Abstract
An animal’s survival strongly depends on its ability to maintain homeostasis in response to the changing quality of its external and internal environment. This is achieved through intracellular and intercellular communication within and among different tissues. One of the organ systems that plays a major role in this communication and the maintenance of homeostasis is the nervous system. Here we highlight different aspects of the neuronal inputs and outputs of pathways that affect aging and longevity. Accordingly, we discuss how sensory inputs influence homeostasis and lifespan through the modulation of different types of neuronal signals, which reflects the complexity of the environmental cues that affect physiology. We also describe feedback, compensatory, and feed-forward mechanisms in these longevity-modulating pathways that are necessary for homeostasis. Finally, we consider the temporal requirements for these neuronal processes and the potential role of natural genetic variation in shaping the neurobiology of aging.
Introduction
The study of aging is the study of an open system, where tissues and organs within the whole animal regularly exchange information not only with each other but also with their external environment during the course of the animal’s lifespan. These exchanges in information allow the animal to maintain a stable internal environment, known as homeostasis, which is necessary for survival amid the constant flux in the animal’s external environment. An important node within this flow of information is the nervous system, which serves as an interface between the animal’s external and internal environments. Not surprisingly, neuronal signaling activities and their regulation have a major influence on the animal’s survival and aging process. Here we address the role of the nervous system in maintaining homeostasis and its consequent impact on longevity and aging.
Signaling Networks: Intracellular, Intercellular, and Interorgan Communication in Homeostatic Maintenance – the Influence on Lifespan
The nervous system is a network of specialized cells that relay information between different organ systems and the environment. Sensory neurons perceive environmental cues, whose information are transmitted to non-neuronal tissues either directly or indirectly via neural circuits that consist of interneurons and/or other types of neurons, like motor neurons. These intercellular and interorgan communications involve different types of signaling molecules that range from small molecule neurotransmitters to neuropeptides and hormones (Figure 1; reviewed in Alcedo et al., ). Indeed, consistent with the findings that the nervous system affects longevity, the processing of environmental information by sensory neurons and the corresponding neural circuitries can modulate hormonal secretions that maintain homeostasis (Figure 1; reviewed in Alcedo et al., ).
Figure 1
Sensory influence on homeostasis and lifespan
Sensory perception can alter a number of physiological processes, from circadian clocks (Wurtman et al., 1963, 1964; la Fleur et al., 2001; Challet et al., ; Ha et al., ), developmental plasticity (Bargmann and Horvitz, ; Schackwitz et al., 1996) and metabolism (Zafra et al., 2006; Greer et al., ) to reproduction (Yoon et al., 2005), and stress responses (Prahlad et al., 2008). Similarly, sensory neurons have been found to affect lifespan in the nematode worm C. elegans (Apfeld and Kenyon, ; Alcedo and Kenyon, ; Bishop and Guarente, ; Lee and Kenyon, 2009) and in the fruit fly Drosophila (Libert et al., 2007; Poon et al., 2010). This influence on lifespan involves positive or negative inputs from gustatory, olfactory, and thermosensory neurons that can modulate the activities of different peptide or steroid hormones (Apfeld and Kenyon, ; Alcedo and Kenyon, ; Libert et al., 2007; Lee and Kenyon, 2009), which would in turn presumably affect different homeostatic mechanisms (reviewed in Fielenbach and Antebi, ; Kenyon, 2010). The above studies demonstrating the sensory influence on C. elegans and Drosophila lifespan have been reviewed in greater detail by Jeong et al. (2012), as part of this Research Topic.
The nature of some of these neurons suggests that some of the cues that affect lifespan are food-derived, which agrees with the observation that some olfactory inputs are involved in the lifespan effects of restricting food intake levels (Libert et al., 2007), a phenomenon that is commonly known as calorie restriction (Klass, 1977; Weindruch and Walford, 1988). However, the longevity-promoting effects of food-level restriction are linked to changes in feeding rates, delayed development, and decreased reproduction (Klass, 1977; Weindruch and Walford, 1988). In contrast, the sensory influence on lifespan does not always correlate with the sensory effects on feeding behaviors, development, and reproduction (Apfeld and Kenyon, ; Alcedo and Kenyon, ; Poon et al., 2010), which suggests that the sensory system will affect lifespan through more than one mechanism. This would be expected since different types of sensory neurons can perceive a wide variety of environmental cues, ranging from temperature (Lee and Kenyon, 2009; Xiao et al., 2013) or the inherent complexity of food sources (Libert et al., 2007; Maier et al., 2010; Poon et al., 2010) to other types of cues, many of which can potentially alter organismal homeostasis and affect lifespan.
Recently, the sensory system has been shown to promote another form of dietary influence on lifespan – dependence on food-type/composition, which is distinct from the lifespan effects of food-level restriction (Maier et al., 2010). This is consistent with the previous observation that only a subset of gustatory and olfactory neurons affects lifespan in a given environment (Alcedo and Kenyon, ), i.e., the presence of a specific set of lifespan-influencing cues in some food sources will only be detected by a specific set of sensory neurons. Indeed, this is supported by the recent identification of a monocarboxylate-like transporter (MCT-1) that mediates the lifespan effects of only certain sensory neurons, suggesting that MCT-1 will transport some, but not all, small metabolites (Gaglia et al., ).
The sensory influence on lifespan via food-type recognition has also been shown to involve the activities of specific neuropeptide signaling pathways under certain environmental conditions (Maier et al., 2010). For example, a neuropeptide neuromedin U pathway processes food-type information that alters C. elegans lifespan, independent of food intake levels (Maier et al., 2010). Considering that many species have a large repertoire of neuropeptide ligands and receptors, many of which are expressed in the nervous system (Bargmann, ; Strand, 1999), these neuropeptide signaling pathways could presumably process distinct sets of sensory information into physiological responses that would optimize survival.
Modulation of lifespan and aging by neuronal insulin/IGF signaling
The sensory influence on lifespan can be mediated by insulin/insulin-like peptides (ILPs) and their corresponding signaling pathway(s), IIS (Apfeld and Kenyon, ; Alcedo and Kenyon, ), which are also known to play a central role in regulating various aspects of growth, development, metabolism, and reproduction. Indeed, among the molecular pathways known to affect longevity, IIS is probably the best-known, and perhaps the most important, mainly due to its major, evolutionarily conserved effects on lifespan in various model organisms, from invertebrates to mammals (reviewed in Tatar et al., 2003; Taguchi and White, 2008; Partridge et al., 2011). Here we provide a brief overview of recent studies suggesting that, among the many tissues affected by this endocrine pathway, IIS action in the central nervous system (CNS) is of special importance for modulating aging and longevity (reviewed in Broughton and Partridge, ).
IIS in the CNS has essentially two roles in aging. On the one hand, it can have local, neuroprotective effects in the CNS itself, for example, by promoting neuronal survival under neurodegenerative conditions (Chrysis et al., ; Schubert et al., 2004; Plum et al., 2005; Bateman and McNeill, ). On the other hand, in response to environmental cues, some of which could be food-derived, CNS-acting factors could regulate the production and release of ILPs, which in turn systemically act to influence whole-organismal aging. Here we focus on such CNS-mediated, lifespan-promoting effects of reduced IIS in worms, flies, and mice (reviewed in Tatar et al., 2003; Fielenbach and Antebi, ; Alcedo et al., ).
The worm C. elegans has 40 genes that are predicted to encode ILPs, many of which are expressed in sensory neurons and interneurons and can function as ligands for the insulin receptor ortholog DAF-2 (Pierce et al., 2001; Li et al., 2003; Cornils et al., ). Consistent with the notion that sensory neurons produce and release ILPs that regulate lifespan by influencing IIS in remote tissues, mutations that cause defects in ciliated sensory neurons or targeted ablation of gustatory and olfactory neurons extend lifespan in a manner that is fully or partially dependent on DAF-16/FOXO, a forkhead transcription factor downstream of IIS that becomes activated when IIS is reduced (Apfeld and Kenyon, ; Alcedo and Kenyon, ; Shen et al., 2010). The central role of the CNS in the IIS modulation of longevity is further underscored by the fact that the extended lifespan due to mutations in daf-2 and age-1/PI-3K, a central kinase downstream of DAF-2, can be largely or fully rescued, when wild-type daf-2 or age-1 is expressed in the neurons of the corresponding mutants (Wolkow et al., 2000; Iser et al., 2007). In contrast, neuronal activity of DAF-16/FOXO seems to be less important for lifespan extension in animals with impaired IIS (Libina et al., 2003; Iser et al., 2007; also, see below). However, expression of the microRNA mir-71 in the nervous system mediates the lifespan extension in germline-ablated worms in a fashion that depends upon intestinal DAF-16 activity, revealing a complex signaling interaction between the CNS, the intestine, and the gonad in IIS-mediated lifespan regulation (Boulias and Horvitz, ).
Work in the fruit fly Drosophila melanogaster reveals remarkable parallels to these observations in worms. In the adult fly, three out of seven distinct ILPs are produced in specialized median neurosecretory cells (also called insulin-producing cells, IPCs) in the pars intercerebralis of the CNS (Rulifson et al., 2002; Grönke et al., ), and ablation of the IPCs significantly extends lifespan (Wessells et al., 2004; Broughton et al., ; Haselton et al., ), presumably due to reduced levels of ILP2, ILP3, and ILP5 (Broughton et al., ; Grönke et al., ). Consistent with these observations, several factors that regulate the production and/or release of ILPs affect IIS and lifespan. These factors include the metabotropic GABA receptors or uncoupling proteins (UCPs) expressed in the IPCs (Fridell et al., ; Humphrey et al., 2009; Enell et al., ) and short neuropeptide F (sNPF) expressed in the CNS (Lee et al., 2008, 2009). In addition, downregulation of p53 in the IPCs extends lifespan by reducing ILP levels and inhibiting PI-3K activity in peripheral tissues (Bauer et al., ). Similarly, the stress-responsive Jun kinase (JNK) in the IPCs promotes longevity by downregulating ILP2 through activation of FOXO (Wang et al., 2005). In contrast, and similar to the above-mentioned findings in C. elegans, activation of FOXO in the CNS, either pan-neuronally, in the neurolemma or in glial cells, is not sufficient to extend lifespan, whereas its downregulation in head fat body tissues promotes longevity (Hwangbo et al., 2004).
