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Abstract

mTOR signalling is implicated in the development of disease and in lifespan extension in model organisms. This pathway has been associated with human diseases such as diabetes and cancer, but has not been investigated for its impact on longevity per se. Here, we investigated whether transcriptional variation within the mTOR pathway is associated with human longevity using whole blood samples from the Leiden Longevity Study (LLS). This is an unique cohort of Dutch families with extended survival across generations, decreased morbidity and beneficial metabolic profiles in middle-age. By comparing mRNA levels of nonagenarians and middle-aged controls, the mTOR signalling gene set was found to associate with old age (p=4.6 x 10(-7) ). Single gene analysis showed that seven out of 40 mTOR pathway genes had a significant differential expression of at least 5%. Of these, the RPTOR (Raptor) gene was found to be differentially expressed also when the offspring of nonagenarians was compared to their spouses, indicating association with familial longevity in middle-age. This association was not explained by variation between the groups in the prevalence of type 2 diabetes and cancer or glucose levels. Thus, the mTOR pathway not only plays a role in the regulation of disease and aging in animal models, but also in human health and longevity. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

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... Between 417 nonagenarians and younger controls, EIF4EBP2 upregulation was once again seen in nonagenarian samples, along with LAMTOR2, AKT1S1, PRR5L and RHOA, whereas FOXO1 and RAPTOR expression were lower. The study found RAPTOR, AKT1S1 and E1F4BP2 to be associated with old age and/or familial longevity, thereby suggesting a transcriptional downregulation of mTORC1 [91]. ...
... Diet impacts our basic metabolism on a cellular and organismal level and affects microbiota, bioenergetics, growth, differentiation, healthspan, and ultimately, lifespan. Differential gene expression studies have shown that nutrient perception genes are key with, for example, RAPTOR, AKT1S1 and E1F4BP2 being associated with old age and/or familial longevity, suggesting a transcriptional downregulation of mTORC1 [91]. In addition to APOE2 and ANRIL, GWAS studies have pointed to the relation of nutrient response with human lifespan; FOXO3A, a transcription factor related to IGF signaling, is a significant locus, robustly appearing in such studies. ...
Article
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Cellular, small invertebrate and vertebrate models are a driving force in biogerontology studies. Using various models, such as yeasts, appropriate tissue culture cells, Drosophila, the nematode Caenorhabditis elegans and the mouse, has tremendously increased our knowledge around the relationship between diet, nutrient-response signaling pathways and lifespan regulation. In recent years, combinatorial drug treatments combined with mutagenesis, high-throughput screens, as well as multi-omics approaches, have provided unprecedented insights in cellular metabolism, development, differentiation, and aging. Scientists are, therefore, moving towards characterizing the fine architecture and cross-talks of growth and stress pathways towards identifying possible interventions that could lead to healthy aging and the amelioration of age-related diseases in humans. In this short review, we briefly examine recently uncovered knowledge around nutrient-response pathways, such as the Insulin Growth Factor (IGF) and the mechanistic Target of Rapamycin signaling pathways, as well as specific GWAS and some EWAS studies on lifespan and age-related disease that have enhanced our current understanding within the aging and biogerontology fields. We discuss what is learned from the rich and diverse generated data, as well as challenges and next frontiers in these scientific disciplines.
... Long-lived animal species have decreased rptor but increased mtor. Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). ...
... Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). In the present investigation, protein content of mTOR and Raptor was also lower in long-lived animals, supporting a role for Raptor in longevity. ...
Article
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Species longevity varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of longevity could converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study focuses on the comparative approach in heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot, and mass spectrometry, respectively. Our results demonstrate (1) the existence of differences in species-specific gene expression and protein content of mTORC1, (2) that the achievement of a high longevity phenotype correlates with decreased and inhibited mTORC1, (3) a decreased content of mTORC1 activators in long-lived animals, and (4) that these differences are independent of phylogeny. Our findings, taken together, support an important role for mTORC1 downregulation in the evolution of long-lived mammals.
... Some authors have focused on the involvement of target of rapamycin (mTOR) in extending life span (Passtoors et al. 2013;Morris et al. 2015). It plays a crucial role in regulating several processes as autophagy, cell growth and metabolism in response to nutrients, growth factors and stress (Dibble and Manning 2013;Laplante and Sabatini 2012). ...
... Despite the evidences concerning the involvement of mTOR polymorphisms in different cancer types (Le Rhun et al. 2017;Ge et al. 2018), no SNPs have been associated to longevity in humans. Only one study has showed that two genes of mTOR pathway (RPTOR and PRR5L) were differentially expressed in middleage subjects of longevity families compared to controls, whereas no differences between nonagenarians and controls was observed (Passtoors et al. 2013). Morris et al. have no found association between common genetic variation in mTOR-related protein (MTOR, RPTOR, RICTOR, and RPS6KA1) and longevity in American men (of Japanese ancestry) with up to 95 years (Morris et al. 2015). ...
Article
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Longevity is mainly conditioned by genetic, epigenetic and environmental factors. Different genetic modifications seem to be positively associated to longevity, including SNPs in SIRT1, APOE, FOXO3A, ACE, ATM, NOS1 and NOS2 gene. Epigenetic changes as DNA hyper- and hypo-methylation influence significantly human longevity by activating/deactivating different genes involved in physiological mechanisms. Several studies have confirmed that centenarians have a lower DNA methylation content compared to young subjects, which showed more homogeneously methylated DNA region. Also the up-regulation of miR-21 seems to be more associated with longevity in different populations of long-lived subjects, suggesting its role as potential epigenetic biomarkers. A non-pharmacological treatment that seems to contrast age-related diseases and promote longevity is represented by dietary intervention. It has been evaluated the effects of dietary restriction of both single nutrients or total calories to extend lifespan. However, in daily practice it is very difficult to guarantee adherence/compliance of the subjects to dietary restriction and at the same time avoid dangerous nutritional deficiencies. As consequence, the attention has focused on a variety of substances both drugs and natural compounds able to mime the beneficial effects of caloric restriction, including resveratrol, quercetin, rapamycin, metformin and 2-deoxy-d-glucose.
... Long-lived animal species have decreased rptor but increased mtor. Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). ...
... Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). In the present investigation, protein content of mTOR and Raptor was also lower in long-lived animals, supporting a role for Raptor in longevity. ...
Article
Full-text available
Many specific cell afferent signalling pathways like the insulin/IGF-1-like or the mechanistic target of rapamycin (mTOR) pathways contribute to modify longevity by modulating the nuclear aging program (AP) [1,2] target gene expression, which modulates the activity of its various aging effectors [2]. © 2021 Barja and Pamplona. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
... These mutant animals show a prolonged healthspan and are protected against both natural aging-related decline and the pathology associated with genetic models of human age-related diseases [7]. Remarkably, genetic variants in, and altered expression of, the orthologues of the genes encoding components of this network are also associated with survival to advanced ages in humans [147][148][149][150][151][152]. The IIS/TOR network contains many potential drug targets, and rapamycin, a licensed drug that targets a protein complex in the TOR network, can extend lifespan in diverse laboratory organisms, including mice [153][154][155][156][157]. ...
... Although the IIS/TOR network is a major regulator of life history in many taxa [46,64,163,175], several mapping studies and artificial selection experiments in D. melanogaster have failed to identify canonical IIS/TOR genes as harboring natural variation for lifespan or other life-history traits [165,[176][177][178][179], with a few exceptions [164,66]. 'Longevity genes' , discovered via strong loss-of-function mutations in the laboratory, might thus not always harbor variants in natural populations [47,177], even though segregating IIS polymorphisms seem to contribute to the exceptional longevity of human centenarians [147][148][149][150][151][152]. Given the conserved role of IIS/TOR in regulating life-history physiology in response to the external and internal 'milieu' , a possible explanation for the lack of standing variation is that the plasticity of the network has been optimized by selection but that it is now under selective constraint, with most newly arising mutations being deleterious and purged by purifying selection [180,181]. ...
