Energy restriction controls aging through neuroendocrine signal transduction

Ageing Research Reviews 3 (2004) 189–198

Review

Energy restriction controls aging through neuroendocrine signal transduction Yitshal N. Berner a , Felicia Stern b,∗ a

Geriatric Medicine, Meir Hospital, Kfar Saba, Affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel b Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel Received 6 October 2003; received in revised form 30 October 2003; accepted 30 October 2003

Abstract Since the work of McCay in 1935, demonstrating the effect of energy restricted diet on the lifespan of rats, many studies have confirmed these findings in different species. Several mechanisms have been suggested, including among others, growth retardation, diminished apoptosis, decreased oxidative damage, altered glucose utilization, changes in gene expression, enhanced stress responsiveness and hormesis. There is some evidence that energy restriction (ER) exerts important metabolic effects on the aging process and longevity through intra- and intercellular signal transduction transmitters, with several signaling pathways mediating its beneficial action. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Energy restriction; Aging; Neuroendocrine; Signal transduction; Lifespan

1. Introduction Throughout history people have been striving to preserve youthfulness and to extend healthy longevity. Physiological function, and therefore health and well-being are significantly affected by nutrition. Since the work of McCay in 1935, demonstrating the beneficial effect of energy restricted diet by about 30% of the “ad libitum” eating, on median and maximal lifespan in a cohort of rats (McCay et al., 1935), many studies (restricting energy intake to 50–70% of that eaten by ad libitum fed animals), have confirmed these findings in different species including rat, mice, hamsters, fish, flies, protozoa, worms, water fleas ∗

Corresponding author. Tel.: +972-8-9489280; (mobile): +972-52-497525; fax: +972-8-9476189. E-mail address: [email protected] (F. Stern).

1568-1637/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.arr.2003.10.004

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and partially in several mammals (Masoro, 2000). Some studies have demonstrated a minor effect of protein restriction, but the greatest impact was when energy intake was restricted starting in young adult life or even in early middle age. Changes in numerous important intracellular and intercellular events, associated with aging, have been shown to be modulated by energy restriction (ER), including increased expression of several metabolic response genes (Yu, 1996). Some of the changes induced by ER include: the release of calcium from the endoplasmic and sarcoplasmic reticulum stimulated by inositol-triphosphate (Undie and Friedman, 1993; Salih et al., 1997); the effect on ␤-adrenergic receptors (Snyder et al., 1998); mitogenactivated protein kinase activation (Zhen et al., 1999); the activation of receptors by growth hormone (GH) (Xu and Sonntag, 1996); the expression of several metabolic response genes (including the heat shock protein—HSP 70) (Heydari et al., 1993); increased levels of mRNA transcripts for superoxide dismutase (SOD) and catalase (Van Remmen et al., 1995); expression of calnexin in mouse liver (Dhahbi et al., 1997); expression of IL-2 in rat splenic T-cells correlated to changes in the transcription factor NFAT (Pahlavani et al., 1997); synthesis of p53 and its phosphorylation in response to retinoic acid (Pipkin et al., 1997); regulation of hormone secretion, e.g. gonadotropins (McShane and Wise, 1996) and precursors of androgen steroids like dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) (Lane et al., 1999), neuropeptide-Y (McShane et al., 1999), GH (Xu and Sonntag, 1996; Han et al., 1998; Vuagnat et al., 1998), leptin (Shimokawa and Higami, 2001), insulin (Masoro et al., 1992), prolactin, but not proopiomelanocortin (Han et al., 1998); increased glutathione concentration and decreased oxidative damage (Armeni et al., 1998); DNA repair (Guo et al., 1998); decreased exhalation of aldehydes (Matsuo et al., 1993); and decreased lipid peroxidation (Cook and Yu, 1998). The mechanisms underlying the ability of ER to extend lifespan remain elusive (de Cabo et al., 2003), although several mechanisms (based on animal experimentation) have been suggested including decreased oxygen radical damage (Sohal et al., 1994), reduced glycation or glycoxidation of macromolecules (Cefalu et al., 1995), altered glucose utilization (Masoro, 2000), changes in gene expression (Van Remmen et al., 1995) enhanced stress responsiveness (de Cabo et al., 2003), diminished apoptosis (Sharp et al., 1999) and increases in stress hormones (Sabatino et al., 1991). Definitive conclusions regarding the anti-aging effect of ER in humans to be deduced from studies in non-human primates will not be forthcoming for at least 10–20 years (Masoro, 2000). According to the epidemiological observation from Okinawa, a southern Japanese island, the people there live longer, the rate of centenarians being about 40 times higher than in the rest of Japan. Those people are shorter by about 4.1 cm. They also differ in their average energy intake, which is about 83% of the average consumption in Japan (Kagawa, 1978). In the Baltimore Longitudinal Study of Aging, an enhanced survival has been recently found in a human aging cohort of men with lower temperature and insulin levels but higher DHEAS levels, consistent with the beneficial effects of ER on aging and lifespan observed in monkeys (Roth et al., 2002). Cellular function is controlled by hormones, cytokines and neurotransmitters acting through the cell receptors and altered cellular function (Lane et al., 1999). The purpose of this review is to show how ER by modulating impulse transduction involved in the neuroendocrine system affects cell metabolism to extend lifespan.