In mammals, the CNS also seems to play an important role in regulating the production and release of insulin-like hormones, although the bulk of insulin or IGF-1 is produced outside the brain. For example, mice with certain mutations affecting the so-called hypothalamic-pituitary-somatotropic growth hormone (GH-IIS) axis, known to regulate the release of insulin/insulin-like hormones, are long-lived, presumably due to downregulation of IIS (reviewed in Tatar et al., 2003; Holzenberger et al., ; Berryman et al., ). More direct evidence for a role of IIS in affecting mammalian lifespan via the nervous system comes from studies with transgenic or mutant mice with impaired IIS. Mice with a brain-specific deletion of the insulin receptor substrate-2 (Irs2) locus are 14% longer lived than control mice, despite being hyperinsulinemic, obese, and insulin-resistant (Taguchi et al., 2007). Similarly, partial genetic inactivation of the IGF-1 receptor (IGF-1R) gene in the embryonic mouse brain inhibits GH and IGF-1 signaling after birth, which leads to growth retardation, small adult size, metabolic changes, and prolonged mean lifespan (Kappeler et al., 2008).
While much future work remains to be done for a detailed understanding of the underlying regulatory mechanisms, the available studies in worms, flies, and mice to date clearly show that neuroendocrine processes in the CNS are critically important for modulating the lifespan effects of IIS.
The effects of neuronal stress-sensing pathways on lifespan and aging
The nervous system not only perceives a variety of environmental stressors but also integrates these information, which are then converted into appropriate physiological and behavioral adaptive responses. Below we discuss two such examples and their possible consequent effects on lifespan.
Exposure to acute stress, like heat, heavy metals, or toxins, can lead to proteotoxicity, as a result of protein misfolding within the animal (reviewed in Åkerfelt et al., ). To survive such insults, the animal activates its heat shock response, which is mediated by the heat shock transcription factor 1 (HSF-1; (Hsu et al., 2003; Morley and Morimoto, 2004; Cohen et al., ). For example, Kourtis et al. (2012) have shown that HSF-1 is required to protect the animal against cytotoxicity that is induced by thermal or other stresses through activation of the small heat shock protein HSP-16.1. This mechanism, which also protects against neurodegeneration, has been found to be conserved across species (Kourtis et al., 2012). Since thermosensory neurons and their associated neuronal circuitry can regulate the C. elegans heat shock responses non-autonomously (Prahlad et al., 2008; Prahlad and Morimoto, 2011), it is possible that the sensory regulation of the HSF-1/HSP-16.1 response is similarly conserved.
However, HSF-1 activity promotes longevity not only in the presence, but also in the absence, of acute stress (Hsu et al., 2003; Morley and Morimoto, 2004). Intriguingly, protein misfolding, whether it is mediated (Morley et al., 2002; van Ham et al., 2010) or not (David et al., ) by polyglutamine repeats, increases with age. This suggests that protein aggregation is inherent with age and is not restricted to a subset of proteins that have been implicated in diseases like neurodegeneration (David et al., ). Hence, given the role of HSF-1 in promoting protein disaggregation (Cohen et al., ), it is not surprising that HSF-1 activity in multiple tissues affects lifespan even in the absence of acute stress (Hsu et al., 2003; Morley and Morimoto, 2004).
Animals also employ different sensors for different types of gases that are required and/or affect important physiological processes. Some examples are the mechanisms through which animals perceive oxygen levels within their environment. For example, environmental oxygen is sensed by specific soluble guanylyl cyclases (sGCs) in specific sensory neurons in C. elegans and Drosophila (Cheung et al., ; Chang et al., ; Rogers et al., 2006; Vermehren-Schmaedick et al., 2010). These sGCs regulate the aerotactic behaviors of the animals: C. elegans prefers 7–11% ambient oxygen and is repelled by hypoxic (<5% O2) and hyperoxic (>14% O2) environments (Cheung et al., ; Chang et al., ; Rogers et al., 2006); whereas Drosophila larvae prefer a more restricted range of O2 concentration (∼21%) (Vermehren-Schmaedick et al., 2010). Besides the sGC-expressing neurons, the avoidance of hyperoxia, i.e., in C. elegans, also depends on the activities of neurons that sense pain and neurons that integrate information about food availability and population density (Chang et al., ; Rogers et al., 2006). Thus, these different sensory neurons together allow the animals to generate rapid behavioral responses to ambient O2, so that they can migrate to environments with the optimal O2 levels necessary for their survival. At present, none of the sGCs are known to affect lifespan, unlike the receptor guanylyl cyclases for which a few have been reported to inhibit longevity (Murphy et al., 2003; Alcedo and Kenyon, ).
There are also many other cells that respond to O2, albeit more slowly, through the hypoxia-inducible transcription factor HIF-1, which modifies the activities of the above O2-sensing neurons and existing neural circuitries (Chang and Bargmann, ; Pocock and Hobert, 2010). Hypoxic activation of HIF-1 shifts the animal’s preferences to lower oxygen concentrations and eliminates the dependence on some neurons, e.g., those that integrate information about food and population density, in promoting O2-dependent responses (Chang and Bargmann, ). Interestingly, this HIF-1 effect requires that it acts coordinately in neuronal and gonadal cells (Chang and Bargmann, ), whose outputs are known to affect lifespan (Apfeld and Kenyon, ; Hsin and Kenyon, ; Wolkow et al., 2000; Broughton et al., ; Flatt et al., ).
Indeed, the HIF-1 pathway has been recently found to influence C. elegans lifespan and that these lifespan effects depend on environmental context (Chen et al., ; Mehta et al., 2009; Zhang et al., 2009; Lee et al., 2010; Leiser et al., 2011). Particularly, loss of hif-1 can extend C. elegans lifespan at higher temperatures (25°C; Chen et al., ; Leiser et al., 2011) or shorten lifespan at lower temperatures (20°C; Mehta et al., 2009; Lee et al., 2010). Since O2 perception can be modulated by food-derived information (Chang et al., ; Rogers et al., 2006; Chang and Bargmann, ; Pocock and Hobert, 2010), these temperature-dependent effects of HIF-1 may also reflect differences in the animal’s bacterial food sources grown at 25 versus 20°C. Consistent with this idea, an interaction between HIF-1 and the food-dependent TOR pathway has been observed in affecting lifespan (Chen et al., ). Likewise, because O2-sensing is also subject to population density (Chang et al., ; Rogers et al., 2006), the hif-1 lifespan effects observed by Zhang et al. (2009) might reflect the higher density of animals used in their assays. Thus, HIF-1 function nicely illustrates how environmental context and its perception can modulate the effects of a signaling pathway on lifespan.
The role of mitochondria in brain aging and longevity
Mitochondria are among the most important cellular organelles that contribute to the aging process, mainly through respiratory chain dysfunction, changes in redox status, or by generating reactive oxygen species (ROS; Humphries et al., 2006; Mattson, 2006). It is therefore not surprising that the nervous system exhibits a highly active mitochondrial metabolism, especially because of the high energetic demands associated with processes such as ion homeostasis, neurotransmission, or the firing of action potentials.
Indeed in mammals, structural impairments in mitochondrial DNA and an age-dependent reduction in brain mitochondrial function are correlated with the age-dependent decrease in cognitive function and neuromuscular coordination (reviewed in Bishop et al., ; Escames et al., ; Chakrabarti et al., ; Yin et al., 2012). Similarly, mitochondrial dysfunction has been implicated in neurodegenerative diseases (reviewed in Eckert et al., ; Reddy and Reddy, 2011; Swerdlow, 2011; Troulinaki and Bano, 2012; Yin et al., 2012), although it remains unclear whether the functional changes seen in the healthily aging brain are distinct from the pathological processes associated with neurodegenerative diseases. The empirical evidence at hand today thus suggests that neuronal mitochondria play an important role in maintaining organismal homeostasis and in influencing aging.
Several observations support the importance of proper neuronal mitochondrial function for lifespan and healthy aging. As mentioned previously, expression of human mitochondrial UCPs, which can uncouple mitochondrial respiration from ATP synthesis, in the neurons of adult flies extends lifespan (Fridell et al., , ; Humphrey et al., 2009). This effect is likely to occur through reduced secretion of ILPs (Fridell et al., ; Humphrey et al., 2009), since the human UCP2 is known to regulate insulin secretion (Zhang et al., 2001). Interestingly, while moderate levels of neuronal UCP expression lengthen lifespan (Fridell et al., ; Humphrey et al., 2009), high levels have the opposite effect (Humphrey et al., 2009; Figure 2). This is reminiscent of previous studies that show a mild reduction of mitochondrial function can extend lifespan, whereas a strong functional impairment shortens lifespan (Rea et al., 2007). Therefore, hypothetically, mild mitochondrial dysfunction may cause (1) a change in levels of ROS production, e.g., a decrease that ensures preservation of DNA and protein structures or a mild increase that leads to compensatory mechanisms, or (2) a change in the types of ROS produced, which would then stimulate the expression of longevity-promoting genes. Together these data suggest that the increased lifespan associated with mild impairment of neuronal mitochondrial function (Dillin et al., ; Rea and Johnson, 2003; Morrow et al., 2004; Fridell et al., , ; Conti et al., ; Rea et al., 2007; Copeland et al., ; Humphrey et al., 2009; Lee et al., 2010; Figure 2) represents a compensatory mechanism that enables the maintenance of homeostasis.
Figure 2
A reduction of the function of the mitochondrial respiratory chain in the nervous system has also been shown to induce a mitochondria-specific unfolded protein response (UPRmt) in intestinal cells and to extend lifespan (Durieux et al., ; Figure 2). Interestingly, a similar impairment of mitochondrial function in muscle cells can also induce UPRmt, but this does not cause lifespan extension (Durieux et al., ), which could suggest that UPRmt by itself is not sufficient for promoting longevity. On the other hand, the induction of UPRmt has been found to be necessary for the long-life phenotype due to reduced mitochondrial respiration (Durieux et al., ). Thus, these findings suggest that mitochondrial dysfunction in neurons extends lifespan by producing an unknown signal that acts together with the UPRmt-inducing signal. While the nature of this additional signal remains unknown, it is tempting to speculate about the possible role of the HIF-1 pathway in this process. Indeed, HIF-1 not only modifies neuronal activities (Chang and Bargmann, ; Pocock and Hobert, 2010), but also promotes longevity in response to mild inhibition of mitochondrial respiration through increased ROS levels (Lee et al., 2010). Although the longevity-promoting effects of increased ROS (Lee et al., 2010) contradict a previous hypothesis that ROS would shorten lifespan through increased oxidative damage (Humphries et al., 2006; Mattson, 2006), this observation is consistent with the more recent hypothesis of mitohormesis, where higher ROS subsequently leads to increased stress resistance (Schulz et al., 2007). Alternatively, it is conceivable that certain types of ROS act as signaling molecules to activate survival pathways (Bishop et al., ; Lee et al., 2010; Durieux et al., ).