Article
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Abstract Between the 1930s and 50s, evolutionary biologists developed a successful theory of why organisms age, firmly rooted in population genetic principles. By the 1980s the evolution of aging had a secure experimental basis. Since the force of selection declines with age, aging evolves due to mutation accumulation or a benefit to fitness early in life. Here we review major insights and challenges that have emerged over the last 35 years: selection does not always necessarily decline with age; higher extrinsic (i.e., environmentally caused) mortality does not always accelerate aging; conserved pathways control aging rate; senescence patterns are more diverse than previously thought; aging is not universal; trade-offs involving lifespan can be ‘broken’; aging might be ‘druggable’; and human life expectancy continues to rise but compressing late-life morbidity remains a pressing challenge.
... Long-lived animal species have decreased rptor but increased mtor. Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). ...
... Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). In the present investigation, protein content of mTOR and Raptor was also lower in long-lived animals, supporting a role for Raptor in longevity. ...
Article
Full-text available
LOCALIZATION OF NDUFV2 (CONTAINING THE FeS CLUSTER N1a) OF THE HYDROPHILIC DOMAIN, AND ndufv2 SINGLE GENE, POSSIBLY RESPONSIBLE FOR MOST OF THE REGULATION OF MITOCHONDRIAL ROS PRODUCTION OF COMPLEX I RELATED TO LONGEVITY BOTH ACCROS SPECIES AND IN CALORIE RESTRICTION
... Long-lived animal species have decreased rptor but increased mtor. Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). ...
... Accordingly, it has been reported that nonagenarians' blood has decreased mRNA content of akt1s1 (PRAS40) and rptor (Raptor) when compared with middle-aged controls (Passtoors et al. 2013). Moreover, the offspring of those long-lived individuals also has decreased rptor gene expression, which emerges as a potential biomarker of familiar longevity (Passtoors et al. 2013). In the present investigation, protein content of mTOR and Raptor was also lower in long-lived animals, supporting a role for Raptor in longevity. ...
Preprint
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Species longevity varies significantly across animal species, but the underlying molecular mechanisms remain poorly understood. Recent studies and omics approaches suggest that phenotypic traits of lon-gevity could converge in the mammalian target of rapamycin (mTOR) signalling pathway. The present study focuses on the comparative approach in heart tissue from 8 mammalian species with a ML ranging from 3.5 to 46 years. Gene expression, protein content, and concentration of regulatory metabolites of the mTOR complex 1 (mTORC1) were measured using droplet digital PCR, western blot, and mass spectrome-try, respectively. Our results demonstrate (1) the existence of differences in species-specific gene expression and protein content of mTORC1, (2) that the achievement of a high longevity phenotype correlates with decreased and inhibited mTORC1, (3) a decreased content of mTORC1 activators in long-lived animals, and (4) that these differences are independent of phylogeny. Our findings, taken together, support an important role for mTORC1 downregulation in the evolution of long-lived mammals.
... In mammals, two distinct multiprotein complexes, mTORC1 and mTORC2, are formed by mTOR kinases. Gene expression analysis of mTOR signaling identified interesting associations with longevity in humans [148]. Insulin and IGF1 significantly activate mTORC1, which further promotes translation via ribosomal protein S6K1 (mammalian homolog of Sch9), synthesis of fatty acids via sterol regulatory element-binding protein (SREBP) and differentiation of adipocytes via peroxisome proliferator-activated receptor gamma (PPARγ) and suppresses autophagy and biosynthesis of lysosomes via transcription factor EB (TFEB) [148]. ...
... Gene expression analysis of mTOR signaling identified interesting associations with longevity in humans [148]. Insulin and IGF1 significantly activate mTORC1, which further promotes translation via ribosomal protein S6K1 (mammalian homolog of Sch9), synthesis of fatty acids via sterol regulatory element-binding protein (SREBP) and differentiation of adipocytes via peroxisome proliferator-activated receptor gamma (PPARγ) and suppresses autophagy and biosynthesis of lysosomes via transcription factor EB (TFEB) [148]. Interestingly, activation of mTOR-PIK3CA-AKT is frequently observed in many human cancers, leading to the development of various small-molecule inhibitors targeting diverse nodes in these pathways. ...
Article
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Aging represents a significant biological process having strong associations with cancer, diabetes, and neurodegenerative and cardiovascular disorders, which leads to progressive loss of cellular functions and viability. Astonishingly, age-related disorders share several genetic and molecular mechanisms with the normal aging process. Over the last three decades, budding yeast Saccharomyces cerevisiae has emerged as a powerful yet simple model organism for aging research. Genetic approaches using yeast RLS have led to the identification of hundreds of genes impacting lifespan in higher eukaryotes. Numerous interventions to extend yeast lifespan showed an analogous outcome in multi-cellular eukaryotes like fruit flies, nematodes, rodents, and humans. We collected and analyzed a multitude of observations from published literature and provide the contribution of yeast in the understanding of aging hallmarks most applicable to humans. Here, we discuss key pathways and molecular mechanisms that underpin the evolutionarily conserved aging process and summarize the current understanding and clinical applicability of its trajectories. Gathering critical information on aging biology would pave the way for future investigation targeted at the discovery of aging interventions.
... Inhibiting the mTOR pathway can extend the life span of several species, such as worms [66,67], fruit flies [68] and mice [69]. Analysis of gene expression profiles indicated that the mTOR pathway is closely related to AGING human health and life span [70]. Recently, rapamycin, an inhibitor of mTOR and a new type of macrolide immunosuppressant, has also been shown to inhibit the activation of the initial follicle by regulating the mTOR and sirtuin signaling pathways, thus protecting ovarian reserve and extending the reproductive life of the ovary [71][72][73]. ...
Article
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Aging has been regarded as a treatable condition, and delaying aging could prevent some diseases. Ovarian aging, a special type of organ senescence, is the earliest-aging organ, as ovaries exhibit an accelerated rate of aging with characteristics of gradual declines in ovarian follicle quantity and quality since birth, compared to other organs. Ovarian aging is considered as the pacemaker of female body aging, which drives the aging of multiple organs of the body. Hence, anti-ovarian aging has become a research topic broadly interesting to both biomedical scientists and pharmaceutical industry. A marked progress has been made in exploration of possible anti-ovarian agents or approaches, such as calorie restriction mimetics, antioxidants, autophagy inducers etc., over the past years. This review is attempted to discuss recent advances in the area of anti-ovarian aging pharmacology and to offer new insights into our better understanding of molecular mechanisms underlying ovarian aging, which might be informative for future prevention and treatment of ovarian aging and its related diseases.
... Previous studies have reported a reduction of approximately 50% in nuclear Nrf2 levels and ARE binding in livers of aged rats [10,12]. e mammalian target of rapamycin (mTOR) pathway has been shown to play important role in human diseases, and inhibition of this pathway extends life span in model organisms [13]. mTOR forms two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [14]. ...