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2. Cytoprotective effects of ER It has been hypothesized that the mammalian aging is associated with a reduced ability to activate pro-survival signaling pathways in response to oxidative stress, leading to cell oxidative damage (Ikeyama et al., 2002). Reactive oxygen species (ROS) are constantly time generated as a result of normal oxygen metabolism, which is enhanced with aging (Masoro, 2000). Oxidative stress occurs when ROS are produced in excess and the natural cell defenses fail. Reduced ROS production has been observed in isolated mitochondria from mice grown on ER (Sohal et al., 1994) and ER has been shown to suppress a variety of oxidative cellular damages and to maintain antioxidant defense systems (which decline with aging), including ROS-scavengers (Yu, 1996). In transgenic flies, expressing high levels of SOD, an increase in the lifespan was observed (Lin et al., 1998). In the liver of rodents, ER prevented the decrease in the level of mRNA transcripts for two enzymes, catalase and SOD, functioning as free radical scavengers (Van Remmen et al., 1995). Energy restricted rats have demonstrated suppression of the age-dependent increase in the exhalation of the aldehyde pentane (a marker of oxidative activity) (Matsuo et al., 1993) and decreased age-dependent accumulation of glycoxidation products in the skin collagen (Cefalu et al., 1995). ER also induces mild cellular stress, in response to which the cell takes adaptive measures by synthesizing many cytoprotective proteins (Fig. 1), including neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins, all of which enhance neuronal plasticity and resistance to oxidative and metabolic insults (Mattson et al., 2003). For example, HSP 70 can provide neuronal protection by several mechanisms, including better regulation of Ca2+ , attenuation of ROS-mediated damage, and inhibition of necrosis and apoptosis (Yenari et al., 1999). ER has been shown to enhance, in rat hepatocytes, the expression of HSP 70 and other stress response genes (decreasing with aging) in response to stress, an enhancement that correlates with an increase in binding of its transcription factor (Heydari et al., 1993). Hormones Glucocorticoids Thyroids Adrenals Gonads Leptin

Energy Restriction

Antioxidants SOD Catalase Protein Synthesis Protein Chaperons (HSP70) Protein Kinases (MAPKs, Akt kinase) Mitochondrial uncoupling protein Neurotrophic factors (BDNF) Protein Glycosylation

Fig. 1. Neuroendocrine stress pathways.