As the major source of ROS, the mitochondria are intimately involved in crosstalk among different pathways. Not surprisingly, mitochondrial activity is also regulated by major pathways that affect longevity, including the IIS, TOR, and JNK signaling pathways (reviewed in Troulinaki and Bano, 2012, as part of this Research Topic). Indeed, the ROS-mediated induction of JNK activity (Wang et al., 2005), which leads to translocation of JNK from the cytoplasm to the mitochondria, has been proposed to be of fundamental importance in the transduction of cytosolic signals to the mitochondria in the aging mammalian brain Schroeter et al., 2003; Eminel et al., ; Zhou et al., 2008, 2009).
Reactive oxygen species signaling itself also modulates mitochondrial homeostasis, which involves constant remodeling of this organelle, i.e., through mitochondrial fusion, fission, and autophagy (reviewed in Lemasters, 2005; Lee et al., 2012; Palikaras and Tavernarakis, 2012; Liesa and Shirihai, 2013). Such remodeling, which is tightly regulated, appears to be an adaptive response to the cell’s energy expenditure and demands (reviewed in Liesa and Shirihai, 2013). However, mitochondrial fusion and fission have also been proposed to distribute damaged organelle components across the cell’s mitochondrial network, whereas mitochondrial autophagy, known as mitophagy, removes highly damaged mitochondria (reviewed in Lemasters, 2005; Lee et al., 2012; Palikaras and Tavernarakis, 2012). Thus, an increase in ROS levels can shift the balance between fusion and fission to mitophagy (reviewed in Lemasters, 2005; Lee et al., 2012; Palikaras and Tavernarakis, 2012). Interestingly, mitophagy requires genes that have been implicated in the neurodegenerative Parkinson’s disease, i.e., the serine/threonine kinase PINK1 and the E3 ubiquitin ligase Parkin, where PINK1 senses the damaged mitochondria and recruits Parkin to induce mitophagy (Narendra et al., 2008, 2010). Thus, dysregulation of mitochondrial remodeling, including mitophagy, through excess ROS, likely contributes to the onset and progression of several age-associated neurodegenerative diseases (reviewed in Batlevi and La Spada, ; Palikaras and Tavernarakis, 2012).
Feedback, Compensatory, and Feed-Forward Mechanisms in Longevity-Modulating Pathways
The studies discussed above point to the existence of major feedback mechanisms within the nervous system. Feedback loops are critically important in regulating physiology and metabolism, particularly with respect to homeostasis, and are often controlled by hormones (reviewed in Baker and Thummel, ; Leopold and Perrimon, 2007; Fielenbach and Antebi, ; Rajan and Perrimon, 2011; Hill et al., ). Notably, many such endocrine feedback mechanisms are thought to modulate aging and lifespan (Tatar et al., 2003; Murphy et al., 2007; Fielenbach and Antebi, ; Broughton and Partridge, ; Karpac and Jasper, 2009; Karpac et al., 2009; Tazearslan et al., 2009; Landis and Murphy, 2010), and the nervous system has been implicated in several of them (Hwangbo et al., 2004; Broughton et al., ; Flatt et al., ; Grönke et al., ; Alic et al., ; Boulias and Horvitz, ). Here, we focus on a few examples of feedback mechanisms that involve IIS and the nervous system.
A first example concerns the communication between adipose tissue and the brain via IIS. Hwangbo et al. (2004) found that in D. melanogaster overexpression of FOXO in the head fat body (equivalent of mammalian liver and adipose) extends lifespan and – remarkably – reduces the levels of ILP2 produced in the IPCs of the CNS, suggesting that lifespan extension is caused by FOXO-mediated negative feedback regulation of neural ILP production. This is consistent with the observation that ablation of IPCs extends lifespan (Wessells et al., 2004; Broughton et al., ), probably due to lowered levels of the ILP2, ILP3, and ILP5 ligands (Broughton et al., ; Grönke et al., ). Moreover, these findings are particularly interesting in view of the fact that a humoral factor produced by the fat body has been found to remotely control insulin secretion from the IPCs (Geminard et al., ; Tatar, 2009), yet whether this factor itself modulates lifespan remains unknown.
Another example is the existence of endocrine communication between the gonad and the brain. Similar to previous findings in C. elegans (Hsin and Kenyon, ; Arantes-Oliveira et al., ), Flatt et al. () found that ablation of germline stem cells (GSCs) extends Drosophila lifespan. However, despite evidence of impaired IIS in peripheral tissues, fly GSC ablation also upregulates the production of ILP2, ILP3, and ILP5 in the brain IPCs (Flatt et al., ). Since neurally produced ILPs are known to bind to the insulin-like receptor (InR) on GSCs to regulate GSC proliferation in the gonad (LaFever and Drummond-Barbosa, 2005; Hsu et al., 2008), it is tempting to speculate that GSCs in the gonad exert negative feedback on ILP production in the brain. Although the nature of the signal that relays this communication remains unknown, a promising candidate may be IMP-L2, an insulin-binding protein. IMP-L2, which is expressed in the germline niche, among other tissues (Terry et al., 2006), limits the availability of free ILPs by sequestering them away from the InR, thereby antagonizing systemic IIS (Honegger et al., ). Interestingly, this protein is upregulated in germline-less, long-lived flies exhibiting ILP overproduction (Flatt et al., ). Moreover, similar to the phenotypes seen in germline-less flies, the Partridge group has shown that direct upregulation of IMP-L2 itself extends lifespan and increases ILP2, ILP3, and ILP5 levels, whereas genetic deletion of the ilp2, ilp3, and ilp5 loci decreases IMP-L2 (Grönke et al., ; Alic et al., ). Together these observations support the hypothesis that IMP-L2 is part of a gonad-brain signaling circuit that regulates neural ILP levels (Figure 3).
Figure 3
While the detailed consequences for physiology, and in particular for aging and longevity, are in most cases still unknown, feedback mechanisms also occur at the level of transcriptional regulation. For example, some of the seven different Drosophila ILPs demonstrate feedback regulation of each other (Figure 4): IPC-expressedilp3 is required for the normal expression of ilp2 and ilp5 in the IPCs, whereas knockdown of ilp2 leads to upregulation of ilp3 and ilp5 expression in the IPCs (Broughton et al., ; Grönke et al., ). Similar feedback loops also exist for other components of IIS: Drosophila FOXO (dFOXO), which is activated when InR signaling is downregulated, activates the transcription of InR (Puig et al., 2003; Puig and Tjian, 2005).
Figure 4
Intriguingly, besides feedback loops, the genetic study of aging is also beginning to uncover other types of regulatory motifs, e.g., compensatory and feed-forward regulatory mechanisms. For instance, upregulation of the fat body-specific ilp6 seems to compensate for the loss of the brain-specific ilp2, ilp3, and ilp5 (Figure 4; Grönke et al., ). Moreover, like in Drosophila, C. elegans exhibits feed-forward regulation between ILPs (Murphy et al., 2007). Increased DAF-16/FOXO activity in a specific tissue is shown to increase the activity of DAF-16/FOXO in other tissues through feed-forward regulation that requires the inhibition of the ILP ins-7 expression in the C. elegans intestine (Figure 4; Murphy et al., 2003, 2007). Thus, these studies beautifully exemplify the complexity of existing feedback, compensatory, and feed-forward mechanisms that may be relevant for modulating aging and longevity.
Temporal Requirements of Longevity-Influencing Genes
The experimental data available today suggest that adult-expressed neuronal genes may have important effects on aging and longevity (e.g., reviewed in Broughton and Partridge, ). However, to what extent genes that regulate the development of the nervous system and its circuitry also influence homeostasis and longevity remains presently unclear. Interestingly, several data support the notion that early-life environmental influences might have “carry-over” effects into adulthood and might thus impact lifespan (Gavrilov and Gavrilova, ; Saino et al., 2012). For example, putative biomarkers of aging that affect gene activity and chromosome structure at an early age have been shown to predict life expectancy (Baeriswyl et al., ; Pincus and Slack, 2010; Heidinger et al., ). Similarly, newly emerging data from C. elegans show that age-related behaviors are associated with distinct transcriptomes and that the statistical analysis of these aggregate gene expression profiles can predict age and health states (Golden et al., ). Thus, such data tempt one to speculate that genes involved in developmental canalization (or “robustness”) might also have long-term effects on physiological homeostasis and somatic maintenance later in life. This canalization has been predicted to be a generic feature of developmental gene networks (Siegal and Bergman, 2002; Flatt, ).
A particularly plausible mechanism underlying these “carry-over” effects on adult lifespan is pleiotropic gene action, whereby one gene’s effect during development differs from its effect in adulthood, i.e., the same gene variant might have pleiotropic roles in affecting development versus lifespan (e.g., see Dillin et al., ). On the other hand, a gene could also have different lifespan effects that depend on its temporal activity, as has been observed with the overexpression of different p53 constructs in Drosophila: this can lead to different lifespan effects in females and males depending on whether expression was driven during development versus adulthood (Waskar et al., 2009). Indeed, several key lifespan modulators, like the mitochondrial electron transport chain, microRNAs, HSF-1, and FOXO, can have “carry-over” effects on adult lifespan when manipulated (e.g., overexpressed or silenced) during early larval development and/or early adulthood (Dillin et al., ,; Giannakou et al., ; Rea et al., 2007; Durieux et al., ; Pincus et al., 2011; Volovik et al., 2012). Other examples are the age-dependent expression changes in neocortical genes, which not only play a role during development but also in altered neocortical function that is observed during age-related cognitive decline and brain dysfunction (reviewed in Huffman, 2012, as part of this Research Topic).
