Alcedo, Joy

Flatt, Thomas

Pasyukova, Elena G.

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EDITORIALpublished: 27 June 2013doi: 10.3389/fgene.2013.00124The role of the nervous system in aging and longevityJoy Alcedo1*†, Thomas Flatt 2*† and Elena G. Pasyukova3*†1 Department of Biological Sciences, Wayne State University, Detroit, MI, USA2 Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland3 Laboratory of Genome Variation, Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia*Correspondence: joy.alcedo@wayne.edu; thomas.flatt@unil.ch; egpas@rambler.ru†These authors have contributed equally to this work.Edited by:Blanka Rogina, University of Connecticut Health Center, USAThe connections between the nervous system, aging and longevityare manifold and profound. On the one hand, the nervous sys-tem plays an important role in processing complex informationfrom the environment, which has a major influence on an ani-mal’s aging and longevity. Accordingly, environmental signals arereceived and integrated by this organ system, leading to diversephysiological outputs that can have pervasive effects on home-ostasis and lifespan. Thus, an animal’s nervous system not onlycontrols its homeostatic responses but can also alter its lifespanand aging process. On the other hand, similar to the feedbackregulation that characterizes homeostatic mechanisms, aging alsoimpacts the functional state of the nervous system, as exemplified,for instance, by the prevalence of age-associated neurodegenera-tive diseases.The lead review (Alcedo et al., 2013) in this collection of arti-cles introduces different aspects of neuronal inputs and outputsof signaling pathways that affect homeostasis, and consequentlylongevity and aging. A number of these inputs, which can bedetected by sensory neurons acting at the interface between ananimal’s external and internal environments, have been found toeither shorten or lengthen lifespan. Jeong et al. (2012) describemore explicitly how gustatory, olfactory and thermosensory cuesaffect invertebrate lifespan and the possible implications onmam-malian aging. In mammals, these sensory cues likely modulatehypothalamic function and the neuroendocrine systems requiredfor maintaining homeostasis [reviewed in Alcedo et al. (2010,2013); Jeong et al. (2012)]. Consistent with this notion, Bartfaiand Conti (2012) discuss how nutrient signals act on heat-sensing hypothalamic neurons to regulate energy expenditure bymaintaining mammalian core body temperature, which has beenpreviously shown to affect lifespan (Conti et al., 2006).In addition to nutritional and temperature cues, the ner-vous system can sense other environmental cues and stressors(Alcedo et al., 2013). Iranon and Miller (2012) focus on onesuch stressor—i.e., low oxygen availability, which compromisesmany important physiological processes; in their paper, theauthors review the mechanisms animals use to maintain oxy-gen homeostasis in response to hypoxia. In contrast, Kagias et al.(2012) elaborate on different types of stressors and the neuronalresponses that these elicit. Besides extrinsic environmental fac-tors, they also discuss how the processes of development andaging generate intrinsic stress (Kagias et al., 2012).Neuronal inputs are integrated by neural circuits, which canthen lead to longevity-modulating outputs. Because of the centralrole that calcium signaling plays in processing neural infor-mation, Nikoletopoulou and Tavernarakis (2012) highlight theimportance of maintaining calcium homeostasis. They discusshow loss of calcium homeostasis increases the risk for neu-rodegenerative diseases and how aging itself can impair thishomeostasis (Nikoletopoulou and Tavernarakis, 2012). Calciumhomeostasis requires the coordinated function of differentorganelles, including that of the mitochondria (Nikoletopoulouand Tavernarakis, 2012). Troulinaki and Bano (2012) furtherunderscores the involvement of mitochondria in known longevitypathways and their dual role in aging and neurodegeneration.They review how the decline of mitochondrial activity signifi-cantly contributes to age-related impairment of neural circuits(Troulinaki and Bano, 2012).Consistent with this idea, several reviews discuss evidencesuggesting that impaired, aging neurons can modulate the func-tional outputs of the nervous system, such as protein homeostasis(David, 2012), learning, memory (Stein and Murphy, 2012), andemotional state (McKinney et al., 2012). The review of David(2012) focuses on the role of protein aggregation and protein-quality control in the aging brain. Of note, several reviewsdiscuss how neuronal signaling upon mitochondrial dysfunc-tion, in addition to other stimuli, plays a role in coordinatingthe mitochondrial unfolded protein response, which in turnaffects protein misfolding and polyglutamine aggregation in non-neuronal tissues (David, 2012; Kagias et al., 2012; Alcedo et al.,2013).McKinney et al. (2012) and Stein and Murphy (2012) presentother mechanisms through which aging neurons affect the rate oforganismal senescence. The impact of neuronal aging on cogni-tive and psychological states can be observed through consistentand specific age-dependent gene expression