Article
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Purpose . In the present study, we aimed to investigate the effects of tomato powder (TP) on glucose and lipid metabolism, as well as oxidative stress and the NF- κ B, mTOR, and Nrf2 pathways during the aging process in healthy rats. Methods and Results . Male Wistar rats were randomly assigned to four groups as follows: (i) Control group 1 ( n=15 , 3-week old): rats were fed standard diet for 7 weeks; (ii) TP group 1 ( n=15 , 3-week old): rats were fed standard diet supplemented with TP for 7 weeks; (iii) Control group 2 ( n=15 , 8-week old): rats were fed standard diet for 69 weeks; and (iv) TP group 2 (8-week old): rats were fed standard diet supplemented with TP for 69 weeks. TP supplementation significantly reduced the hyperglycemia, hypertriglyceridemia, and hypercholesterolemia and improved liver function and kidney function in 77-week old rats compared with the control animals ( P<0.05 ). In addition, TP significantly decreased the serum and liver MDA levels ( P<0.003 and P<0.001 , respectively) while increasing the activities of liver SOD ( P<0.001 ), CAT ( P<0.008 ), and GPx ( P<0.01 ) compared with the control groups in both 10-week-old and 77-week-old rats ( P<0.05 ). Age-related increases in phosphorylation of NF- κ Bp65, mTOR, 4E-BP1, and P70S6K were observed in livers of 77-week-old rats compared to those of 10-week-old rats ( P<0.001 ). TP supplementation decreased the expression of NF- κ Bp65 and activation of mTOR, 4E-BP1, and P70S6K in livers of 77-week-old rats compared to the control animals. Moreover, TP supplementation significantly elevated Nrf2 expression in livers of both 10-week-old and 77-week-old rats ( P<0.05 ). Conclusion . TP ameliorates age-associated inflammation and oxidative stress through the inhibition of NF- κ Bp65, mTOR pathways, and Nrf2 activation may explain the observed improvement in glucose and lipid metabolism as well as the improved liver and kidney functions.
... These long-lived mutants are protected against many natural pathologies of old age and also those associated with genetic models of age-related diseases. Genetic variants in orthologous genes in humans are associated with survival to advanced ages [26][27][28]. Mechanisms of ageing are highly conserved during evolution, and the process shows a set of characteristic hallmarks of ageing [29], which are also present in the aetiology of age-related diseases [7,29]. Interventions that improve health during ageing and increase lifespan in laboratory animals do so by reducing the impact of one or more of these hallmarks. ...
Article
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Increasing human life expectancy has posed increasing challenges for healthcare systems. As people age, they become more susceptible to chronic diseases, with an increasing burden of multimorbidity, and the associated polypharmacy. Accumulating evidence from work with laboratory animals has shown that ageing is a malleable process that can be ameliorated by genetic and environmental interventions. Drugs that modulate the ageing process may delay or even prevent the incidence of multiple diseases of ageing. To identify novel, anti-ageing drugs, several studies have developed computational drug-repurposing strategies. We review published studies showing the potential of current drugs to modulate ageing. Future studies should integrate current knowledge with multi-omics, health records, and drug safety data to predict drugs that can improve health in late life.
... Multiple genetic interventions can also induce broad improvements in health in laboratory animals 89 . For example, reduced activity of the insulin-insulin-like growth factor (IGF) signalling (IIS)-mammalian target of rapamycin (mTOR) signalling network can extend lifespan in yeast, worms, fruitflies and mice 21 , and genetic variants in candidate orthologous genes, or their gene expression patterns, in humans can be associated with survival to advanced ages 41,42,[90][91][92] . As for dietary protein, any benefits of modulating the activity of the IIS-mTOR signalling network in humans may depend on age 71 . ...
Article
Longer human lives have led to a global burden of late-life disease. However, some older people experience little ill health, a trait that should be extended to the general population. Interventions into lifestyle, including increased exercise and reduction in food intake and obesity, can help to maintain healthspan. Altered gut microbiota, removal of senescent cells, blood factors obtained from young individuals and drugs can all improve late-life health in animals. Application to humans will require better biomarkers of disease risk and responses to interventions, closer alignment of work in animals and humans, and increased use of electronic health records, biobank resources and cohort studies.
... In addition, DR also improves late-life health (healthspan) in a range of organisms [1,5,9,10]. Similarly, genetic modulation of a number of signalling pathways, most notably the nutrient sensing insulin/ insulin-like growth factor (IIS) and mechanistic target of rapamycin (mTOR) pathways, extends both lifespan and healthspan in model organisms [11][12][13][14][15][16][17], and genetic polymorphisms within these same pathways correlate with longevity in humans [18,19]. ...
Article
Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice.
... The signaling network of nutrient-sensing, insulin/insulin growth factor signaling (IIS) and Target of Rapamycin (TOR) influences healthy lifespan in diverse eukaryotic organisms, including mammals . Specific alleles of IIS genes (Li et al., 2009;Pawlikowska et al., 2009;Suh et al., 2008;Willcox et al., 2008) and transcriptional variation of genes encoding components of the TOR pathway (Passtoors et al., 2013) are associated with survival to advanced ages in humans. Reduced network activity can induce a broad-spectrum resistance to age-related loss of function and disease in animal models (Clancy et al., 2001;Kenyon et al., 1993;Selman et al., 2008;Tatar et al., 2001), making it an attractive target for pharmacological intervention to improve human health during aging (de Cabo et al., 2014). ...
Article
Full-text available
Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. We show that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies. Additionally, it increases the expression of nutrient transporters, as does lowered IIS. Evolutionary conservation of this effect of lowered IIS is suggested by the upregulation of related nutrient transporters in insulin receptor substrate 1 knockout mouse intestine. Our study highlights a critical role played by FKH in the gut in mediating anti-aging effects of reduced IIS. Malnutrition caused by poor intestinal absorption is a major problem in the elderly, and a better understanding of the mechanisms involved will have important therapeutic implications for human aging.
... For instance, Rictor loss-offunction mutants in Caenorhabditis elegans had decreased life spans by 24-43% on a standard diet (12), muscle-specific inactivation of Rictor in mice produced glucose intolerance (13), kidney-specific knockout of Rictor reduced protection of kidneys from stress (14), and adipose-specific knockout of Rictor led to a disproportionately enlarged pancreas and hyperinsulinemia (15). Interestingly, transcriptional down-regulation of mTORC1 and transcriptional up-regulation of mTORC2 was reported to be associated with human longevity (16). It is vital to understand how mTORC2 regulates aging in a mammal. ...
Article
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It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.
... The enrichment of the same "longevity-assurance" genes as seen in these members of long-lived families may explain the BELFRAIL data indicating that CMV-seropositive women have better 3-year survival. Currently, it is unclear which or how many such genes are active in this respect, but several candidates have been identified which are relevant in immunology and may shed light on this issue in future (Passtoors et al. 2015;Passtoors et al. 2013). Dissecting out the IRPs for different birth cohorts of different populations will remain a grand challenge. ...
Article
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The pioneering Swedish OCTO/NONA-Immune longitudinal studies led by Anders Wikby in Jönköping in the 1990s established a cluster of simple baseline immune parameters associated with excess mortality in 85 year-old non-institutionalized individuals over 2, 4 and 6-year follow-up. We dubbed this cluster the “Immune Risk Profile” (IRP) consisting of poor proliferative responses of peripheral blood mononuclear cells to T cell mitogens, accumulations of CD8+ CD28− T-cells resulting in an inverted CD4:8 ratio, decreased amounts of B-cells, and seropositivity for Cytomegalovirus (CMV). The concept of the IRP has since been applied by others to many different populations in different circumstances and at different ages, but in general without specifically establishing whether the same risk factors were relevant in the tested subjects. However, our own later studies showed that risk factors in aged populations from The Netherlands and Belgium were markedly different, indicating that the IRP cannot simply be transferred between populations. Moreover, there was a striking sex difference in the Belgian study, which was the only one large enough to include sufficient numbers of old men. The reasons for these marked differences between populations which one might have assumed a priori to be quite similar to one another are not clear, and many candidates can be speculated upon, but the important lesson is that there is a marked context-dependency of immune biomarkers of ageing, suggesting that IRPs cannot be assumed to be identical in different populations.
