Promoting longevity by maintaining metabolic and proliferative homeostasis - PubMed (original) (raw)
Review
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.
Figures
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.
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.
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).
Similar articles
- Lifespan extension by preserving proliferative homeostasis in Drosophila.
Biteau B, Karpac J, Supoyo S, Degennaro M, Lehmann R, Jasper H. Biteau B, et al. PLoS Genet. 2010 Oct 14;6(10):e1001159. doi: 10.1371/journal.pgen.1001159. PLoS Genet. 2010. PMID: 20976250 Free PMC article. - JNK Signaling in Drosophila Aging and Longevity.
Gan T, Fan L, Zhao L, Misra M, Liu M, Zhang M, Su Y. Gan T, et al. Int J Mol Sci. 2021 Sep 6;22(17):9649. doi: 10.3390/ijms22179649. Int J Mol Sci. 2021. PMID: 34502551 Free PMC article. Review. - JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling.
Wang MC, Bohmann D, Jasper H. Wang MC, et al. Cell. 2005 Apr 8;121(1):115-25. doi: 10.1016/j.cell.2005.02.030. Cell. 2005. PMID: 15820683 - Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz.
Hull-Thompson J, Muffat J, Sanchez D, Walker DW, Benzer S, Ganfornina MD, Jasper H. Hull-Thompson J, et al. PLoS Genet. 2009 Apr;5(4):e1000460. doi: 10.1371/journal.pgen.1000460. Epub 2009 Apr 24. PLoS Genet. 2009. PMID: 19390610 Free PMC article. - Regulation of Drosophila lifespan by JNK signaling.
Biteau B, Karpac J, Hwangbo D, Jasper H. Biteau B, et al. Exp Gerontol. 2011 May;46(5):349-54. doi: 10.1016/j.exger.2010.11.003. Epub 2010 Nov 25. Exp Gerontol. 2011. PMID: 21111799 Free PMC article. Review.
Cited by
- Analysis of Cancer-Resisting Evolutionary Adaptations in Wild Animals and Applications for Human Oncology.
Zhang BK, Gines L. Zhang BK, et al. J Mol Evol. 2024 Sep 11. doi: 10.1007/s00239-024-10204-w. Online ahead of print. J Mol Evol. 2024. PMID: 39256250 Review. - JAK/STAT mediated insulin resistance in muscles is essential for effective immune response.
McMullen E, Strych L, Chodakova L, Krebs A, Dolezal T. McMullen E, et al. Cell Commun Signal. 2024 Apr 2;22(1):203. doi: 10.1186/s12964-024-01575-0. Cell Commun Signal. 2024. PMID: 38566182 Free PMC article. - Azot expression in the Drosophila gut modulates organismal lifespan.
Merino MM. Merino MM. Commun Integr Biol. 2022 Dec 28;16(1):2156735. doi: 10.1080/19420889.2022.2156735. eCollection 2023. Commun Integr Biol. 2022. PMID: 36606245 Free PMC article. - Beyond the Lab: What We Can Learn about Cancer from Wild and Domestic Animals.
Schraverus H, Larondelle Y, Page MM. Schraverus H, et al. Cancers (Basel). 2022 Dec 14;14(24):6177. doi: 10.3390/cancers14246177. Cancers (Basel). 2022. PMID: 36551658 Free PMC article. Review. - Honeysuckle extract (Lonicera pallasii L.) exerts antioxidant properties and extends the lifespan and healthspan of Drosophila melanogaster.
Golubev D, Zemskaya N, Shevchenko O, Shaposhnikov M, Kukuman D, Patov S, Punegov V, Moskalev A. Golubev D, et al. Biogerontology. 2022 Apr;23(2):215-235. doi: 10.1007/s10522-022-09954-1. Epub 2022 Feb 5. Biogerontology. 2022. PMID: 35122571
References
- Accili D., Arden K. C. (2004). Foxos at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421-426 - PubMed
- Aguirre V., Uchida T., Yenush L., Davis R., White M. F. (2000). The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 275, 9047-9054 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- R01 AG028127/AG/NIA NIH HHS/United States
- R01 GM100196/GM/NIGMS NIH HHS/United States
- NIH RO1 GM100196/GM/NIGMS NIH HHS/United States
- NIH RO1 AG028127/AG/NIA NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases