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Mechanisms of anti-aging and prolongation of life span associated with calorie restriction: data from studies of genetically modified animals.
It is well known that calorie restriction (CR) increases life expectancy and suppresses various pathophysiological changes. CR suppresses the signaling of growth hormone /insulin-like growth factor and mTORC? activates sirtuin and enhances mitochondrial redox regulation. But the exact mechanisms are under discussion. In this review, we will discuss the mechanisms of CR using data from studies of animals that have been genetically modified in accordance with recent advances in molecular and genetic technologies from the point of view of the adaptive response hypothesis proposed by Holliday in 1989. We will also explain the positive effects of CR, classified according to whether they are acting in a diet or fasting.
In 193? it was described that CR increases the lifespan in rats[1 ]. CR, also known as dietary restriction or energy restriction, is widely used in aging studies as a strong and simply reproducible dietary manipulation to prolong the life span. The effect of CR was observed in several species, from yeasts and nematodes to mammals. In mammals, it was mainly studied using rodents, in which CR suppresses various age-related pathophysiological changes and prolongs the average and maximum life span. However, the useful effects of CR disappear in certain strains and /or states. A recent review details these limitations of[2 ]. The extent to which CR has beneficial effects depends on factors such as rodent species, strains, and timing of onset of CR. In general, however, long-term CR, started at a young age, suppresses age-related pathophysiological changes and prolongs the longevity of different rodents. It is also important that the limitations of individual nutrients (eg, glucose, lipid, protein) without limiting energy do not cause such beneficial effects[3, 4 ].
More than 20 years ago it was discovered that Ames dwarf mice that have a mutation of the Prop1 gene live longer than wild-type mice[5 ]. This was the first report that one gene mutation or genetic modification can prolong longevity in mammals. According to our information, more than 40 mice and rats with a single gene mutation or genetic modification live longer than wild-type animals. Of these mice and rats, about one-third demonstrate suppressed signaling of growth hormone (GH) /insulin-like growth factor 1 (IGF1). Since CR also suppresses the GH /IGF1 signaling, the useful CR actions can be based on this. Other molecular mechanisms that have been proposed for regulating the beneficial effects of CR include the inhibition of the activity of the target of the rapamycin complex 1 (mTORC1), the activation of autophagy, the activation of the metabolism of NAD + and sirtuin, and an increase in the redox regulation of mitochondria[6, 7 ]. However, these mechanisms are not fully understood.
Fig.1. Suggested mechanisms for the action of caloric restriction (CR) against aging and on extending the life span based on the hypothesis of an adaptive response. It is proposed that the CR regulatory mechanisms be divided into two systems. The first system is activated under sufficient energy conditions, when there is a possibility for free energy use, and the animals grow well, reproduce more and conserve excess energy in the form of triglycerides (TG) in white adipose tissue (WAT) for later use. This system includes growth hormone (GH) /insulin-like growth factor 1 (IGF1), Akt, FOXO, mTORC, adiponectin and BMAL1. The second system is activated in conditions of insufficient energy resources, when there is no benefit from excessive use of energy, and animals suppress growth and reproduction and use the saved energy to maintain biological function. This system includes such signaling pathways as SREBP-1c protein, sirtuin (SIRT), PGC-1α protein, mitochondrial reactive oxygen species (ROS), leptin and neuropeptide Y (NPY). In CR animals, these signals are effective for use of energy. Moreover, various signals and /or factors can contribute to beneficial actions associated with CR, including antioxidant, anti-inflammatory, antineoplastic and other effects of CR to varying degrees in each tissue or organ and thereby lead to rejuvenation and longer life. .
Objectives and molecular mechanisms of CR.
GH, IGF1 and FOXO1 signaling.
GH positively regulates the production of IGF1 primarily in the liver via the GH receptor (GHR). IGF1 acts on the IGF1 receptor, and then phosphorylates Akt, serine /threonine kinase in target cells. Then the phosphorylated form of Akt phosphorylates FOXO transcription factors, promoting nuclear export. Therefore, suppression of GH /IGF1 signaling transcriptionally increases the expression of several genes activated by FOXO transcription factors.
Several modified species of mice, Ames dwarf, Snell dwarf and GHR knockout (GHR KO), show suppressed GH signaling and have an extended lifespan. These dwarf mice have similar phenotypes with CR mice, including suppressed GH /IGF1 signaling, reduced levels of the thyroid hormone, insulin and glucose, lower body temperature and lower obesity. However, the liver gene expression profile is significantly different between the GHR KO mice and the CR[8 ]mice. . We also reported that part of the gene expression profile in the white adipose tissue (WAT) of CR rats is significantly different from that in lifelong dwarf rats bearing the antisense GH transgene[9 ].
Bonkowski et al. reported that CR increases insulin sensitivity and prolongs life expectancy in wild-type mice, but not in GHR KOmice. . Therefore, they suggested that the effect of increasing the life span of CR depends on the suppression of GH /IGF1 signaling. In dwarf mice and dwarf rats bearing the antisense GH transgene, CR further increased the life span of[11, 12 ]. These data suggest that actions against aging and increasing the life span of CR can be regulated as dependent on the GH /IGF1 signal, and independently.
The transcription factors of FOXO in mammals consist of four isoforms, i.e. FOXO? ? 4 and 6. In FOXO1 KO mice (with knockout of this gene) the extended life of CR, but there was no antitumor effect associated with CR[13 ]. Conversely, in the FOXO3 KO mice, the addition of CR suppressed tumorigenesis, but there was no CR-induced increase in the[14 ]lifetime. . These differences may be associated with a differential activation pattern in the tissues and /or cells of the four isoforms of the transcription factors FOXO induced by CR.
BMAL1 protein is a transcription factor involved in the regulation of circadian rhythm. In BMAL1 KO mice (with knockout of this gene), food intake increased, body weight decreased, and the phenotypes of aging accelerated. In these same mice, CR did not lower insulin levels and IGF1 and did not increase life expectancy. What shows the involvement of BMAL1 in the useful action of CR and that this useful action depends on the signaling of GH /IGF1[15 ].
mTOR kinase, serine /threonine kinase, was identified as a target molecule of rapamycin. It forms two separate multi-protein complexes, known as mTORC1 and mTORC2. It is known that mTORC1 is activated by amino acids and growth factors (for example, insulin and IGF1). Activation of mTORC1 promotes protein synthesis through ribosomal protein kinase S6 ? the synthesis of fatty acids via a steroid regulatory regulating protein (SREBP) 1 and adipocyte differentiation by peroxisome proliferator activated receptors (PPARγ). mTORC1 suppresses autophagy and lysosomal biosynthesis via EB transcription factor (TFEB). The mTORC2 function is poorly understood, but it is believed that it includes anabolic enhancement and catabolic suppression, as for mTORC1[16 ].
Mice given rapamycin negatively regulating mTORC? for a long period after middle age, had an increase in the lifetime of[17 ]. According to this finding, transgenic mice with overexpression of the TSC1 protein, which negatively regulates mTORC? live longer than wild-type mice[18 ]. In addition, knockout mice, ribosomal protein kinase S6 1 and mutant mTOR mice also lived longer than wild-type mice[19, 20 ].
To our knowledge, the beneficial effect of CR has not yet been studied in mice with the defective mTORC1 function. However, in yeast with genetic inhibition mTOR CR did not increase the life span of[21 ]. The autophagy is enhanced by the suppression of mTORC1. In nematodes deficient in genes associated with autophagy, CR did not increase the life span of[22 ]. Based on these data, it is likely that a decrease in mTOR activity and activation of the autophagic apparatus is associated with a positive CR effect.
Sir2 was discovered as a new gene involved in the suppression of transcription in yeast. After that, it was reported that he plays a key role in extending life at CR[23, 24]. Seven sirtuin orthologs, Sirt1-Sirt7 sirtuins, have been identified in mammals. Proteins SIRT? 6 and 7 are mainly localized in the nucleus, SIRT2 in the nucleus and cytoplasm, and SIRTs ? 4 and 5 are predominantly in the mitochondria. Sirtuins catalyze deacetylation reactions of various proteins, including histones, depending on NAD[25 ].
Among seven mammalian sirtuins, it is reported that SIRT? 3 and 6 are involved in age-related pathophysiology and regulation of the life span of[26 ]. Transgenic mice in which the SIRT1 protein was selectively overexpressed in hypothalamic neurons had a longer life span than wild-type mice.[27 ]. Transgenic female mice in which the SIRT6 protein was overexpressed had a longer lifetime than wild-type mice[28 ]. In elderly mice CR for 6 months increased the expression of SIRT6 and improved renal failure. In addition, while the overexpression of SIRT6 suppressed cell aging by reducing the activity of the inflammation-related NF-κB transcription factor, the SIKT6 knockout accelerated the cell aging of[29 ]. SIRT3 KO mice previously had different age-related pathologies[30 ]. Although CR prevented age-related hearing loss in wild-type mice, this effect was not observed in SIRT3 KO[31 ]mice. .
Transcription factor NRF2.
NRF2 binds to antioxidant response elements to induce the expression of target genes in response to oxidative stress and enhances the expression of genes involved in antioxidant and detoxification responses. Under physiological conditions, NRF2 binds to the Keap1 protein in the cytoplasm, where it degrades. Under stress, including oxidative stress, after Keap1 is captured by phosphorylated p6? NRF2 is translocated into the nucleus, binds to the antioxidant elements of the response and activates the transcription of the antioxidant genes[32 ].
Since NRF2 expression decreases with rodent aging, it is assumed that the levels of reactive oxygen species and the various risks of cancer occurrence increase. However, CR suppresses the age-related decline in antioxidant capacity by increasing the expression of genes involved in antioxidation and detoxification. In nematodes, Skn-? the homologue of NRF? is indispensable for the effect of CR on prolonging the life span. Mice with knockout NRF2 demonstrate a decrease in the expression of genes involved in antioxidant response and detoxification, which accelerates oncogenesis. The role of NRF2 in the beneficial effects of CR was investigated using NRF2 KO mice. The results showed that NRF2 is important for the antitumor effect of CR, but does not participate in effects related to longevity and increased sensitivity to insulin CR.
Neuropeptide Y (NPY).
In mammals, neurons in the hypothalamic arcuate nucleus feel the energy status from the levels of circulation of hormones. CR-associated negative energy balance and subsequent reduction in fat mass increase circulation of ghrelin and adiponectin levels and decrease levels of leptin, insulin and IGF1 in the blood. These hormonal changes activate NPY-neurons in the hypothalamic arcuate nucleus. Most of these neurons synthesize the Agrp protein, weakening the activity of POMC neurons in an arcuate nucleus. A change in the activity of primary neurons inhibits secondary hypothalamic neurons secreting somatotropin, gonadotropin and thyrotropin-releasing hormone, and activates neurons secreting corticotropin-releasing hormone. This hypothalamic alteration suppresses GH /IGF1 signaling, thyroid function and reproduction and activates the function of adrenal glukocorticoids. Most of these altered neuronal secretion profiles are observed in mice and rats at CR[34 ].
In knockout NPY KO mice, the addition of CR did not increase life expectancy, caused tolerance to oxidative stress in the liver, and altered the profile of neuronal secretion. However, CR reduced insulin and IGF1 levels in the blood, increased adiponectin levels in blood and corticosterone levels, and reduced expression of genes involved in beta-oxidation in the liver. Thus, NPY should be a key factor associated with the independent actions of CR[3, 4 ]? independent of GF /IGF1. .
Mitochondrial DNA mutation (mtDNA).
It is generally believed that the accumulation of mutations of mtDNA is one of the key factors of pathogenesis in age-related diseases. PolgA D257A /D257A mice carry a mutation in mtDNA polymerase gamma and show an earlier development of age accumulation of mtDNA mutations and age phenotypes in various[36 ]tissues. . In PolgA mice, the D257A /D257A CR did not prolong life expectancy, did not affect the accumulation of mtDNA deletion in skeletal muscles, and did not improve cardiac function, and this contributed to sarcopenia. These data suggest that the accumulation of mtDNA mutations can inhibit the beneficial effects of CR.
Our new results: remodeling of adipose tissue under the influence of CR
Visceral obesity associated with diabetes, hyperlipidemia and hypertension, collectively known as the "metabolic syndrome," is a known risk factor for the development of atherosclerotic diseases associated with the development of life, including myocardial infarction and cerebral infarction. Adipose tissue, initially thought to be only related to the energy function, has recently been described as an endocrine organ that secretes various biologically active molecules called adipokines. Large adipocytes that accumulate triglycerides (TG) excessively increase the secretion of inflammatory adipokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and decrease the secretion of adiponectin compared to small adipocytesand, which accumulate less TG. These adipokine secretion profiles are directly involved in age-related pathologies, including insulin resistance, hypertension and atherosclerosis[38 ]. In addition, it has recently been reported that adipose tissue and adipokines are key players in regulating life expectancy. For example, mice with an insulin receptor knockout in adipocytes showed a decrease in obesity, an increase in the biogenesis of mitochondria and a longer life span than wild-type mice[39 ]. Transgenic mice with excessive expression of adiponectin in the liver showed greater survival than control of[40 ]. Transcription factors PPARγ and CCAAT /enhancer-binding proteins α (C /EBPα) and β (C /EBPβ) are involved in the differentiation of adipocytes. Mice with decomposition of the C /EBPβ gene at the C /EBP locus showed enhanced biogenesis of mitochondria and longer lifetimes of[41 ]. In contrast, the knockout PPARγ KO mice had shorter life spans than the control[42 ].
It is reported that CR increases the active form of adiponectin in mice of any age. This CR-associated regulation of adiponectin is dependent on the signaling of GH /IGF1[43, 44 ]. We analyzed the CR-associated change in chronological order and obtained the following results. CR increased the expression of genes and /or proteins involved in the biosynthesis of fatty acids (FA) and the biogenesis of mitochondria in adipose tissue after the early phase of CR. The CR-related change occurred more predominantly in adipose tissue than in other tissues or organs. After this, morphological changes took place, including a decrease in adipocyte size and metabolic changes in the liver[45 ]. In order to clarify the metabolic changes in the adipose tissue associated with CR that originated independently of the GH /IGF1 signal, we then compared the gene expression profile for CR in adipose tissue of wild-type rats with transgenic rats given ad libitum (AL). Our results showed that CR enhances the expression of genes involved in the biosynthesis of fatty acids, in particular, in the main transcription factor of fatty acid biosynthesis, regulatory SREBP-1 genes, regardless of GH /IGF1[9 ].
Therefore, we then compared the effect of CR with various parameters, including the lifespan between knockout mice SREBP-1c KO and wild-type mice. Mice SREBP-1c KO had a slightly shorter life span than wild-type mice. In wild-type mice with increased life expectancy, CR increased the expression of proteins involved in the biosynthesis of fatty acids and the biogenesis of mitochondria, and suppressed oxidative stress. Most of these changes were observed mainly in adipose tissue, but not in other tissues. In contrast, CR-associated prolongation of life and changes in adipose tissue were not observed in SREBP-1c KO mice. It is reported that the PGC-1α protein is the key regulator of CR-induced mitochondrial biogenesis[46 ]. We observed that SREBP-1c binds to the promoter of the Pgc-1α gene, suggesting that SREBP-1c directly regulates the transcription of Pgc-1α[47 ]. Moreover, the results of the fat tissue proteome analysis showed that CR activates the pyruvate /malate cycle[48 ]. Indeed, it has been reported that CR activates the de novo biosynthesis of fatty acids in adipose tissue, but not in the liver of[45 ]. These data show that SREBP-1c KO mice can not effectively use fats in CR conditions. Thus, adipose tissue can not only function as a tissue for energy storage, but it can also play the role of converting glucose into a more energy-intensive fatty acid through SREBP-1c under CR conditions.