... Interestingly, gene expression of Raptor, the defining component of mTORC1 (vs. mTORC2) is lower, but that of proline-rich Akt substrate of 40 kDa (PRAS40), an inhibitory binding protein of mTORC1, is higher in nonagenarians, implicating an inverse relationship between mTORC1 pathway and longevity in human [58]. Thus, aberrant activation of mTORC1 contributes to the decreased levels of autophagy in the aging heart (Fig. 3). ...
Article
Cardiovascular disease (CVD) is the leading cause of death and the prevalence of CVD dramatically increases with age. Cardiac aging is associated with hypertrophy, fibrosis, inflammation, and decreased contractility. Autophagy, a bulk degradation/recycling system, is essential to maintain cellular homeostasis. Cardiac autophagy is decreased with age, and misfolded proteins and dysfunctional mitochondria are accumulated in the aging heart. Inhibition of autophagy leads to exacerbated cardiac aging, while stimulation of autophagy improves cardiac function and also increases lifespan in many organisms. Thus autophagy represents a potential therapeutic target for aging-related cardiac dysfunction. This review discusses recent progress in our understanding of the role and regulation of autophagy in the aging heart.
... Inhibition of mTORC1 has a positive effect in the animal model of age-associated muscular dystrophy (Ramos et al., 2012). Related to this, reduced mTOR signaling has been shown to regulate longevity in human and model organisms (Powers et al., 2006;Bjedov et al., 2010;Robida-Stubbs et al., 2012;Passtoors et al., 2013) and reduce age-related pathologies (Johnson et al., 2013a). Inhibition of mTOR signaling in aged muscle may have similar beneficial effects on multiple age related pathologies (Johnson et al., 2013b). ...
Article
Full-text available
Maintenance of skeletal muscle mass is regulated by the balance between anabolic and catabolic processes. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase, and is known to play vital roles in protein synthesis. Recent findings have continued to refine our understanding of the function of mTOR in maintaining skeletal muscle mass. mTOR controls the anabolic and catabolic signaling of skeletal muscle mass, resulting in the modulation of muscle hypertrophy and muscle wastage. This review will highlight the fundamental role of mTOR in skeletal muscle growth by summarizing the phenotype of skeletal-specific mTOR deficiency. In addition, the evidence that mTOR is a dual regulator of anabolism and catabolism in skeletal muscle mass will be discussed. A full understanding of mTOR signaling in the maintenance of skeletal muscle mass could help to develop mTOR-targeted therapeutics to prevent muscle wasting.
... Members of longevous families show improved immune responses [73,74], glycosylation [75] and diminished immunosenescence as compared to controls [76]. Passtoors et al., [77] reported on the altered expression of genes in the mTOR pathway in longevity families, comparable to observations in lifespan extended animal models. In line with this pathway, the activation-induced autophagy in the CD4 + T-cell compartment was found to be significantly better maintained, which along with improved T-cell functional parameters, supports the notion that proteostatic and regulatory processes confer Tcells increased fitness in longevity families [78]. ...
Article
Human ageing is an extremely personal process leading across the life course of individuals to large population heterogeneity in the decline of functional capacity, health and lifespan. The extremes of this process are witnessed by the healthy vital 100-year-olds on one end and the 60-year-olds suffering from multiple morbid conditions on the other end of the spectrum. Molecular studies into the basis of this heterogeneity have focused on a range of endpoints and methodological approaches. The phenotype definitions most prominently investigated in these studies are either lifespan-related or biomarker based indices of the biological ageing rate of individuals and their tissues. Unlike for many complex, age-related diseases, consensus on the ultimate set of multi-biomarker ageing or lifespan-related phenotypes for genetic and genomic studies has not been reached yet. Comparable to animal models, hallmarks of age-related disease risk, healthy ageing and longevity include immune and metabolic pathways. Potentially novel genomic regions and pathways have been identified among many (epi)genomic studies into chronological age and studies into human lifespan regulation, with APOE and FOXO3A representing yet the most robust loci. Functional analysis of a handful of genes in cell-based and animal models is ongoing. The way forward in human ageing and longevity studies seems through improvements in the interpretation of the biology of the genome, in application of computational and systems biology, integration with animal models and by harmonization of repeated phenotypic and omics measures in longitudinal and intervention studies. This article is part of a Special Issue entitled: Model Systems of Aging - edited by “Houtkooper Riekelt”.
... Over the last couple of decades a significant number of studies have demonstrated that disrupting signalling through the growth hormone (GH) (Brown-Borg et al., 1996;Coschigano et al., 2003), the insulin/IGF-1 (Selman et al., 2008) and the mechanistic target of rapamycin (mTOR) pathways (Selman et al., 2009;Arif et al., 2017) can extend lifespan in mice and improve late-life health. Excitingly, pharmacological manipulation of some of these pathways can also slow ageing in mice (Harrison et al., 2009), and polymorphisms in genes within these pathways are correlated with human longevity Passtoors et al., 2013). Without doubt one of the greatest challenges in mouse ageing research currently is to try and identify mechanistically how these interventions act to elicit their favourable effects, and to determine whether shared mechanisms drive longevity and healthspan across different mutants or whether such mechanisms are only specific to a particular mutant or specific signalling pathway. ...
Article
The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis- where proteostasis is defined here as the maintenance of the proteome- appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, all appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants. This article is protected by copyright. All rights reserved.
... Autophagy provides another level of control of T cell differentiation and survival [77,78], and in mice, aging of T cells may be associated with a defect in chaperone-mediated autophagy [78]. mTOR signaling has been implicated in mammalian lifespan and human longevity [79,80]. AMPK [81], a sensor of low intracellular glucose, is activated by phosphorylation on Thr172 in its catalytic α-subunit to shift metabolism towards catabolism and inhibit mTOR activity in T cells [82,83]. ...
Article
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The age of an individual is an important, independent risk factor for many of the most common diseases afflicting modern societies. Interleukin-7 (IL-7) plays a central, critical role in the homeostasis of the immune system. Recent studies support a critical role for IL-7 in the maintenance of a vigorous healthspan. We describe the role of IL-7 and its receptor in immunosenescence, the aging of the immune system. An understanding of the role that IL-7 plays in aging may permit parsimonious preventative or therapeutic solutions for diverse conditions. Perhaps IL-7 might be used to “tune” the immune system to optimize human healthspan and longevity.
... Genetic inhibition of the TOR signaling resulted in life extension in nematode (Jia et al., 2004;Vellai et al., 2003), fruit fly (Kapahi et al., 2004), and rodents . Recent transcriptional analysis revealed that the TOR pathway is strongly related to human health and lifespan (Passtoors et al., 2013). Therefore, TOR is believed to be a most promising target for pharmacological interventions to modulate the nutrient-sensitive pathways and for slowing the aging process. ...
Article
The target of rapamycin (TOR) pathway integrates signals from extracellular and intracellular agents, such as growth factors, nutrients, mediators of energy balance, oxygen availability and other environmental cues. It allows the regulation of multiple cellular processes including protein and lipid synthesis, ribosome biogenesis, autophagy and metabolic processes. Being conserved across different phyla, TOR regulates longevity of various organisms in response to dietary conditions. In this review we described the main components of the TOR pathway and its upstream effectors and downstream processes in relation to aging. The potential contribution of the TOR pathway in lifespan-extending effects of varied dietary interventions, and the anti-aging drugs rapamycin and metformin direct or indirect regulation of TOR activity in yeasts, worms, flies and mammals are also discussed.