changes in the brain.The review by McKinney et al. (2012) also supports the impor-tant notion that naturally occurring individual variation in therates of gene expression changes during brain aging can deter-mine the onset of senescence and of developing age-related braindisorders. Last but not least, the paper by Huffman (2012) reviewsthe intimate links between the regulation of development andaging by discussing how patterns of neocortical gene expressionand neocortical sensory-motor axonal connections develop andchange throughout the lifespan of the animal and how they affectaging.Collectively, the reviews in this Special Topic provide ampleevidence from recent literature that show how aging is modulatedby a complex interplay between the environment, genes, signal-ing networks and tissues. In particular, they highlight the keyrole in aging and longevity played by the nervous system, whichis the central integrator of information from both the externalwww.frontiersin.org June 2013 | Volume 4 | Article 124 | 1Alcedo et al. The role of the nervous system in aging and longevityenvironment and the inner “milieu” intrinsic to the organism.In discussing the state-of-the-art, these papers also illustratekey areas for future work. For example, our current under-standing of the sensory perception of environmental cues andthe signals that integrate and process these cues in affect-ing lifespan and aging is still very limited. Moreover, majorand unresolved questions remain about the mechanistic rela-tionship between the neuronal regulation of lifespan and thesenescence of neuronal and cognitive function. Finally, we stilllack essential information on the evolutionary conservation ofthe neuronal inputs and outputs of longevity and aging. Suchinformation might prove to be extremely helpful in generatingtherapeutic/pharmacological interventions in the future. As isclearly demonstrated by the review articles in this Special Topic,the neurobiology of aging is a rapidly developing field; at thesame time, numerous difficult problems remain to be solved infuture work, making this vibrant field a major frontier in agingresearch.REFERENCESAlcedo, J., Flatt, T., and Pasyukova,E. G. (2013). Neuronal inputsand outputs of aging andlongevity. Front. Genet. 4:71.doi: 10.3389/fgene.2013.00071Alcedo, J., Maier, W., and Ch’ng,Q. (2010). “Sensory influenceon homeostasis and lifespan:molecules and circuits,” in ProteinMetabolism and Homeostasisin Aging, ed. N. Tavernarakis(Austin, TX: Landes Bioscience),197–210.Bartfai, T., and Conti, B. (2012).Molecules affecting hypothalamiccontrol of core body temper-ature in response to calorieintake. Front. Genet. 3:184. doi:10.3389/fgene.2012.00184Conti, B., Sanchez-Alavez, M., Winsky-Sommerer, R., Morale, M. C.,Lucero, J., Brownell, S., et al. (2006).Transgenic mice with a reduced corebody temperature have an increasedlife span. Science 314, 825–828.David, D. C. (2012). Aging andthe aggregating proteome.Front. Genet. 3:247. doi:10.3389/fgene.2012.00247Huffman, K. (2012). The developing,aging neocortex: how genetics andepigenetics influence early develop-mental patterning and age-relatedchange. Front. Genet. 3:212. doi:10.3389/fgene.2012.00212Iranon, N. N., and Miller, D. L.(2012). Interactions betweenoxygen homeostasis, food avail-ability, and hydrogen sulfidesignaling. Front. Genet. 3:257. doi:10.3389/fgene.2012.00257Jeong, D.-E., Artan, M., Seo, K., andLee, S.-J. (2012). Regulation oflifespan by chemosensory andthermosensory systems: find-ings in invertebrates and theirimplications in mammalianaging. Front. Genet. 3:218. doi:10.3389/fgene.2012.00218Kagias, K., Nehammer, C., andPocock, R. (2012). Neuronalresponses to physiologicalstress. Front. Genet. 3:222. doi:10.3389/fgene.2012.00222McKinney, B. C., Oh, H., and Sibille,E. (2012). Age-by-disease biologicalinteractions: implications for late-life depression. Front. Genet. 3:237.doi: 10.3389/fgene.2012.00237Nikoletopoulou, V., and Tavernarakis,N. (2012). Calcium homeostasis inaging neurons. Front. Genet. 3:200.doi: 10.3389/fgene.2012.00200Stein, G. M., and Murphy, C. T. (2012).The intersection of aging, longevitypathways, and learning andmemoryin C. elegans. Front. Genet. 3:259.doi: 10.3389/fgene.2012.00259Troulinaki, K., and Bano, D.(2012). Mitochondrial defi-ciency: a double-edged swordfor aging and neurodegenera-tion. Front. Genet. 3:244. doi:10.3389/fgene.2012.00244Received: 07 June 2013; accepted: 09 June2013; published online: 27 June 2013.Citation: Alcedo J, Flatt T and PasyukovaEG (2013) The role of the nervous sys-tem in aging and longevity. Front. Genet.4:124. doi: 10.3389/fgene.2013.00124This article was submitted to Frontiers inGenetics of Aging, a specialty of Frontiersin Genetics.Copyright © 2013 Alcedo, Flatt andPasyukova. This is an open-access articledistributed under the terms of theCreative Commons Attribution License,which permits use, distribution andreproduction in other forums, providedthe original authors and source arecredited and subject to any copyrightnotices concerning any third-partygraphics etc.Frontiers in Genetics | Genetics of Aging June 2013 | Volume 4 | Article 124 | 2

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