The distinct functional roles of pleiotropic genes during development versus aging are also demonstrated by the uncoupling of their gene functions between these two processes (Chen et al., ; Shen et al., 2009; Thyagarajan et al., 2010). In some cases, strong loss-of-function (or null) mutations have been found to affect embryonic development in C. elegans, whereas weaker mutant alleles of the same gene have been shown to affect adult lifespan (Kenyon et al., 1993; Kimura et al., 1997; Gems et al., ; Boehm and Slack, ), suggesting that essential developmental genes can have deleterious effects late in life. To neutralize these late-acting deleterious effects, Liu et al. (2012) have shown that miRNA signaling is involved in specifically silencing a set of these developmental genes in adulthood, thereby restricting the pleiotropic “carry-over” effects of such genes. This is exemplified by the miRNA miR-34-mediated silencing of the steroid pathway gene E74A in Drosophila adults to maintain brain integrity and viability (Liu et al., 2012).
Another obvious mechanism that might play a role in “carry-over” effects on lifespan and aging are epigenetic modifications. Experiments in rodents, for instance, have shown that experiences during sensitive periods of brain development influence DNA methylation patterns, which in turn could alter gene transcription throughout life and promote specific phenotypic outcomes (Roth and Sweatt, 2011). In a similar vein, the “heterochromatin loss model of aging” posits that heterochromatin domains that are set up early in embryogenesis are gradually lost with age, which results in aberrant and age-associated gene expression patterns (Villeponteau, 1997). In support of this hypothesis, genetic manipulation of HP1 levels and JAK/STAT signaling suggests that heterochromatin formation contributes to the prevention of premature aging (Larson et al., 2012). These are intriguing preliminary observations and it will be interesting to learn more about the role of epigenetic changes in aging and lifespan in future work.
Evolutionary Implications of Longevity-Modulating Neuronal Mechanisms
Although the classical evolutionary theory of aging posits that aging should be affected by different mechanisms in different species (Williams, 1957; Reznick, 2005), recent studies suggest that several pathways have conserved effects on longevity (reviewed in Partridge and Gems, 2002; Tatar et al., 2003; Kenyon, 2005; Partridge et al., 2005; Smith et al., 2008; Flatt and Schmidt, ; Fontana et al., ; Nakagawa et al., 2012; Wuttke et al., 2012). Whereas lifespan can vary by several orders of magnitude across different species (Finch, ; Stearns, 1992; Nabholz et al., 2008; Li and de Magalhães, 2011), the molecular underpinnings of longevity have so far been mainly studied in a few short-lived and genetically tractable model systems, suggesting that our current understanding of the mechanisms of aging might be biased (Deweerdt, ). Moreover, while many of the conserved, pleiotropic signaling pathways implicated in aging have neuronal roles, not all of these functions might directly impinge on aging. Therefore, the extent to which the neuronal mechanisms of longevity are evolutionarily conserved remains largely unclear.
A recent study directly comparing gene expression profiles during aging in mouse, rhesus macaque and human brains indicates that only a small subset of the age-dependent expression changes might be conserved (Loerch et al., 2008). These few genes include the neuroprotective gene apolipoprotein D (APOD), which is robustly upregulated with age in all three species and whose two Drosophila homologs are known to affect lifespan (Ruiz et al., 2011). Another example is the calcium/calmodulin-dependent protein kinase IV (CAMK4), which has been shown to regulate synaptic plasticity (Ho et al., ) and is downregulated with age in all three species (Loerch et al., 2008). In contrast, most genes did not show a consistent age-dependent pattern across species, leading the authors to conclude that humans and rhesus macaques have greatly diverged from mice as demonstrated by a dramatic increase in age-dependent repression of human and macaque neuronal genes (Loerch et al., 2008). While these results indicate that the neuronal mechanisms of aging and longevity might not be highly conserved among different taxa, a study by Fonseca et al. () provides a remarkable counter-example. Across a range of terrestrial, freshwater, marine, tropical, and temperate arthropods, whose lifespans vary by three orders of magnitude, the neuronal deposition of lipofuscin, a lipid-protein aggregate, is highly correlated with lifespan. This suggests that age-dependent damage accumulation in the brain might be the primary driver of senescence (Fonseca et al., ).
Similarly, at the microevolutionary or intraspecies level, it is still unclear whether natural variation in lifespan is based on allelic variation within the same genes and pathways that have already been previously found to affect longevity in laboratory studies of mutant or transgenic model organisms (Flatt, ; Paaby and Schmidt, 2008; Flatt and Schmidt, ). On the one hand, some studies have failed to confirm the lifespan effects of natural variants of candidate longevity genes (Geiger-Thornsberry and Mackay, ). On the other hand, there is increasing evidence that genetic variation in candidate longevity genes might indeed contribute to variation in lifespan, as well as life history traits, in natural populations (Schmidt et al., 2000; Paaby and Schmidt, 2008; Suh et al., 2008; Paaby et al., 2010; Rose et al., 2010, 2011; Pijpe et al., 2011; Luisi et al., 2012).
A particularly striking example of such a variant is the gene FOXO3A, a human ortholog of Drosophila FOXO and C. elegans DAF-16. Several independent studies of natural polymorphisms in FOXO3A in Japanese, German, French, Italian, and Han Chinese populations have found that specific variants in this gene are associated with exceptional longevity among human centenarians (Willcox et al., 2008; Anselmi et al., ; Flachsbart et al., ; Li et al., 2009; Pawlikowska et al., 2009; Soerensen et al., 2010; Zeng et al., 2010). Although one cannot rule out a certain level of ascertainment bias, these results suggest that FOXO not only plays a functional role in regulating lifespan in laboratory model organisms, but that naturally occurring alleles can also have measurable effects on lifespan. Similar associations between natural polymorphisms and human longevity have been identified for IGF-1R (Suh et al., 2008). Likewise, evidence from Drosophila indicates that natural alleles in the InR locus do affect life history traits that are closely linked to longevity (Paaby et al., 2010).
Finally, a similar pattern appears to be emerging with regard to natural variants of genes involved in the neuronal regulation of lifespan: correlations have been found between longevity and genes that function in (1) neuronal development (Rybina and Pasyukova, 2010; Walter et al., 2011), (2) in neural circuitry (De Benedictis et al., ; De Luca et al., , ; Carbone et al., ), or (3) in the uncoupling process in neuronal tissues (Rose et al., 2011).
Conclusions and Perspectives
Here we have provided a review of the recent knowledge about the neuronal inputs and outputs that affect aging and longevity, mainly by focusing on the latest work in genetically tractable model organisms, such as flies, worms, and mice. Even though many details remain to be discovered, it is amply clear today that aging and longevity are profoundly influenced by neuronal activities. Indeed, given that the nervous system (especially, the neuroendocrine system) is intimately involved in regulating an animal’s physiology, e.g., its homeostasis and survival, in response to environmental changes, such a role for this organ system in the aging process is not surprising, both from a physiological and evolutionary perspective. Yet numerous difficult puzzles remain to be solved in future work. For example, with regard to IIS, we know that downregulation of this pathway can have positive effects on lifespan; however, at the same time such downregulation can severely impair neuronal survival and CNS function in old age (also, see discussion in Broughton and Partridge, ). Perhaps these distinct effects of IIS on animal physiology could depend on the tissue- or temporal-specific activities of the pathway. Hence, these pleiotropic effects of IIS highlight our need for a much better understanding of how, why, and when “brain aging” and “organismal aging” are exactly coupled or decoupled. More generally, understanding the developmental “carry-over” effects on adult lifespan will require us to gain further insight into the tissue-, age-, and stage-specificity of the neuronal effects on aging and longevity. Similarly, our current knowledge of the intricate interactions involved in the neuronal regulation of aging and longevity is still extremely rudimentary. For instance, not much is known about the interactions between different “longevity” pathways in the brain, or how different tissues (such as the gonad or adipose tissue) cross-talk with the CNS in the modulation of whole-organism lifespan. Thus, despite the fact that recent years have witnessed a lot of progress in this area, there are clearly very exciting times and novel discoveries ahead in the elucidation of the neuronal aspects of aging and longevity.
Statements
Acknowledgments
Joy Alcedo has been supported by the Novartis Research Foundation, the Swiss National Science Foundation (SNF, 31003A_134958) and Wayne State University. Thomas Flatt acknowledges support from the Austrian Science Foundation (FWF, P21498-B11), the Swiss National Science Foundation (SNF, PP00P3_133641), and the Wissenschaftskolleg zu Berlin. Elena G. Pasyukova was supported by the Presidium of the Russian Academy of Sciences and the Russian Foundation for Basic Research (#12-04-01182-a).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
ÅkerfeltM.MorimotoR. I.SistonenL. (2010). Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol.11, 545–555.10.1038/nrm2938
2
AlcedoJ.KenyonC. (2004). Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron41, 45–55.10.1016/S0896-6273(03)00816-X
3
AlcedoJ.MaierW.Ch’ngQ. (2010). “Sensory influence on homeostasis and lifespan: molecules and circuits,” in Protein Metabolism and Homeostasis in Aging, ed. TavernarakisN. (Austin, TX: Landes Bioscience), 197–210.