... Moving from a simple approach based on one biomarker at a time to a systems analysis approach that simultaneously integrates multiple biological markers provides an opportunity to identify comprehensive biomarker signatures of aging (Zierer et al., 2015). Analogous to this approach, molecular signatures of gene expression have been correlated with age and survival (Kerber et al., 2009;Passtoors et al., 2013), and a regression model based on gene expression predicts chronological age with substantial accuracy, although differences between predicted and attained age could be attributed to some aging-related diseases (Peters et al., 2015). The well-known DNA methylation clock developed by Horvath has been argued to predict chronological age (Horvath, 2013). ...
Article
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Because people age differently, age is not a sufficient marker of susceptibility to disabilities, morbidities, and mortality. We measured nineteen blood biomarkers that include constituents of standard hematological measures, lipid biomarkers, and markers of inflammation and frailty in 4704 participants of the Long Life Family Study (LLFS), age range 30-110 years, and used an agglomerative algorithm to group LLFS participants into clusters thus yielding 26 different biomarker signatures. To test whether these signatures were associated with differences in biological aging, we correlated them with longitudinal changes in physiological functions and incident risk of cancer, cardiovascular disease, type 2 diabetes, and mortality using longitudinal data collected in the LLFS. Signature 2 was associated with significantly lower mortality, morbidity, and better physical function relative to the most common biomarker signature in LLFS, while nine other signatures were associated with less successful aging, characterized by higher risks for frailty, morbidity, and mortality. The predictive values of seven signatures were replicated in an independent data set from the Framingham Heart Study with comparable significant effects, and an additional three signatures showed consistent effects. This analysis shows that various biomarker signatures exist, and their significant associations with physical function, morbidity, and mortality suggest that these patterns represent differences in biological aging. The signatures show that dysregulation of a single biomarker can change with patterns of other biomarkers, and age-related changes of individual biomarkers alone do not necessarily indicate disease or functional decline.
... For 4E-BP and p70S6K expression, an identical expression pattern was observed. Because these proteins are related to the TOR pathway, their expression pattern was expected to follow that of TOR and BDNF.Passtoors et al. (2013) studied patterns of gene expression in human blood and found different response in whole blood comparing nonagenarians and middle age people. This study demonstrated down-regulation of ...
Article
Target of rapamycin (TOR) is a protein kinase involved in the modulation of mRNA translation and, therefore, in the regulation of protein synthesis. In neurons, the role of TOR is particularly important in the consolidation of long-term memory (LTM). One of the modulators of TOR is brain-derived neurotrophic factor (BDNF), which activates the TOR signaling pathway to promote protein synthesis, synapse strengthening, and the creation of new neural networks. We investigated the gene expression pattern of this pathway during memory consolidation in zebrafish of different ages. Our findings demonstrate that TOR activation in old animals occurs in the early phase of consolidation, and follows a pattern identical to that of BDNF expression. In younger animals, this increase in activation did not occur, and changes in BDNF expression were also not so remarkable. Furthermore, the expression of the main proteins regulated by the synthesis of TOR (i.e., 4E-BP and p70S6K) remained identical to that of TOR in all age groups.
... In support, the role of down-regulation of mTORC2 on reducing proliferation of colon cancer cell lines and inhibition of the formation of tumor xenografts in vivo has been deciphered earlier [36]. Previously expression profiles of AKT1 and p70S6K1 have been demonstrated as molecular marker for role of mTOR based pathogenesis and progression in panel of Gastric cancer cell lines such as AGS, MKN28 and MKN45 [37,38]. Gene expression analysis of cells treated with Torin2 and DHAP showed reduced expression of AKT1, P70S6K1 relative to the corresponding untreated control HCT8 cells (Fig. 4a-b). ...
... Numerous studies presented a direct connection between dysregulated ribosome biogenesis and aging. For instance, the downregulation of ribosome biogenesis components or nutrient sensing pathways, which stimulate ribosome production, have been shown to increase the lifespan of multiple organisms including C. elegans, D. melanogaster, yeast, mice and human [236][237][238][239][240][241][242][243][244][245][246][247][248][249]. Therefore, enhanced ribosome biogenesis, visualized by enlarged nucleoli, is believed to accelerate aging. ...
Article
The biosynthesis of ribosomes is a complex process that requires the coordinated action of many factors and a huge energy investment from the cell. Ribosomes are essential for protein production, and thus for cellular survival, growth and proliferation. Ribosome biogenesis is initiated in the nucleolus and includes: the synthesis and processing of ribosomal RNAs, assembly of ribosomal proteins, transport to the cytoplasm and association of ribosomal subunits. The disruption of ribosome biogenesis at various steps, with either increased or decreased expression of different ribosomal components, can promote cell cycle arrest, senescence or apoptosis. Additionally, interference with ribosomal biogenesis is often associated with cancer, aging and age-related degenerative diseases. Here, we review current knowledge on impaired ribosome biogenesis, discuss the main factors involved in stress responses under such circumstances and focus on examples with clinical relevance.
... As a paradigm of successful human aging, long-lived individuals (LLIs) achieve extreme old age without developing serious agerelated diseases (e.g., cardiovascular disease, neurodegenerative disorders, and cancer) (7,8). Gene expression is thought to have a close association with the activity of processes involved in healthy aging and longevity in LLIs (9,10). Here, to find the processes displaying reduced biological activities in long-lived people, we obtained and analyzed the transcriptomes of peripheral white blood cells from 185 female LLIs and 86 gender-matched spouses of LLI children (F1SPs) from two independent Chinese longevity cohorts. ...
Article
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Adaptation to reduced energy production during aging is a fundamental issue for maintaining healthspan or prolonging life span. Currently, however, the underlying mechanism in long-lived people remains poorly understood. Here, we analyzed transcriptomes of 193 long-lived individuals (LLIs) and 86 spouses of their children from two independent Chinese longevity cohorts and found that the ribosome pathway was significantly down-regulated in LLIs. We found that the down-regulation is likely controlled by ETS1 (ETS proto-oncogene 1), a transcription factor down-regulated in LLIs and positively coexpressed with most ribosomal protein genes (RPGs). Functional assays showed that ETS1 can bind to RPG promoters, while ETS1 knockdown reduces RPG expression and alleviates cellular senescence in human dermal fibroblast (HDF) and embryonic lung fibroblast (IMR-90) cells. As protein synthesis/turnover in ribosomes is an energy-intensive cellular process, the decline in ribosomal biogenesis governed by ETS1 in certain female LLIs may serve as an alternative mechanism to achieve energy-saving and healthy aging.
... Recent human genetic studies suggest that the same conserved pathways may modulate lifespan and healthspan in humans. Most of these studies have used a candidate approach interrogating specific genes or pathways 7,8 . To advance this genetic discovery to identifying targets for slowing ageing in humans, a systematic approach is needed to discover the key genes and pathways that contribute to human longevity and healthy ageing. ...
Article
Ageing is the greatest risk factor for most common chronic human diseases, and it therefore is a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice. Recent genetic analysis of long-lived individuals is revealing common and rare variants enriched in these same conserved pathways that significantly correlate with longevity. In this Perspective, we summarize recent insights into the genetics of extreme human longevity and propose the use of this rare phenotype to identify genetic variants as molecular targets for gaining insight into the physiology of healthy ageing and the development of new therapies to extend the human healthspan. Zhang et al. discuss insights into the genetics of extreme human longevity and how genetics knowledge can be harnessed to guide the development of new therapies to extend human healthspan.