Survival

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3. Neuroendocrine response to ER The neuroendocrine theory of aging is based on the assumption that failure of cells with specific integrative functions brings about homeostatic failure of the organism, leading to senescence and death. The failure of specific neuroendocrine functions with aging leads to key age-related systemic and physiological failures. Physiological neuroendocrine responses to ER may increase lifespan (Mobbs et al., 2001). The molecular mechanisms by which ER regulates the neuroendocrine systems remain obscure. The effects of ER may be explained from the evolutionary perspective; organisms have developed neuroendocrine signals and metabolic response systems to maximize survival during periods of food shortage. When organisms encounter a period of food shortage, they suspend growth and reproduction and induce defense molecules, like glucocorticoid hormones and heat shock proteins (Holliday, 1989). In Caenorhabditis elegans, during unfavorable environmental conditions, the reproductive system arrests at the dauer diapause stage. Signals from the reproductive system probably regulate lifespan by modulating the activities of insulin signal transduction pathway (Tissenbaum et al., 2000). Increased glucocorticoid hormone levels in response to ER, which constitutes a long-term low intensity stressor (Sabatino et al., 1991), possibly lead to a ‘hormetic effect’. Hormesis’ is defined as the beneficial response of the organism to low intensity stressors (which at higher levels would result in detrimental effects) resulting in an improved ability of an organism to regulate stress responses and the hypothalamic–pituary–adrenal axis (HPAA), which is critical for mobilizing energy reserves and immune responses (Pedersen et al., 2001). Elevated glucocorticoid levels, which occur during aging, are damaging to the hippocampus (DeKloet et al., 1998) and increase the risk of neurodegeneration (Patel and Finch, 2002). DeKloet (DeKloet et al., 1998) suggested that the hyppocampal damage results from the imbalance between mineralocorticoid receptors, which control basal activity, and glucocorticoid receptors, which limit the responsiveness to stress. ER, actually, increases free plasma corticosterone. However, it has been suggested that the neuroprotective effects (e.g., decreased plasma glucose, attenuated oxidative stress, increased expression of heat shock proteins and neurotrophic factors) of ER (Fig. 1) outweigh the deleterious effects of glucocorticoids (Patel and Finch, 2002). Heat shock proteins are encoded by a family of highly conserved genes, most of them constitutively expressed in normal unstressed cells (Lacoste et al., 2001) and serve as molecular chaperones that bind to other proteins and regulate their conformation, receptor availability, enzyme activity or proteins’ movement across membranes and through organelles. Overproduction of HSP 70 (induced among others by ER), the most abundant heat shock protein, can ameliorate apoptotic cell death (Sharp et al., 1999). It has been suggested that the HSP response is integrated with physiological responses through neuroendocrine signaling. Noradrenaline and ␣-adrenergic signaling both induced the transcriptional upregulation of HSP 70 in mollusc hemocytes (Lacoste et al., 2001). An age-dependent decline in ␤ receptor responsiveness was attenuated by ER (Snyder et al., 1998) and a decrease in the ability of epinephrine to increase cytoplasmic calcium ion concentration in parotid acinar cells of male F344 rats was blunted but not prevented by ER (Salih et al., 1997). There is an increased recognition in the bi-directional communication of the neuroendocrine system and immune system in the aging process through complex signaling

