterocyte (EC) or an enteroendocrine cell (EE). Notch (N) signaling, initiated by a Delta (Dl) signal from the ISC, drives EB differentiation. Depending on the levels of N signaling, EBs differentiate into either EEs or ECs. (B) Age-related changes in homeostasis of the intestinal epithelium. In young animals, the epithelium consists of a monolayer of ECs with interspersed EEs and basally located ISCs. In aging flies, ISCs overproliferate, resulting in the accumulation of misdifferentiated EB-like cells that disrupt structure and function of the intestinal epithelium. This phenotype correlates with an expansion of the commensal bacterial population in the lumen (dark ovals).

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