... Moreover, mTOR inhibition in different organisms, through pharmacological interventions, exerts protection against a plethora of age-associated pathologies, thereby promoting longevity. The activity of mTOR is higher in both the aged mice (Hua et al., 2011) and human heart (Passtoors et al., 2013), leading to reduced autophagy activity, subsequently accelerating cardiac aging. ...
Article
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Ageing is a progressive physiological process mediated by changes in biological pathways, resulting in a decline in tissue and cellular function. It is a driving factor in numerous age-related diseases including cardiovascular diseases (CVDs). Cardiomyopathies, hypertension, ischaemic heart disease, and heart failure are some of the age-related CVDs that are the leading causes of death worldwide. Although individual CVDs have distinct clinical and pathophysiological manifestations, a disturbance in cellular homeostasis underlies the majority of diseases which is further compounded with aging. Three key evolutionary conserved signalling pathways, namely, autophagy, mitophagy and the unfolded protein response (UPR) are involved in eliminating damaged and dysfunctional organelle, misfolded proteins, lipids and nucleic acids, together these molecular processes protect and preserve cellular homeostasis. However, amongst the numerous molecular changes during ageing, a decline in the signalling of these key molecular processes occurs. This decline also increases the susceptibility of damage following a stressful insult, promoting the development and pathogenesis of CVDs. In this review, we discuss the role of autophagy, mitophagy and UPR signalling with respect to ageing and cardiac disease. We also highlight potential therapeutic strategies aimed at restoring/rebalancing autophagy and UPR signalling to maintain cellular homeostasis, thus mitigating the pathological effects of ageing and CVDs. Finally, we highlight some limitations that are likely hindering scientific drug research in this field.
... Not unexpectedly, downregulation of the C. elegans mTOR homolog, let-363 (Vellai et al., 2003;Hansen et al., 2007), or the RAPTOR homolog, daf-15 (Jia et al., 2004;Robida-Stubbs et al., 2012) robustly increase lifespan. Notably, human studies suggested that the offspring of nonagenarians show reduced RAPTOR expression in blood cells, which hints that having less mTORC1 is beneficial for human lifespan (Passtoors et al., 2013). Consistently, hypomorphic mTOR mice, that express approximately a quarter of wild-type mTOR levels, live longer and exhibit improved aging tissue biomarkers, compared to their wild-type counterparts (Wu J. J. et al., 2013). ...
Article
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The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.
... The TFs were chosen manually, based on a particular interest or whether they were unique for one category. Interestingly, some of these TFs were already shown to be linked to aging and neurodegeneration, among them YY1, KLF4, and ELF5 [34][35][36][37][38]. ...
Article
Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer's patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addition, we traced these differences in human and mouse samples of Alzheimer's and Parkinson's diseases, healthy aging and calorie restriction (CR). Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.
... In this study, we investigated the changes at the transcriptome level over Previous studies suggest a direct connection between dysregulated ribosome biogenesis and aging. For instance, attenuated protein synthesis via caloric restriction or genetic manipulation of ribosome biogenesis-related genes is known to increase the lifespan of multiple organisms, including C. elegans, mice, and humans [27][28][29]. Therefore, promoting ribosome biogenesis could accelerate aging. ...
Article
African green monkeys (AGMs, Chlorocebus aethiops) are Old World monkeys which are used as experimental models in biomedical research. Recent technological advances in next generation sequencing are useful for unraveling the genetic mechanisms underlying senescence, aging, and age-related disease. To elucidate the normal aging mechanisms in older age, the blood transcriptomes of nine healthy, aged AGMs (15‒23 years old), were analyzed over two years. We identified 910‒1399 accumulated differentially expressed genes (DEGs) in each individual, which increased with age. Aging-related DEGs were sorted across the three time points. A major proportion of the aging-related DEGs belonged to gene ontology (GO) categories involved in translation and rRNA metabolic processes. Next, we sorted common aging-related DEGs across three time points over two years. Common aging-related DEGs belonged to GO categories involved in translation, cellular component biogenesis, rRNA metabolic processes, cellular component organization, biogenesis, and RNA metabolic processes. Furthermore, we identified 29 candidate aging genes that were upregulated across the time series analysis. These candidate aging genes were linked to protein synthesis. This study describes a changing gene expression pattern in AGMs during aging using longitudinal transcriptome sequencing. The candidate aging genes identified here may be potential targets for the treatment of aging.
... 3) Drosophila Sesn (dSesn) has been reported to prevent age-associated pathologies, including fat accumulation and cardiac and skeletal muscle degeneration, by promoting a feedback loop that prevents excessive TORC1 activation and ROS accumulation. 3) As ROS accumulation 4) and TORC1 activation 5,6) are associated with accelerated aging and the development of age-associated pathologies in both invertebrates and vertebrates, we tested whether the loss of Sesn2 induces cellular senescence in mouse embryonic fibroblasts (MEFs) before investigating Sesn2 knockout (KO) mice at the organismal level. ...
Article
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Background: Sestrin2 (Sesn2) is involved in the maintenance of metabolic homeostasis and aging via modulation of the 5&apos; AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway. Methods: Wild-type and Sesn2 knockout (KO) mice of the 129/SvJ background were maintained in a pathogen-free authorized facility under a 12-hour dark/light cycle at 20°C-22°C and 50%-60% humidity. Mouse embryonic fibroblasts (MEFs) were prepared from 13.5-day-old embryos derived from Sesn2-KO mice mated with each other. Results: The MEFs from Sesn2-KO mice showed enlarged and flattened morphologies and senescence-associated β-galactosidase activity, accompanied by an elevated level of reactive oxygen species. These senescence phenotypes recovered following treatment with N-acetyl-cysteine. Notably, the mRNA levels of NADPH oxidase 4 (NOX4) and transforming growth factor (TGF)-β were markedly increased in Sesn2-KO MEFs. Treatment of Sesn2-KO MEFs with the NOX inhibitor diphenyleneiodonium and the TGF-β inhibitor SB431542 restored cell growth inhibited by Sesn2-KO. Conclusion: Sesn2 attenuates cellular senescence via suppression of TGF-β- and NOX4-induced reactive oxygen species generation and subsequent inhibition of AMPK.
... The suppression of mTORC1 activity is associated with a significant improvement in both health and life span in various organisms, while increased activity is associated with old age in humans [80]. Hence, the use of mTORC1 inhibitor rapamycin may have potential applications as a CRM. ...
... The most studied among them is SRT1720, a specific SIRT1 activator that has been shown previously to cause life extension and amelioration of metabolic impairments in mice fed a highfat diet. 213 More recently, it has been found that SRT1720 supplementation can result in life span extension and delayed onset of age-associated metabolic diseases in mice fed a standard diet. 214 In a mice model, SRT1720 has been also demonstrated to be able to reverse the adverse age-related changes such as excessive superoxide production, vascular endothelial dysfunction and inflammation. ...
Chapter
Life expectancy has enhanced dramatically in modern times. This process is, however, not accompanied by equivalent increase in healthspan, representing a great socioeconomic challenge. Efforts to increase healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delay of aging is far more effective than preventing the particular chronic disorders. A number of pharmacological agents targeting basic aging pathways (ie, antioxidants, calorie restriction mimetics, autophagy inductors, etc.) are currently under investigation. This chapter surveys the literature related to advances and perspectives in the field of anti-aging pharmacology.