4
AlicN.HoddinottM. P.VintiG.PartridgeL. (2011). Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor. Aging Cell10, 137–147.10.1111/j.1474-9726.2010.00653.x
5
AnselmiC. V.MaloviniA.RoncaratiR.NovelliV.VillaF.CondorelliG.et al (2009). Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuv. Res.12, 95–104.10.1089/rej.2008.0827
6
ApfeldJ.KenyonC. (1999). Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature402, 804–809.10.1038/45544
7
Arantes-OliveiraN.ApfeldJ.DillinA.KenyonC. (2002). Regulation of life-span by germ-line stem cells in Caenorhabditis elegans. Science295, 502–505.10.1126/science.1065768
8
BaeriswylS.DiardM.MosserT.LeroyM.ManièreX.TaddeiF.et al (2009). Modulation of aging profiles in isogenic populations of Caenorhabditis elegans by bacteria causing different extrinsic mortality rates. Biogerontology11, 53–65.10.1007/s10522-009-9228-0
9
BakerK. D.ThummelC. S. (2007). Diabetic larvae and obese flies – emerging studies of metabolism in Drosophila. Cell Metab.6, 257–266.10.1016/j.cmet.2007.09.002
10
BargmannC. I. (1998). Neurobiology of the Caenorhabditis elegans genome. Science282, 2028–2033.10.1126/science.282.5396.2028
11
BargmannC. I.HorvitzH. R. (1991). Control of larval development by chemosensory neurons in Caenorhabditis elegans. Science251, 1243–1246.10.1126/science.2006412
12
BatemanJ. M.McNeillH. (2006). Insulin/IGF signalling in neurogenesis. Cell. Mol. Life Sci.63, 1701–1705.10.1007/s00018-006-6036-4
13
BatleviY.La SpadaA. R. (2011). Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging. Neurobiol. Dis.43, 46–51.10.1016/j.nbd.2010.09.009
14
BauerJ. H.ChangC.MorrisS. N.HozierS.AndersenS.WaitzmanJ. S.et al (2007). Expression of dominant-negative Dmp53 in the adult fly brain inhibits insulin signaling. Proc. Natl. Acad. Sci. U.S.A.104, 13355–13360.10.1073/pnas.0706121104
15
BerrymanD. E.ChristiansenJ. S.JohannssonG.ThornerM. O.KopchickJ. J. (2008). Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models. Growth Horm. IGF Res.18, 455–471.10.1016/j.ghir.2008.05.005
16
BishopN. A.GuarenteL. (2007). Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature447, 545–549.10.1038/nature05904
17
BishopN. A.LuT.YanknerB. A. (2010). Neural mechanisms of ageing and cognitive decline. Nature464, 529–535.10.1038/nature08983
18
BoehmM.SlackF. (2005). A developmental timing microRNA and its target regulate life span in C. elegans. Science310, 1954–1957.10.1126/science.1115596
19
BouliasK.HorvitzH. R. (2012). The C. elegans microRNA mir-71 acts in neurons to promote germline-mediated longevity through regulation of DAF-16/FOXO. Cell Metab.15, 439–450.10.1016/j.cmet.2012.02.014
20
BroughtonS.AlicN.SlackC.BassT.IkeyaT.VintiG.et al (2008). Reduction of DILP2 in Drosophila triages a metabolic phenotype from lifespan revealing redundancy and compensation among DILPs. PLoS ONE3:e3721.10.1371/journal.pone.0003721
21
BroughtonS.PartridgeL. (2009). Insulin/IGF-like signalling, the central nervous system and aging. Biochem. J.418, 1–12.10.1042/BJ20082389
22
BroughtonS. J.PiperM. D. W.IkeyaT.BassT. M.JacobsenJ.DriegeY.et al (2005). Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc. Natl. Acad. Sci. U.S.A.102, 3105–3110.10.1073/pnas.0405775102
23
CarboneM. A.JordanK. W.LymanR. F.HarbisonS. T.LeipsJ.MorganT. J.et al (2006). Phenotypic variation and natural selection at catsup, a pleiotropic quantitative trait gene in Drosophila. Curr. Biol.16, 912–919.10.1016/j.cub.2006.03.051
24
ChakrabartiS.MunshiS.Kalpita BanerjeeR.Ishita Guha ThakurtaI. G.SinhaM.BaghM. B. (2011). Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxidant supplementation. Aging Dis.2, 242–256.
25
ChalletE.CaldelasI.GraffC.PévetP. (2003). Synchronization of the molecular clockwork by light- and food-related cues in mammals. Biol. Chem.384, 711–719.10.1515/BC.2003.079
26
ChangA. J.BargmannC. I. (2008). Hypoxia and the HIF-1 transcriptional pathway reorganize a neuronal circuit for oxygen-dependent behavior in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A.105, 7321–7326.10.1073/pnas.0709118105
27
ChangA. J.ChronisN.KarowD. S.MarlettaM. A.BargmannC. I. (2006). A distributed chemosensory circuit for oxygen preference in C. elegans. PLoS Biol.4:e274.10.1371/journal.pbio.0040274
28
ChenD.PanK. Z.PalterJ. E.KapahiP. (2007). Longevity determined by developmental arrest genes in Caenorhabditis elegans. Aging Cell6, 525–533.10.1111/j.1474-9726.2007.00305.x
29
ChenD.ThomasE. L.KapahiP. (2009). HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet.5:e1000486.10.1371/journal.pgen.1000486
30
ChenZ.HendricksM.CornilsA.MaierW.AlcedoJ.ZhangY. (2013). Two insulin-like peptides antagonistically regulate aversive olfactory learning in C. elegans. Neuron77, 572–585.10.1016/j.neuron.2012.11.025
31
CheungB. H. H.CohenM.RogersC.AlbayramO.de BonoM. (2005). Experience-dependent modulation of C. elegans behavior by ambient oxygen. Curr. Biol.15, 905–917.10.1016/j.cub.2005.04.017
32
ChrysisD.CalikogluA. S.YeP.D’ErcoleA. J. (2001). Insulin-like growth factor-I overexpression attenuates cerebellar apoptosis by altering the expression of Bcl family proteins in a developmentally specific manner. J. Neurosci.21, 1481–1489.
33
CohenE.BieschkeJ.PerciavalleR. M.KellyJ. W.DillinA. (2006). Opposing activities protect against age-onset proteotoxicity. Science313, 1604–1610.10.1126/science.1124646
34
ContiB.Sanchez-AlavezM.Winsky-SommererR.MoraleM. C.LuceroJ.BrownellS.et al (2006). Transgenic mice with a reduced core body temperature have an increased life span. Science314, 825–828.10.1126/science.1132191
35
CopelandJ. M.ChoJ.LoT.HurJ. H.BahadoraniS.ArabyanT.et al (2009). Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol.19, 1591–1598.10.1016/j.cub.2009.08.016
36
CornilsA.GloeckM.ChenZ.ZhangY.AlcedoJ. (2011). Specific insulin-like peptides encode sensory information to regulate distinct developmental processes. Development138, 1183–1193.10.1242/dev.060905
37
DavidD. C.OllikainenN.TrinidadJ. C.CaryM. P.BurlingameA. L.KenyonC. (2010). Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol.8:e1000450.10.1371/journal.pbio.1000450
38
De BenedictisG.CarotenutoL.CarrieriG.De LucaM.FalconeE.RoseG.et al (1998). Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Eur. J. Hum. Genet.6, 534–541.10.1038/sj.ejhg.5200222
39
De LucaM.RoseG.BonafèM.GarastoS.GrecoV.WeirB. S.et al (2001). Sex-specific longevity associations defined by tyrosine hydroxylase-insulin-insulin growth factor 2 haplotypes on the 11p15.5 chromosomal region. Exp. Gerontol.36, 1663–1671.10.1016/S0531-5565(01)00146-2
40
De LucaM.RoshinaN. V.Geiger-ThornsberryG. L.LymanR. F.PasyukovaE. G.MackayT. F. C. (2003). Dopa decarboxylase (Ddc) affects variation in Drosophila longevity. Nat. Genet.34, 429–433.10.1038/ng1218
41
DeweerdtS. (2012). Comparative biology: looking for a master switch. Nature492, S10–S11.10.1038/492S62a
42
DillinA.HsuA. L.Arantes-OliveiraN.Lehrer-GraiwerJ.HsinH.FraserA. G.et al (2002a). Rates of behavior and aging specified by mitochondrial function during development. Science298, 2398–2401.10.1126/science.1077780
43
DillinA.CrawfordD. K.KenyonC. (2002b). Timing requirements for insulin/IGF-1 signaling in C. elegans. Science298, 830–834.10.1126/science.1077780
44
DurieuxJ.WolffS.DillinA. (2011). The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell144, 79–91.10.1016/j.cell.2010.12.016
45
EckertA.SchmittK.GötzJ. (2011). Mitochondrial dysfunction – the beginning of the end in Alzheimer’s disease? Separate and synergistic modes of tau and amyloid-β toxicity. Alzheimers Res. Ther.3, 15.10.1186/alzrt74
46
EminelS.KlettnerA.RoemerL.HerdegenT.WaetzigV. (2004). JNK2 translocates to the mitochondria and mediates cytochrome c release in PC12 cells in response to 6-hydroxydopamine. J. Biol. Chem.279, 55385–55392.10.1074/jbc.M405858200
47
EnellL. E.KapanN.SöderbergJ. A. E.KahsaiL.NässelD. R. (2010). Insulin signaling, lifespan and stress resistance are modulated by metabotropic GABA receptors on insulin producing cells in the brain of Drosophila. PLoS ONE5:e15780.10.1371/journal.pone.0015780
48
EscamesG.LópezA.GarcíaJ. A.GarcíaL.Acuña-CastroviejoD.GarcíaJ. J.et al (2010). The role of mitochondria in brain aging and the effects of melatonin. Curr. Neuropharmacol.8, 182–193.10.2174/157015910792246245
49
FielenbachN.AntebiA. (2008). C. elegans dauer formation and the molecular basis of plasticity. Genes Dev.22, 2149–2165.10.1101/gad.1701508
50
FinchC. E. (1990). Longevity, Senescence, and the Genome. Chicago: The University of Chicago Press.
51
FlachsbartF.CaliebeA.KleindorpR.BlanchéH.von Eller-EbersteinH.NikolausS.et al (2009). Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl. Acad. Sci. U.S.A.106, 2700–2705.10.1073/pnas.0809594106
52
FlattT. (2004). Assessing natural variation in genes affecting Drosophila lifespan. Mech. Ageing Dev.125, 155–159.10.1016/j.mad.2004.02.004
53
FlattT. (2005). The evolutionary genetics of canalization. Q. Rev. Biol.80, 287–316.10.1086/432265
54
FlattT.MinK.-J.D’AlterioC.Villa-CuestaE.CumbersJ.LehmannR.et al (2008). Drosophila germ-line modulation of insulin signaling and lifespan. Proc. Natl. Acad. Sci. U.S.A.105, 6368–6373.10.1073/pnas.0709128105
55
FlattT.SchmidtP. S. (2009). Integrating evolutionary and molecular genetics of aging. Biochim. Biophys. Acta1790, 951–962.10.1016/j.bbagen.2009.07.010
56
FonsecaD. B.BrancatoC. L.PriorA. E.SheltonP. M.SheehyM. R. (2005). Death rates reflect accumulating brain damage in arthropods. Proc. Biol. Sci.272, 1941–1947.10.1098/rspb.2005.3192
57
FontanaL.PartridgeL.LongoV. D. (2010). Extending healthy life span – from yeast to humans. Science328, 321–328.10.1126/science.1172539
58
FridellY. W.HohM.KréneiszO.HosierS.ChangC.ScantlingD.et al (2009). Increased uncoupling protein (UCP) activity in Drosophila insulin-producing neurons attenuates insulin signaling and extends lifespan. Aging (Albany, NY)1, 699–713.