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pathways of neurotransmitters. The accumulation of free-radicals producing oxidative stress (particularly activated during immune reactivity) and the inability to remove them associated with reduced SOD and catalase activities in the spleen as found in rodents (Byun et al., 1995) probably account for the sympathetic noradrenergic (NA) loss of nerve fibers in the spleen during aging. Adrenergic receptors are present on many cells of the immune system, facilitating signaling between nerves and the immune cells through the release of norepinephrine (NE) that subsequently binds with adrenoreceptors. Accumulation of toxic free radicals (NE toxic oxidative catabolites) during repeated high level release of NE, in response to immune challenges, may be driven by cytokines and other immunological products and cause destruction of NA nerve fibers, thereby interfering with NE presence and availability in the spleen. Since ER prevents the decline in antioxidant enzymes it may aid in the regeneration and survival of NA nerve fibers in the spleen (ThyagaRajan and Felten, 2002). The neuroendocrine system may mediate effects of ER on the aging process also by reducing exposure of glucose-sensitive neuroendocrine cells to glucose, thus limiting their erosion (Mobbs et al., 2001), because normal glucose metabolism in glucose-sensitive neuroendocrine cells (especially in the hypothalamus) cumulatively impairs the function of these cells and leads to age-associated metabolic impairments. Both leptin (Spanswick et al., 1997) and insulin (Spanswick et al., 2000) inhibit glucose-receptive hypothalamic neurons by activation of ATP-sensitive potassium channels, resulting in a decline of neuronal firing rates. This decline might lead to the alteration of the set point of neuronal activation, which might be a crucial mechanism for neuroendocrine adaptation by ER. Reduced leptin and insulin levels by ER might have synergistic effects on longevity (Chiba et al., 2002). 3.1. Leptin Leptin is a hormone secreted by adipose cells that serves as a metabolic signal (Vuagnat et al., 1998). As a long-term food intake regulator (Havel, 2001), it signals nutritional status to several other physiologic systems and modulates their function (Shimokawa and Higami, 2001). Leptin has been proposed to have a dominant physiological role as a signal for the switch between fed and fasted states (Chiba et al., 2002). There seems to be a dual regulation of circulating plasma leptin levels; when there is an energy balance, leptin regulates energy storage in the adipose tissue, whereas during acute perturbations in energy balance, leptin levels change independently of the available adipose fat stores (Schwartz et al., 2000). That is, when plasma leptin levels decline (Fig. 2) following fasting or long-term ER, neuroendocrine necessary changes (like the suppression of the gonadal, GH and thyroidal axes and the enhancement of glucocorticoid system) are induced in response to life threatening stress (Ahima et al., 1996) as part of adaptive responses to maximize organism survival (Shimokawa and Higami, 2001). The HPAA is an endocrine regulatory system that responds quickly to stress and the system adapts to chronic stress, so that further responsiveness of the axis is maintained. Negative feedback control of the HPAA by glucocorticoids during stress is well documented (Dallman, 1993). Leptin could provide a further source of negative feedback inhibition to this axis. Leptin’s ability to inhibit (by in vitro hypothalamic perfusion) corticotropin releasing hormone (CRH) hypothalamic release, stimulated beforehand by decreasing glucose concentration, might be the explanation for its ability to inhibit activation of the HPAA in response to stress (Heiman et al., 1997). Although long-term ER

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Energy Restriction Gonads Testosterone

Hormones Glucocorticoids Thyroids

Fat Mass

Insulin Leptin Hypothalamic Neuronal Exposure to Glucose

NPY Somatostatin GH

Fig. 2. Leptin related pathways.

could differ in several aspects of physiology from fasting, the hormonal profile of ER is similar to that of fasting (Nelson, 1994a). Reduced plasma leptin levels, induced by ER, possibly change the thresholds at which negative and positive feedbacks of the neuroendocrine system switch on/off for several hormones (Shimokawa and Higami, 2001). For the adrenal glucocorticoid system, reduced plasma leptin levels lower the threshold at which the positive feedback system switches off (Shimokawa and Higami, 2001), i.e., the rise in corticosterone levels during fasting or ER, may be mediated by falling levels of leptin. Glucocorticoids have a cell-specific effect to reduce prothyrotropin-releasing hormone (proTRH) mRNA levels. Systemic administration of leptin to fasting animals restored plasma thyroxine (T4 ) and proTRH mRNA in the paraventricular nucleus to normal, suggesting that the fall in circulating leptin levels during fasting acts as a signal to hypophysiotropic neurons in the paraventricular nucleus to reset the set point for feedback regulation of proTRH mRNA (inducing proTRH gene expression in the paraventricular nucleus) by thyroid hormone, thereby allowing adaptation to starvation (Legradi et al., 1997, 1998). Leptin can inhibit hypothalamic release of CRH, either directly or indirectly through another hypothalamic neuropeptide such as neuropeptide-Y (NPY). In energy restricted animals GH levels decrease (Nelson, 1994b) as part of metabolic adaptation (Shimokawa and Higami, 2001). NPY, the synthesis and release of which, is clearly increased by ER (McShane et al., 1999), is possibly involved in the neuroendocrine regulation of GH release. Central administration of NPY to normal rats inhibited GH release (Rettori et al., 1990). Leptin, as a metabolic signal, regulates GH secretion in the rat by acting on hypothalamic GH-regulatory hormones (Cocchi et al., 1999; Carro et al., 1997). Leptin administration produced a significant decrease in NPY synthesis in rats. A leptin-NPY-GH axis is postulated, based on the capacity of NPY to actually inhibit GH secretion in coordination with the leptin metabolic signal. It appears that during stressful conditions GH secretion is regulated by leptin and NPY axes (Vuagnat et al., 1998) in addition to somatostatin and growth hormone releasing hormone (GHRH) (Cocchi et al., 1999). 3.2. ROS Another possible neuroprotective effect of ER involves the attenuation of oxidative stress. Recently, ROS have been shown to serve as second messengers. Signals from membrane