... In particular, a number of genes were affected that have been linked to aging and cellular defensive mechanisms. IGF1R and RPTOR (part of the mTOR protein complex) have been linked to human longevity and cellular damage [32,33] and FOXO1 is associated with collagen production and would heal in skin [34]. It is tempting to speculate that the changes in DNA methylation in these genes is a response to limit the damage from UVA. ...
Article
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Aim: UVA radiation drives skin photoaging in the dermis, plausibly via persistent changes to DNA methylation in dermal fibroblasts. Methods: Genome-wide DNA methylation changes after five repeated daily UVA doses were determined at 48 h (transitionary) and 1 week (recovery) post final irradiation. Results: Differential methylation was found at the transitionary time point in active chromatin states near genes that are highly expressed in fibroblasts and are involved in cellular defensive mechanisms; the majority of these methylation differences were restored to control levels after 7 day recovery. At the recovery time point, new differential methylation occurred at repressed regions near developmental genes, normally weakly expressed in fibroblasts. Conclusion: UVA irradiation induces transitionary and recovery-associated DNA methylation responses in fibroblasts with contrasting functional characteristics.
... The gut microbiome also responds swiftly to dietary changes via microbial-derived metabolites (De Filippo et al, 2010;Albenberg & Wu, 2014;Conlon & Bird, 2015) such as short-chain fatty acids (SCFAs). SCFAs are known to regulate the mTOR pathway, one of the key longevity pathways (Cornu et al, 2013;Johnson et al, 2013;Passtoors et al, 2013;Henrique Mazucanti et al, 2015;Park et al, 2015). Interestingly, a gradual loss of SCFA by age has been reported, indicating a potential link between SCFA and ageing regulating pathways (Kundu et al, 2017). ...
Article
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All species, including humans, are cohabited by a myriad of microbial species, which massively influences body function in a diet-, exercise- and age-dependent manner. The microbiome composition differs between individuals, partly due to the polymorphic immune system, as well as the environment, making the microbe-host interplay unique in each one of us. Ageing is a gradual loss of function in part due to reduced repair mechanisms and accumulation of tissue damage through mechanisms largely unknown. Accumulating evidence suggests that our indigenous microbes, a known major regulator of human physiology, are also connected to regulate the ageing process through signalling pathways and metabolites though the biological mechanisms are unknown. At an ageing meeting in Singapore in 2018, investigators discussed the current understanding of microbe regulation and its impact on healthy ageing. This review summarizes the highlights from the meeting and conveys some of the new ideas that emerged around gut microbes and the biology of ageing. While highly speculative, an idea emerged in which gut microbes constantly respond and evolve to environmental cues, as part of an ageing process, thus serving as a second messenger to support and attenuate organ decline in a diet-, gender- and age-dependent manner.
... In humans, polymorphisms in FOXO3A have been associated with lengthened lifespan [83][84][85][86][87][88][89], whereas both mouse and fruit fly models of FOXO3A loss of function result in stronger and longer living model organisms [90][91][92]. Indeed, nonagenarians show downregulation of mTOR pathway genes [93], supporting a role for decreased mTOR signaling in human longevity, whereas in rats, inhibition of mTORC1 via rapalog treatment ameliorates age-related sarcopenia [94]. Here, we show that despite an apparent increase in the oxidative phenotype of muscle, constituent activation of mTORC1 in skeletal muscle decreases lifespan in mice, a finding in consensus with other models of mTORC1 activation [25][26][27]. ...
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The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet- and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.
... This shows the malleability of aging and presumes the existence of mechanisms that mediate these beneficial effects. Decreased activity of TOR kinase is likely crucial for mediating such effects, because mutations in the components of this pathway increase lifespan in various organisms including humans (Jia et al., 2004;Kapahi et al., 2004;Kaeberlein et al., 2005;Passtoors et al., 2013). The TOR complex integrates cellular nutritional and other signals, and acts as the central positive regulator of growth and inhibitor of autophagy. ...
Article
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Autophagy ensures the lysosome-mediated breakdown and recycling of self-material, as it not only degrades obsolete or damaged intracellular constituents but also provides building blocks for biosynthetic and energy producing reactions. Studies in animal models including Drosophila revealed that autophagy defects lead to the rapid decline of neuromuscular function, neurodegeneration, sensitivity to stress (such as starvation or oxidative damage), and stem cell loss. Of note, recently identified human Atg gene mutations cause similar symptoms including ataxia and mental retardation. Physiologically, autophagic degradation (flux) is known to decrease during aging, and this defect likely contributes to the development of such age-associated diseases. Many manipulations that extend lifespan (including dietary restriction, reduced TOR kinase signaling, exercise or treatment with various anti-aging substances) require autophagy for their beneficial effect on longevity, pointing to the key role of this housekeeping process. Importantly, genetic (e.g., Atg8a overexpression in either neurons or muscle) or pharmacological (e.g., feeding rapamycin or spermidine to animals) promotion of autophagy has been successfully used to extend lifespan in Drosophila, suggesting that this intracellular degradation pathway can rejuvenate cells and organisms. In this review, we highlight key discoveries and recent progress in understanding the relationship of autophagy and aging in Drosophila.
... There is no doubt that these mechanisms are determined by genetic, epigenetic and environmental factors. Gene variants correlated with longevity are known, and among them are those protein products involved in lipid metabolism and participate in nutrient sensing signaling pathways, such as the insulin/insulin-like growth factor (IGF-1) and mTOR pathways [47]. ...
Article
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The ageing process is a phenomenon leading to an emergence of a web of interrelated biological processes producing significant changes in the human body. The aim of the paper was to analyse gender-specific differences with regard to selected biochemical parameters in longevity. The study was conducted in Poland in 2017. The study population comprised of long-lived individuals, both living at home and staying at residential care homes. There were 90 people of both genders (69 women and 21 men) aged between 90 and 103 years (mean = 92.36; SD = 2.98). The biochemical markers of longevity in the studied patients were identified by assessing their pro-inflammatory and anti-inflammatory status in various metabolic aspects. The analysis of biochemical variables revealed numerous statistically significant differences, both in the study group as a whole and between the genders. The ageing process is extremely complex, but understanding it will allow for a real intervention in life extension. Research into the processes involved in ageing and longevity will enable a better understanding of the mechanisms responsible for them, and to enjoy those processes in good health.
Article
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Mammalian target of rapamycin complex 1 (mTORC1) plays a major role in cell growth, proliferation, polarity, differentiation, development, and controls transitioning between anabolic and catabolic states of the cell. It collects almost all extracellular and intracellular signals from growth factors, nutrients, and maintains cellular homeostasis, and is involved in several pathological conditions including, neurodegeneration, Type 2 diabetes (T2D), obesity, and cancer. In this review, we summarize current knowledge of upstream signaling of mTORC1 to explain etiology of T2D and hypertriglyceridemia, in which state, the role of telomere attrition is explained. We discuss if chronic inhibition of mTORC1 can reverse adverse effects resulting from hyperactivation. In conclusion, we suggest the regulatory roles of telomerase (TERT) and hexokinase II (HKII) on mTORC1 as possible remedies to treat hyperactivation. The former inhibits mTORC1 under nutrient-rich while the latter under starved condition. We provide an idea of TOS (TOR signaling) motifs that can be used for regulation of mTORC1.
Chapter
Anti-aging medicine has become a popular topic in recent years. It considers biological aging a revertible process that physiologically serves no positive function. Different technologies in systemic delivery and various strategies that characterize and optimize the performance of systemic delivery have been covered in this book. These technologies are essential for the establishment of a technical platform for interventive biogerontology. As the last chapter of this book, we would like to highlight some directions for future applications of systemic drug delivery in anti-aging medicine. We believe that biological aging and aging-related diseases are strongly associated with genetics/genomics and are pre-programmed. Several interventive approaches such as cellular/tissue reprogramming, microbiota supplementation, seno-therapeutics and pharmacological targeting will be discussed in this chapter.