59
FridellY. W.Sanchez_BlancoA.SilviaB. A.HelfandS. L. (2005). Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab.1, 145–152.10.1016/j.cmet.2005.01.005
60
GagliaM. M.JeongD.-E.RyuE.-A.LeeD.KenyonC.LeeS.-J. (2012). Genes that act downstream of sensory neurons to influence longevity, dauer formation, and pathogen responses in Caenorhabditis elegans. PLoS Genet.8:e1003133.10.1371/journal.pgen.1003133
61
GavrilovL. A.GavrilovaN. S. (2011). Season of birth and exceptional longevity: comparative study of American centenarians, their siblings, and spouses. J. Aging Res.2011:104616.10.4061/2011/104616
62
Geiger-ThornsberryG. L.MackayT. F. C. (2004). Quantitative trait loci affecting natural variation in Drosophila longevity. Mech. Ageing Dev.125, 179–189.10.1016/j.mad.2003.12.008
63
GeminardC.RulifsonE. J.LeopoldP. (2009). Remote control of insulin secretion by fat cells in Drosophila. Cell Metab.10, 199–207.10.1016/j.cmet.2009.08.002
64
GemsD.SuttonA. J.SundermeyerM. L.AlbertP. S.KingK. V.EdgleyM. L.et al (1998). Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics150, 129–155.
65
GiannakouM. E.GossM.JacobsonJ.VintiG.LeeversS. J.PartridgeL. (2007). Dynamics of the action of dFOXO on adult mortality in Drosophila. Aging Cell6, 429–438.10.1111/j.1474-9726.2007.00290.x
66
GoldenT. R.HubbardA.DandoC.HerrenM.MelovS. (2008). Age-related behaviors have distinct transcriptional profiles in C. elegans. Aging Cell7, 850–865.10.1111/j.1474-9726.2008.00433.x
67
GreerE. R.PérezC. L.Van GilstM. R.LeeB. H.AshrafiK. (2008). Neural and molecular dissection of a C. elegans sensory circuit that regulates fat and feeding. Cell Metab.8, 118–131.10.1016/j.cmet.2008.06.005
68
GrönkeS.ClarkeD. F.BroughtonS.AndrewsT. D.PartridgeL. (2010). Molecular evolution and functional characterization of Drosophila insulin-like peptides. PLoS Genet.6:e1000857.10.1371/journal.pgen.1000857
69
HaE.YimS.-V.ChungJ.-H.YoonK.-S.KangI.ChoY. H.et al (2006). Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J. Pineal Res.41, 67–72.10.1111/j.1600-079X.2006.00334.x
70
HaseltonA.SharminE.SchraderJ.SahM.PoonP.FridellY. W. (2010). Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance. Cell Cycle9, 3063–3071.10.4161/cc.9.15.12458
71
HeidingerB. J.BlountJ. D.BonerW.GriffithsK.MetcalfeN. B.MonaghanP. (2012). Telomere length in early life predicts lifespan. Proc. Natl. Acad. Sci. U.S.A.109, 1743–1748.10.1073/pnas.1113306109
72
HillR. W.WyseG. A.AndersonM. (2012). Animal Physiology, 3rd Edn. Sunderland, MA: Sinauer Associates, Inc.
73
HoN.LiauwJ. A.BlaeserF.WeiF.HanissianS.MugliaL. M.et al (2000). Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J. Neurosci.20, 6459–6472.
74
HolzenbergerM.KappelerL.De Magalhaes FilhoC. (2004). IGF-1 signaling and aging. Exp. Gerontol.39, 1761–1764.10.1016/j.exger.2004.08.017
75
HoneggerB.GalicM.KohlerK.WittwerF.BrogioloW.HafenE.et al (2008). Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. J. Biol.7:10.10.1186/jbiol72
76
HsinH.KenyonC. (1999). Signals from the reproductive system regulate the lifespan of C. elegans. Nature399, 362–366.10.1038/20694
77
HsuA. L.MurphyC. T.KenyonC. (2003). Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science300, 1142–1145.10.1126/science.1083701
78
HsuH. J.LaFeverL.Drummond-BarbosaD. (2008). Diet controls normal and tumorous germline stem cells via insulin-dependent and -independent mechanisms in Drosophila. Dev. Biol.313, 700–712.10.1016/j.ydbio.2007.11.006
79
HuffmanK. (2012). The developing, aging neocortex: how genetics and epigenetics influence early developmental patterning and age-related change. Front. Genet.3:212.10.3389/fgene.2012.00212
80
HumphreyD. M.ToivonenJ. M.GiannakouM.PartridgeL.BrandM. D. (2009). Expression of human uncoupling protein-3 in Drosophila insulin-producing cells increases insulin-like peptide (DILP) levels and shortens lifespan. Exp. Gerontol.44, 316–327.10.1016/j.exger.2009.02.001
81
HumphriesK. M.SzwedaP. A.SzwedaL. I. (2006). Aging: a shift from redox regulation to oxidative damage. Free Radic. Res.40, 1239–1243.10.1080/10715760600913184
82
HwangboD. S.GershmanB.TuM. P.PalmerM.TatarM. (2004). Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature429, 562–566.10.1038/nature02549
83
IserW. B.GamiM. S.WolkowC. A. (2007). Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs. Dev. Biol.303, 434–447.10.1016/j.ydbio.2006.04.467
84
JeongD.-E.ArtanM.SeoK.LeeS.-J. (2012). Regulation of lifespan by chemosensory and thermosensory systems: findings in invertebrates and their implications in mammalian aging. Front. Genet.3:218.10.3389/fgene.2012.00218
85
KappelerL.De Magalhaes FilhoC.DupontJ.LeneuveP.CerveraP.PérinL.et al (2008). Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol.6:e254.10.1371/journal.pbio.0060254
86
KarpacJ.Hull-ThompsonJ.FalleurM.JasperH. (2009). JNK signaling in insulin-producing cells is required for adaptive responses to stress in Drosophila. Aging Cell8, 288–295.10.1111/j.1474-9726.2009.00476.x
87
KarpacJ.JasperH. (2009). Insulin and JNK: optimizing metabolic homeostasis and lifespan. Trends Endocrinol. Metab.20, 100–106.10.1016/j.tem.2008.11.004
88
KenyonC. (2005). The plasticity of aging: insights from long-lived mutants. Cell120, 449–460.10.1016/j.cell.2005.02.002
89
KenyonC. (2010). The genetics of ageing. Nature464, 504–512.10.1038/nature08980
90
KenyonC.ChangJ.GenschE.RudnerA.TabtiangR. (1993). A C. elegans mutant that lives twice as long as wild type. Nature366, 461–464.10.1038/366461a0
91
KimuraK. D.TissenbaumH. A.LiuY.RuvkunG. (1997). Daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science277, 942–694.
92
KlassM. R. (1977). Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech. Ageing Dev.6, 413–429.10.1016/0047-6374(77)90043-4
93
KourtisN.NikoletopoulouV.TavernarakisN. (2012). Small heat-shock proteins protect from heat-stroke-associated neurodegeneration. Nature490, 213–218.10.1038/nature11417
94
la FleurS. E.KalsbeekA.WortelJ.van der VlietJ.BuijsR. M. (2001). Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J. Neuroendocrinol.13, 1025–1032.10.1046/j.1365-2826.2001.00717.x
95
LaFeverL.Drummond-BarbosaD. (2005). Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science309, 1071–1073.10.1126/science.1111410
96
LandisJ. N.MurphyC. T. (2010). Integration of diverse inputs in the regulation of Caenorhabditis elegans DAF-16/FOXO. Dev. Dyn.239, 1405–1412.
97
LarsonK.YanS. J.TsurumiA.LiuJ.ZhouJ.GaurK.et al (2012). Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet.8:e1002473.10.1371/journal.pgen.1002473
98
LeeJ.GiordanoS.ZhangJ. (2012). Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem. J.441, 523–540.10.1042/BJ20111451
99
LeeK. S.HongS. H.KimA. K.JuS. K.KwonO. Y.YuK. (2009). Processed short neuropeptide F peptides regulate growth through the ERK-insulin pathway in Drosophila melanogaster. FEBS Lett.583, 2573–2577.10.1016/j.febslet.2009.06.028
100
LeeK. S.KwonO. Y.LeeJ. H.KwonK.MinK. J.JungS. A.et al (2008). Drosophila short neuropeptide F signalling regulates growth by ERK-mediated insulin signalling. Nat. Cell Biol.10, 468–475.10.1038/ncb1758
101
LeeS. J.HwangA. B.KenyonC. (2010). Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr. Biol.20, 2131–2136.10.1016/j.cub.2009.12.021
102
LeeS. J.KenyonC. (2009). Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans. Curr. Biol.19, 715–722.10.1016/j.cub.2009.03.041
103
LeiserS. F.BegunA.KaeberleinM. (2011). HIF-1 modulates longevity and healthspan in a temperature-dependent manner. Aging Cell10, 318–326.10.1111/j.1474-9726.2011.00672.x
104
LemastersJ. J. (2005). Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res.8, 3–5.10.1089/rej.2005.8.3
105
LeopoldP.PerrimonN. (2007). Drosophila and the genetics of the internal milieu. Nature450, 186–188.10.1038/nature06286
106
LiW.KennedyS. G.RuvkunG. (2003). daf-28 Encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev.17, 844–858.10.1101/gad.1066503
107
LiY.de MagalhãesJ. P. (2011). Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity. Age (Dordr.)35, 301–314.10.1007/s11357-011-9361-y
108
LiY.WangW. J.CaoH.LuJ.WuC.HuF. Y.et al (2009). Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum. Mol. Genet.18, 4897–4904.10.1093/hmg/ddp015
109
LibertS.ZwienerJ.ChuX.VanVoorhiesW.RomanG.PletcherS. D. (2007). Regulation of Drosophila life span by olfaction and food-derived odors. Science315, 1133–1137.10.1126/science.1136610
110
LibinaN.BermanJ. R.KenyonC. (2003). Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell115, 489–502.10.1016/S0092-8674(03)00889-4
111
LiesaM.ShirihaiO. S. (2013). Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab.17, 491–506.10.1016/j.cmet.2013.03.002
112
LiuN.LandrehM.CaoK.AbeM.HendriksG. J.KennerdellJ. R.et al (2012). The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature482, 519–523.10.1038/nature10749
113
LoerchP. M.LuT.DakinK. A.VannJ. M.IsaacsA.GeulaC.et al (2008). Evolution of the aging brain transcriptome and synaptic regulation. PLoS ONE3:e3329.10.1371/journal.pone.0003329
114
LuisiP.Alvarez-PonceD.Dall’OlioG. M.SikoraM.BertranpetitJ.LaayouniH. (2012). Network-level and population genetics analysis of the insulin/TOR signal transduction pathway across human populations. Mol. Biol. Evol.29, 1379–1392.10.1093/molbev/msr298
115
MaierW.AdilovB.RegenassM.AlcedoJ. (2010). A neuromedin U receptor acts with the sensory system to modulate food type-dependent effects on C. elegans lifespan. PLoS Biol.8:e1000376.10.1371/journal.pbio.1000376
116
MattsonM. P. (2006). Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid. Redox Signal.8, 1997–2006.10.1089/ars.2006.8.1997
117
MehtaR.SteinkrausK. A.SutphinG. L.RamosF. J.ShamiehL. S.HuhA.et al (2009). Proteasomal regulation of the hypoxic response modulates aging in C. elegans. Science324, 1196–1198.10.1126/science.1173507
118
MorleyJ. F.BrignullH. R.WeyersJ. J.MorimotoR. I. (2002). The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A.99, 10417–10422.10.1073/pnas.152161099
119
MorleyJ. F.MorimotoR. I. (2004). Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol. Biol. Cell15, 657–664.10.1091/mbc.E03-07-0532
120
MorrowG.SamsonM.MichaudS.TanguayR. M. (2004). Overexpression of the small mitochondrial Hsp22 extends Drosophila lifespan and increases resistance to oxidative stress. FASEB J.18, 598–609.