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surface receptors and oxidative stimuli that occur in the cytoplasm may be transmitted through cellular signal transduction pathways to the nucleus for the maintenance of the normal cell functions. Under oxidative stress conditions, many transcription factors and protein kinases (Fig. 1), like serine-threonine kinase Akt (survival signal) and extracellular signal regulated kinase (ERK), one of the mitogen activated protein kinases (MAPKs), are activated (Ikeyama et al., 2002; Kim et al., 2002). Free radicals were shown to activate the MAPKs (Irani et al., 1997), which play a central role in transducing extracellular signals to the nucleus (Su and Karin, 1996). During aging increased oxidative stress caused intensified activation of MAPKs in rat kidney, which can be prevented by ER. However, contradicting data have been reported on the changes during aging in MAPKs activity in different tissues. The selective modulation of different MAPKs in different tissues by ER may be related to the defense mechanisms of the organism for survival (Kim et al., 2002). 3.3. Insulin and growth factors ER also induces the expression of genes that encode proteins, which promote cell survival and adaptive plasticity by increasing insulin-like and neurotrophin signaling pathways (Mattson et al., 2003). Studies in nematodes, flies and rodents have shown that insulin-like signaling in the nervous system can control lifespan, possibly by modulating stress responses and energy metabolism. Receptors coupled to the phosphatidylinositol-3-kinase-Akt signaling pathways are involved in the signaling system involved in regulating cellular and organismal energy metabolism and stress responses as well as in sensing and responding to energy/food-related environmental signals (Mattson, 2002). In a search for lifespanextending genes a set of genes, identified in Caenorhabditis elegans and Drosophila, was found to encode proteins (homologs of the insulin signaling pathway in mammals) controlling the activation of phosphatidylinositol-3-kinase-Akt signaling pathway, which results in the inactivation of glycogen synthase kinase-3␤ and forkhead transcription factors (Van Weeren et al., 1998). It should be noted that ER prevented, in the brain of male F344 rats, the age-associated decline in inositol triphosphate, a common intracellular messenger and an important signal transducer (Undie and Friedman, 1993). A prominent effect of ER in rodent’s muscle and liver cells is to enhance their insulin sensitivity. Insulin receptors are coupled to a protein called insulin receptor substrate-1 (IRS-1), which is essential for the activation of the phosphatidylinositol-3 kinase–Akt pathway (Mattson et al., 2003). Major activators of this pathway are insulin, insulin-like growth factors and BDNF (Mattson, 2002). The high-afinity of the BDNF receptor trkB is coupled to the IRS-1, phosphatidylinositol-3 kinase–Akt pathway, as are insulin-like growth factor (IGF) receptors that are expressed by neurons (Mattson et al., 2003). Powerful evidence for the direct role of IGF-1 signaling in the control of mammalian aging was provided by female mice mutant for the IGF-1 receptor, which lived 33% longer than wild-type controls (Tatar et al., 2003). Lifespan was also increased by 50% and more in FIRKO mice (fat-specific insulin receptor knockout mice) lacking the insulin receptor in adipose tissue, as a result of knocking out insulin signaling. The phenotype of aging FIRKO mice shows similarities with the phenotype of energy-restricted mice, such as reduced adiposity, trend to lower insulin levels and protection from decreased insulin sensitivity (Bluher et al., 2003).