Discussion of CR from the point of view of the hypothesis of the adaptive response
In 198? Holliday explained the effects of anti-aging and extending the life span from CR from the evolutionary point of view of organisms that developed adaptive response systems to maximize survival in times of food shortage[49, 50 ]. On the basis of this evolutionary point of view, we divided the beneficial effects of CR into two systems; "Systems activated under sufficient conditions of energy resources" and "systems operating under insufficient energy conditions". The first is activated in the natural environment, which gives animals free energy use by providing abundant food. In other words, when there is plenty of food for free energy use, animals grow well, reproduce more and conserve excess energy like TG in adipose tissue for later use, but not so much that they are obese. The second system is activated in the natural environment, which does not allow free use of energy due to food shortages. In other words, when there is no use of free energy use, animals suppress growth and reproduction and use the saved energy from growth and reproduction to maintain biological function. Adaptation to natural changes in the environment is the main priority for the survival of animals.
Based on the hypothesis of the adaptive response and recent findings mentioned above, we propose a set of mechanisms for useful CR actions.
Since the experimental CR conditions can mimic inadequate energy conditions, we assumed that CR suppresses "systems activated under sufficient energy conditions" and activates "systems activated under insufficient energy conditions" and addively induces action against aging and prolongation of life. The first set of systems includes signals GH /IGF? FOXO, mTORC, adiponectin and BMAL? and CR appears to suppress these anabolic reactions. The second set of systems includes SREBP-1c /mitochondria, SIRT and NPY signaling, and it is likely that CR activates these responses for optimal use of insufficient energy resources. Moreover, different signals and /or factors can contribute to anti-aging and life-prolonging effects of CR to varying degrees with antioxidant, anti-inflammatory, antitumor and other actions in various tissues.
Regarding the paradigms of dietary intervention, not only CR, but also intermittent energy restriction (IER) and power-down time (TRF)[2 ]were applied. . IER usually includes a post every other day or 2-3 days a week. TRF, which is more popular in obesity research than biogeonology research, generally involves limiting access to food (high in fat) for several hours a day. The beneficial effects caused by IER or TRF are partially similar to those caused by CR. However, as far as we know, no studies have used rigorous research plans, including nutrition charts, to compare the three dietary interventions. Therefore, in the future, comparative studies of CR, IER and TRF may be required.
Studies using monkeys show that useful effects of CR can occur in humans as well as in other mammals[51 ]. Current CR research focuses on two topics, that is, on the detection of CR molecular mechanisms, as well as on the development of CR mimetic preparations. We believe that the development of new drugs acting as CR can be difficult without understanding the molecular mechanisms of CR. To develop such drugs that are applicable to humans, further research is needed on the molecular mechanisms of CR, especially in primates. In this report, we propose to classify and discuss the molecular mechanisms of the beneficial actions of the Cheka, depending on whether they work in conditions of rich or insufficient energy resources. Further research on the molecular mechanisms of the beneficial effects of CR should also take into account the extent to which the involved signals /factors contribute to antioxidant, anti-inflammatory, antitumor and other effects of CR in each tissue or organ, and thereby lead to rejuvenation and an increase in life expectancy. Studies of genetically modified animals with emphasis on one of the two systems mentioned above show differences in the degree of CR-induced effects in mice of various origins and those that compare the useful effects of CR with IER or TRF factors, will help clarify not only the further molecular mechanisms of CR, but also those that are related to life expectancy.
Hoshino S, Kobayashi M, Higami Y. Mechanisms of the anti-aging and prolongevity effects of caloric restriction: evidence from studies of genetically modified animals. Aging (Albany NY). 2018 Sep 16.
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