121
MurphyC. T.LeeS. J.KenyonC. (2007). Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A.104, 19046–19050.10.1073/pnas.0608451104
122
MurphyC. T.McCarrollS.BargmannC.FraserA.KamathR. S.AhringerJ.et al (2003). Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature424, 277–284.10.1038/nature01789
123
NabholzB.GléminS.GaltierN. (2008). Strong variations of mitochondrial mutation rate across mammals – the longevity hypothesis. Mol. Biol. Evol.25, 120–130.10.1093/molbev/msm248
124
NakagawaS.LagiszM.HectorK. L.SpencerH. G. (2012). Comparative and meta-analytic insights into life-extension via dietary restriction. Aging Cell11, 401–409.10.1111/j.1474-9726.2012.00798.x
125
NarendraD.TanakaA.SuenD. F.YouleR. J. (2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol.183, 795–803.10.1083/jcb.200809125
126
NarendraD. P.JinS. M.TanakaA.SuenD. F.GautierC. A.ShenJ.et al (2010). PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol.8:e1000298.10.1371/journal.pbio.1000298
127
PaabyA. B.BlacketM. J.HoffmannA. A.SchmidtP. S. (2010). Identification of a candidate adaptive polymorphism for Drosophila life history by parallel independent clines on two continents. Mol. Ecol.19, 760–774.10.1111/j.1365-294X.2009.04508.x
128
PaabyA. B.SchmidtP. S. (2008). Functional significance of allelic variation at methuselah, an aging gene in Drosophila. PLoS ONE3:e1987.10.1371/journal.pone.0001987
129
PalikarasK.TavernarakisN. (2012). Mitophagy in neurodegeneration and aging. Front. Genet.3:297.10.3389/fgene.2012.00297
130
PartridgeL.GemsD. (2002). Mechanisms of ageing: public or private?Nat. Rev. Genet.3, 165–175.10.1038/nrn764
131
PartridgeL.AlicN.BjedovI.PiperM. D. W. (2011). Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network. Exp. Gerontol.46, 376–381.10.1016/j.exger.2010.09.003
132
PartridgeL.GemsD.WithersD. J. (2005). Sex and death: what is the connection?Cell120, 461–472.10.1016/j.cell.2005.01.026
133
PawlikowskaL.HuD.HuntsmanS.SungA.ChuC.ChenJ.et al (2009). Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell8, 460–472.10.1111/j.1474-9726.2009.00493.x
134
PierceS. B.CostaM.WisotzkeyR.DevadharS.HomburgerS. A.BuchmanA. R.et al (2001). Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev.15, 672–686.10.1101/gad.867301
135
PijpeJ.PulN.van DuijnS.BrakefieldP. M.ZwaanB. J. (2011). Changed gene expression for candidate ageing genes in long-lived Bicyclus anynana butterflies. Exp. Gerontol.46, 426–434.10.1016/j.exger.2010.11.033
136
PincusZ.SlackF. J. (2010). Developmental biomarkers of aging in Caenorhabditis elegans. Dev. Dyn.239, 1306–1314.
137
PincusZ.Smith-VikosT.SlackF. J. (2011). MicroRNA predictors of longevity in Caenorhabditis elegans. PLoS Genet.7:e1002306.10.1371/journal.pgen.1002306
138
PlumL.SchubertM.BruningJ. C. (2005). The role of insulin receptor signaling in the brain. Trends Endocrinol. Metab.16, 59–65.10.1016/j.tem.2005.01.008
139
PocockR.HobertO. (2010). Hypoxia activates a latent circuit for processing gustatory information in C. elegans. Nat. Neurosci.13, 610–614.10.1038/nn.2537
140
PoonP. C.KuoT.-H.LinfordN. J.RomanG.PletcherS. D. (2010). Carbon dioxide sensing modulates lifespan and physiology in Drosophila. PLoS Biol.8:e1000356.10.1371/journal.pbio.1000356
141
PrahladV.CorneliusT.MorimotoR. I. (2008). Regulation of the cellular heat shock response in Caenorhabditis elegans by thermosensory neurons. Science320, 811–814.10.1126/science.1156093
142
PrahladV.MorimotoR. I. (2011). Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins. Proc. Natl. Acad. Sci. U.S.A.108, 14204–14209.10.1073/pnas.1106557108
143
PuigO.MarrM. T.IIRuhfM. L.TjianR. (2003). Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev.17, 2006–2020.10.1101/gad.1098703
144
PuigO.TjianR. (2005). Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev.19, 2435–2446.10.1101/gad.1340505
145
RajanA.PerrimonN. (2011). Drosophila as a model for interorgan communication: lessons from studies on energy homeostasis. Dev. Cell21, 29–31.10.1016/j.devcel.2011.06.034
146
ReaS.JohnsonT. E. (2003). A metabolic model for life span determination in Caenorhabditis elegans. Dev. Cell5, 197–203.10.1016/S1534-5807(03)00242-9
147
ReaS. L.VenturaN.JohnsonT. E. (2007). Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS Biol.5:e259.10.1371/journal.pbio.0050259
148
ReddyP. H.ReddyT. P. (2011). Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Curr. Alzheimer Res.8, 393–409.10.2174/156720511795745401
149
ReznickD. N. (2005). The genetic basis of aging: an evolutionary biologist’s perspective. Sci. Aging Knowledge Environ.2005, e7.10.1126/sageke.2005.11.pe7
150
RogersC.PerssonA.CheungB.de BonoM. (2006). Behavioral motifs and neural pathways coordinating O2 responses and aggregation in C. elegans. Curr. Biol.16, 649–659.10.1016/j.cub.2006.03.023
151
RoseG.CroccoP.De RangoF.MontesantoA.PassarinoG. (2011). Further support to the uncoupling-to-survive theory: the genetic variation of human UCP genes is associated with longevity. PLoS ONE6:e29650.10.1371/journal.pone.0029650
152
RoseG.RomeoG.DatoS.CroccoP.BruniA. C.HervonenA.et al (2010). Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA study. PLoS ONE5:e13395.10.1371/journal.pone.0013395
153
RothT. L.SweattJ. D. (2011). Annual research review: epigenetic mechanisms and environmental shaping of the brain during sensitive periods of development. J. Child Psychol. Psychiatry52, 398–408.10.1111/j.1469-7610.2010.02282.x
154
RuizM.SanchezD.CanalI.AcebesA.GanforninaM. D. (2011). Sex-dependent modulation of longevity by two Drosophila homologues of human apolipoprotein D, GLaz and NLaz. Exp. Gerontol.46, 579–589.10.1016/j.exger.2011.02.014
155
RulifsonE. J.KimS. K.NusseR. (2002). Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science296, 1118–1120.10.1126/science.1070058
156
RybinaO. Y.PasyukovaE. G. (2010). A naturally occurring polymorphism at Drosophila melanogasterLim3 locus, a homolog of human LHX3/4, affects Lim3 transcription and fly lifespan. PLoS ONE5:e12621.10.1371/journal.pone.0012621
157
SainoN.RomanoM.AmbrosiniR.RuboliniD.BoncoraglioG.CaprioliM.et al (2012). Longevity and lifetime reproductive success of barn swallow offspring are predicted by their hatching date and phenotypic quality. J. Anim. Ecol.81, 1004–1012.10.1111/j.1365-2656.2012.01989.x
158
SchackwitzW. S.InoueT.ThomasJ. H. (1996). Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans. Neuron17, 719–728.10.1016/S0896-6273(00)80203-2
159
SchmidtP. S.DuvernellD. D.EanesW. F. (2000). Adaptive evolution of a candidate gene for aging in Drosophila. Proc. Natl. Acad. Sci. U.S.A.97, 10861–10865.10.1073/pnas.190338897
160
SchroeterH.BoydC. S.AhmedR.SpencerJ. P.DuncanR. F.Rice-EvansC.et al (2003). c-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis. Biochem. J.372, 359–369.10.1042/BJ20030201
161
SchubertM.GautamD.SurjoD.UekiK.BaudlerS.SchubertD.et al (2004). Role for neuronal insulin resistance in neurodegenerative diseases. Proc. Natl. Acad. Sci. U.S.A.101, 3100–3105.10.1073/pnas.0403216101
162
SchulzT. J.ZarseK.VoigtA.UrbanN.BirringerM.RistowM. (2007). Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab.6, 280–293.10.1016/j.cmet.2007.08.011
163
ShenJ.FordD.LandisG. N.TowerJ. (2009). Identifying sexual differentiation genes that affect Drosophila life span. BMC Geriatr.9:5610.1186/1471-2318-9-56
164
ShenL. L.DuM.LinX. F.CaiT.WangD. Y. (2010). Genes required for the functions of olfactory AWA neuron regulate the longevity of Caenorhabditis elegans in an insulin/IGF signaling-dependent fashion. Neurosci. Bull.26, 91–103.10.1007/s12264-010-0162-6
165
SiegalM. L.BergmanA. (2002). Waddington’s canalization revisited: developmental stability and evolution. Proc. Natl. Acad. Sci. U.S.A.99, 10528–10532.10.1073/pnas.102303999
166
SmithE. D.TsuchiyaM.FoxL. A.DangN.HuD.KerrE. O.et al (2008). Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res.18, 564–570.10.1101/gr.077008.108
167
SoerensenM.DatoS.ChristensenK.McGueM.StevnsnerT.BohrV. A.et al (2010). Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell9, 1010–1017.10.1111/j.1474-9726.2010.00627.x
168
StearnsS. C. (1992). The Evolution of Life Histories. Oxford: Oxford University Press.