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4. Conclusions Regulated by the neuroendocrine system, energy metabolism and responses to oxidative stress are probably the main biological pathways that control lifespan. It has been shown that ER affects metabolic activities through transmitters of intra- and intercellular signals. Neurotransmitters signaling pathways may be affected by ER, thus influencing metabolic and immunologic activities. However, more studies using ER manipulations are needed to further elucidate the mechanisms by which neuroendocrine system may mediate the effects of ER, and to assess the optimal intake for regulating maximum lifespan and securing better life preservation. References Ahima, R.S., Prabakaran, D., Mantzoros, C., Qu, D., Lowell, B., Maratos-Flier, E., Flier, J.S., 1996. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252. Armeni, T., Pieri, C., Marra, M., Saccucci, F., Principato, G., 1998. Studies on the life prolonging effect of food restriction: glutathione levels and glyoxalase enzymes in rat liver. Mech. Ageing Dev. 101, 101–110. Bluher, M., Kahn, B.B., Kahn, R., 2003. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574. Byun, D.S., Venkatraman, J.T., Yu, B.P., Fernandes, G., 1995. Modulation of antioxidant activities and immune response by food restriction in aging Fisher-344 rats. Aging Clin. Exp. Res. 7, 40–48. Carro, E., Senaris, R., Considine, R.V., Casanueva, F.F., Dieguez, C., 1997. Regulation of in vivo growth hormone secretion by leptin. Endocrinology 138, 2203–2206. Cefalu, W.T., Bell-Farrow, A.D., Wang, Z.Q., Sonntag, W.E., Fu, M.X., Baynes, J.W., Thorpe, S.R., 1995. Caloric restriction decreases age-dependent accumulation of the glycoxidation products, N epsilon-(carboxymethyl)lysine and pentosidine, in rat skin collagen. J. Gerontol. A Biol. Sci. Med. Sci. 50, B337–B341. Chiba, T., Yamaza, H., Higami, Y., Shimokawa, I., 2002. Anti-aging effects of caloric restriction: involvement of neuroendocrine adaptation by peripheral signaling. Microsc. Res. Tech. 59, 317–324. Cocchi, D., De Gennaro-Colonna, V., Bagnasco, M., Bonnaci, D., Muller, E.E., 1999. Leptin regulates GH secretion in the rat by acting on GHRH and somatostalinergic functions. J. Endcrinol. 162, 95–99. Cook, C.I., Yu, B.P., 1998. Iron accumulation in aging: modulation by dietary restriction. Mech. Ageing Dev. 102, 1–13. de Cabo, R., Furer-Galban, S., Anson, R.M., Gilman, C., Gorospe, M., Lane, M.A., 2003. An in vitro model of caloric restriction. Exp. Gerontol. 38, 631–639. Dallman, M.F., 1993. Stress update: adaptation of the hypothalamic-pituitary-adrenal axis to chronic stress. Trends Endocrinol. Metab. 4, 62–69. DeKloet, E.R., Vreugdenhil, E., Oitzl, M.S., Joels, M., 1998. Brain corticosteroid receptor balance in health and disease. Endocrine Rev. 19, 269–301. Dhahbi, J.M., Mote, P.L., Tillman, J.B., Walford, R.L., Spindler, S.R., 1997. Dietary energy tissue-specifically regulates endoplasmatic reticulum chaperone gene expression in liver of mice. J. Nutr. 127, 1758–1764. Guo, Z.M., Heydari, A., Richardson, A., 1998. Nucleotide excision repair of actively transcribed versus nontranscribed DNA in rat hepatocytes: effect of age and dietary restriction. Exp. Cell Res. 245, 228–238. Han, E., Lu, D.H., Nelson, J.F., 1998. Food restriction differentially affects mRNAs encoding the major anterior pituary tropic hormones. J. Gerontol. Biol. A Sci. 53, B322–B329. Havel, P.J., 2001. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp. Biol. Med. 226, 963–977. Heydari, A.R., Wu, B., Takahashi, R., Strong, R., Richardson, A., 1993. Expression of heat shock protein 70 is altered by age and diet at the level of transcription. Mol. Cell Biol. 13, 2909–2918. Heiman, M.L., Ahima, R.S., Craft, L.S., Schoner, B., Stephens, T.W., Flier, J.S., 1997. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology 138, 3859–3863.

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