169
StrandF. L. (1999). Neuropeptides – Regulators of Physiological Processes. Cambridge, MA: MIT Press.
170
SuhY.AtzmonG.ChoM. O.HwangD.LiuB.LeahyD. J.et al (2008). Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl. Acad. Sci. U.S.A.105, 3438–3442.10.1073/pnas.0705467105
171
SwerdlowR. H. (2011). Brain aging, Alzheimer’s disease, and mitochondria. Biochim. Biophys. Acta1812, 1630–1639.10.1016/j.bbadis.2011.08.012
172
TaguchiA.WartschowL. M.WhiteM. F. (2007). Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science317, 369–372.10.1126/science.1142179
173
TaguchiA.WhiteM. F. (2008). Insulin-like signaling, nutrient homeostasis, and life span. Annu. Rev. Physiol.70, 191–212.10.1146/annurev.physiol.70.113006.100533
174
TatarM. (2009). Metabolism by remote control. Cell Metab.10, 164–166.10.1016/j.cmet.2009.08.007
175
TatarM.BartkeA.AntebiA. (2003). The endocrine regulation of aging by insulin-like signals. Science299, 1346–1351.10.1126/science.1081447
176
TazearslanC.AyyadevaraS.BharillP.Shmookler ReisR. J. (2009). Positive feedback between transcriptional and kinase suppression in nematodes with extraordinary longevity and stress resistance. PLoS Genet.5:e1000452.10.1371/journal.pgen.1000452
177
TerryN. A.TulinaN.MatunisE.DiNardoS. (2006). Novel regulators revealed by profiling Drosophila testis stem cells within their niche. Dev. Biol.294, 246–257.10.1016/j.ydbio.2006.02.048
178
ThyagarajanB.BlaszczakA. G.ChandlerK. J.WattsJ. L.JohnsonW. E.GravesB. J. (2010). ETS-4 is a transcriptional regulator of life span in Caenorhabditis elegans. PLoS Genet.6:e1001125.10.1371/journal.pgen.1001125
179
TroulinakiK.BanoD. (2012). Mitochondrial deficiency: a double-edged sword for aging and neurodegeneration. Front. Genet.3:244.10.3389/fgene.2012.00244
180
van HamT. J.HolmbergM. A.van der GootA. T.TeulingE.Garcia-ArencibiaM.KimH. E.et al (2010). Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity. Cell142, 601–612.10.1016/j.cell.2010.07.020
181
Vermehren-SchmaedickA.AinsleyJ. A.JohnsonW. A.DaviesS.-A.MortonD. B. (2010). Behavioral responses to hypoxia in Drosophila larvae are mediated by atypical soluble guanylyl cyclases. Genetics186, 183–196.10.1534/genetics.110.118166
182
VilleponteauB. (1997). The heterochromatin loss model of aging. Exp. Gerontol.32, 383–394.10.1016/S0531-5565(96)00155-6
183
VolovikY.MamanM.DubnikovT.Bejerano-SagieM.JoyceD.KapernickE. A.et al (2012). Temporal requirements of heat shock factor-1 for longevity assurance. Aging Cell11, 491–499.10.1111/j.1474-9726.2012.00811.x
184
WalterS.AtzmonG.DemerathE. W.GarciaM. E.KaplanR. C.KumariM.et al (2011). A genome-wide association study of aging. Neurobiol. Aging32, 2109.e15–28.10.1016/j.neurobiolaging.2011.05.026
185
WangM. C.BohmannD.JasperH. (2005). JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell121, 115–125.10.1016/j.cell.2005.02.030
186
WaskarM.LandisG. N.ShenJ.CurtisC.TozerK.AbduevaD.et al (2009). Drosophila melanogaster p53 has developmental stage-specific and sex-specific effects on adult life span indicative of sexual antagonistic pleiotropy. Aging (Albany, NY)1, 903–936.
187
WeindruchR.WalfordR. L. (1988). The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: C. C. Thomas.
188
WessellsR. J.FitzgeraldE.CypserJ. R.TatarM.BodmerR. (2004). Insulin regulation of heart function in aging fruit flies. Nat. Genet.36, 1275–1281.10.1038/ng1476
189
WillcoxB. J.DonlonT. A.HeQ.ChenR.GroveJ. S.YanoK.et al (2008). FOXO3A genotype is strongly associated with human longevity. Proc. Natl. Acad. Sci. U.S.A.105, 13987–13992.10.1073/pnas.0801030105
190
WilliamsG. C. (1957). Pleiotropy, natural selection, and the evolution of senescence. Evolution11, 398–411.10.2307/2405809
191
WolkowC. A.KimuraK. D.LeeM. S.RuvkunG. (2000). Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science290, 147–150.10.1126/science.290.5489.147
192
WurtmanR. J.AxelrodJ.FischerJ. E. (1964). Melatonin synthesis in the pineal gland: effect of light mediated by the sympathetic nervous system. Science143, 1328–1329.10.1126/science.143.3612.1328
193
WurtmanR. J.AxelrodJ.PhillipsL. S. (1963). Melatonin synthesis in the pineal gland: control by light. Science142, 1071–1073.10.1126/science.142.3595.1071
194
WuttkeD.ConnorR.VoraC.CraigT.LiY.WoodS.et al (2012). Dissecting the gene network of dietary restriction to identify evolutionarily conserved pathways and new functional genes. PLoS Genet.8:e1002834.10.1371/journal.pgen.1002834
195
XiaoR.ZhangB.DongY.GongJ.XuT.JianfengL.et al (2013). A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell152, 806–817.10.1016/j.cell.2013.01.020
196
YinF.BoverisA.CadenasE. (2012). Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid. Redox Signal.10.1089/ars.2012.4774
197
YoonH.EnquistL. W.DulacC. (2005). Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell123, 669–682.10.1016/j.cell.2005.08.039
198
ZafraM. A.MolinaF.PuertoA. (2006). The neural/cephalic phase reflexes in the physiology of nutrition. Neurosci. Biobehav. Rev.30, 1032–1044.10.1016/j.neubiorev.2006.03.005
199
ZengY.ChengL.ChenH.CaoH.HauserE. R.LiuY.et al (2010). Effects of FOXO genotypes on longevity: a biodemographic analysis. J. Gerontol. A Biol. Sci. Med. Sci.65, 1285–1299.10.1093/gerona/glq156
200
ZhangC. Y.BaffyG.PerretP.KraussS.PeroniO.GrujicD.et al (2001). Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell105, 745–755.10.1016/S0092-8674(01)00385-3
201
ZhangY.ShaoZ.ZhaiZ.ShenC.Powell-CoffmanJ. A. (2009). The HIF-1 hypoxia-inducible factor modulates lifespan in C. elegans. PLoS ONE4:e6348.10.1371/journal.pone.0006348
202
ZhouQ.LamP. Y.HanD.CadenasE. (2008). c-Jun N-terminal kinase regulates mitochondrial bioenergetics by modulating pyruvate dehydrogenase activity in primary cortical neurons. J. Neurochem.104, 325–335.
203
ZhouQ.LamP. Y.HanD.CadenasE. (2009). Activation of c-Jun-N-terminal kinase and decline of mitochondrial pyruvate dehydrogenase activity during brain aging. FEBS Lett.583, 1132–1140.10.1016/j.febslet.2009.02.043
Summary
Keywords
aging, longevity, homeostasis, brain, nervous system, neuroendocrine system
Citation
Alcedo J, Flatt T and Pasyukova EG (2013) Neuronal Inputs and Outputs of Aging and Longevity. Front. Genet. 4:71. doi: 10.3389/fgene.2013.00071
Received
01 March 2013
Accepted
13 April 2013
Published
06 May 2013
Volume
4 - 2013
Edited by
Nektarios Tavernarakis, University of Crete, Foundation for Research and Technology – Hellas, Greece
Reviewed by
Vassiliki Nikoletopoulou, Institute of Molecular Biology and Biotechnology, Greece; Maria Markaki, Foundation for Research and Technology – Hellas, Greece; Marta Artal Sanz, University Pablo de Olavide, Spain
Copyright
© 2013 Alcedo, Flatt and Pasyukova.
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*Correspondence: Joy Alcedo, Department of Biological Sciences, Wayne State University, 5047 Gullen Mall, Detroit, MI 48202, USA. e-mail: joy.alcedo@wayne.edu; Thomas Flatt, Department of Ecology and Evolution, University of Lausanne, UNIL Sorge, Biophore, CH-1015 Lausanne, Switzerland. e-mail: thomas.flatt@unil.ch; Elena G. Pasyukova, Institute of Molecular Genetics, Russian Academy of Sciences, 2 Kurchatov Square, Moscow 123182, Russia. e-mail: egpas@rambler.ru
†Present address: Thomas Flatt, Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland.
This article was submitted to Frontiers in Genetics of Aging, a specialty of Frontiers in Genetics.
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