Article
Some types of cancers show a strong relationship with diabetes and play a central role in mortality in the patient population suffering from diabetes mellitus. In this study, HepG2 cells have been used to investigate the toxic effects of hyperglycemia and/or quercetin (Q) on mammalian target of rapamycin (m-TOR) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression as central molecules involved in cancer. HepG2 cells were cultured with different concentrations of glucose (5.5, 30, and 50 mM) and/or Q (25 µM) for 48 and 72 h. Effects of glucose and/or Q on m-TOR and Nrf-2 expression were assayed by quantitative real-time PCR (qRT-PCR). qRT-PCR results revealed that 30 and 50 mM of glucose increased m-TOR expression at 48 h, although after 72 h, only 30 mM had an increasing effect. At 50 mM, glucose-induced Nrf-2 gene expression after both 48 and 72 h. The results also showed that 25 µM of Q reduced m-TOR and Nrf-2 expression at both 30 and 50 mM after 48 and 72 h incubation. Q has potential effects on reducing oxidative stress caused by hyperglycemia and during diabetes may be able to modulate some carcinogenic signaling pathways.
Article
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Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally, through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organization, induces intestinal autophagy through transcriptional regulation, prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription , and alters chromatin organisation in the small intestine, suggesting the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
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Ageing can be defined as the gradual deterioration of physiological functions, increasing the incidence of age-related disorders and the probability of death. Therefore, the term ageing not only reflects the lifespan of an organism but also refers to progressive functional impairment and disease. The nutrient-sensing kinase mTOR (mammalian target of rapamycin) is a major determinant of ageing. mTOR promotes cell growth and controls central metabolic pathways including protein biosynthesis, autophagy and glucose and lipid homoeostasis. The concept that mTOR has a crucial role in ageing is supported by numerous reports on the lifespan-prolonging effects of the mTOR inhibitor rapamycin in invertebrate and vertebrate model organisms. Dietary restriction increases lifespan and delays ageing phenotypes as well and mTOR has been assigned a major role in this process. This may suggest a causal relationship between the lifespan of an organism and its metabolic phenotype. More than 25 years after mTOR's discovery, a wealth of metabolic and ageing-related effects have been reported. In this review, we cover the current view on the contribution of the different elements of the mTOR signalling network to lifespan and age-related metabolic impairment. We specifically focus on distinct roles of isoforms and splice variants across the mTOR network. The comprehensive analysis of mouse knockout studies targeting these variants does not support a tight correlation between lifespan prolongation and improved metabolic phenotypes and questions the strict causal relationship between them.
Chapter
Usually, cells balance their growth with their division. Coordinating growth inputs with cell division ensures the proper timing of division when sufficient cell material is available and affects the overall rate of cell proliferation. At a very fundamental level, cellular replicative lifespan—defined as the number of times a cell can divide, is a manifestation of cell cycle control. Hence, control of mitotic cell divisions, especially when the commitment is made to a new round of cell division, is intimately linked to replicative aging of cells. In this chapter, we review our current understanding, and its shortcomings, of how unbalanced growth and division, can dramatically influence the proliferative potential of cells, often leading to cellular and organismal aging phenotypes. The interplay between growth and division also underpins cellular senescence (i.e., inability to divide) and quiescence, when cells exit the cell cycle but still retain their ability to divide.
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Aims: Vascular calcification/aging can cause different kind of serious diabetic vascular complications. High glucose could induce vascular smooth muscle cells (VSMCs) calcification/aging and then lead to diabetes-related vascular calcification/aging. In this study, we investigated how information in the blood is transmitted to VSMCs and the mechanisms of VSMCs calcification/aging under hyperglycaemic conditions. Materials and methods: Transmission electron microscopy and molecular size analysis were used to assess the morphology and size of exosomes. Alizarin Red S staining and senescence-associated β galactosidase (SA-β-gal) staining were carried out to detect calcification and senescence in VSMCs, respectively. Proteomics analysis was carried out to detect the different expression of exosomal proteins. Protein levels were measured by western blot analysis. Key findings: The results show that exosomes isolated from high glucose stimulated human umbilical vein endothelial cell (HG-HUVEC-Exo) exhibited a bilayer structure morphology with a mean diameter of 63.63 ± 2.96 nm. The presence of exosome markers including CD9, CD63 and TSG101 were also detected in HG-HUVEC-Exo. High glucose could induce VSMCs calcification/aging by increasing the expression of osteocalcin (OC) and p21 as well as the formation of mineralised nodules and SA-β-gal positive cells. Fluorescence microscopy verified that the exosomes were taken up by VSMCs and Notch3 protein was enriched in HG-HUVEC-Exo. Most importantly, mTOR signalling was closely related to Notch3 protein and was involved in regulating HG-HUVEC-Exo-induced VSMCs calcification/aging. Significance: The data demonstrate that Notch3 is required for HG-HUVEC-Exo promoted VSMCs calcification/aging and regulates VSMCs calcification/aging through the mTOR signalling pathway.
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One of the most important issues in improving the competitiveness of the fish production sector is to improve the growth rate of fish. The genetic background to this trait is at present poorly understood. In this study, we compared the relative gene expression levels of the Akt1s1, FGF, GH, IGF1, MSTN, TLR2, TLR4 and TLR5 genes in blood in groups of common carps (Cyprinus carpio), which belonged to different growth types and phenotypes. Fish were divided into groups based on growth rate (normal group: n = 6; slow group: n = 6) and phenotype (scaled group: n = 6; mirror group: n = 6). In the first 18 weeks, we measured significant differences (p < 0.05) between groups in terms of body weight and body length. Over the next 18 weeks, the fish in the slow group showed more intense development. In the same period, the slow group was characterized by lower expression levels for most genes, whereas GH and IGF1 mRNA levels were higher compared to the normal group. We found that phenotype was not a determining factor in differences of relative expression levels of the genes studied.
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Epigenetics in the current times has become a gateway to acquire answers to questions that were left unanswered by classical and modern genetics, be it resolving the complex mystery behind neurodegenerative disorders or understanding the complexity behind life-threatening cancers. It has presented to the world an entirely new dimension and has added a dynamic angle to an otherwise static field of genetics. Alzheimer's disease is one of the most prevalent neurodegenerative disorders is largely found to be a result of alterations in epigenetic pathways. These changes majorly comprise an imbalance in DNA methylation levels and altered acetylation and methylation of histones. They are often seen to cross-link with metabolic regulatory pathways such as that of mTOR, contributing significantly to the pathophysiology of AD. This review focusses on the study of the interplay of the mTOR regulatory pathway with that of epigenetic machinery that may elevate the rate of early diagnosis and prove to be a gateway to the development of an efficient and novel therapeutic strategy for the treatment of Alzheimer's disease at an early stage.
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Colorectal cancer (CRC) is one of the most prevalent cancers diagnosed worldwide. Despite recent advances, resistance to cytotoxic and targeted therapy remains one of the greatest challenges in long-term management of colorectal cancer therapy. Recently established role of mTOR signaling in proliferation of CRC has incited for evaluation of mTOR kinase specific inhibitors in CRC therapy. Second generation mTOR kinase inhibitors including Torin2 has demonstrated efficient anticancer properties against variety of cancers and are in various stages of drug development. The time and financial constraints concomitant from discovery to development of efficient chemical inhibitors has redirected attention towards investigation of wide spread naturally occurring largely inexpensive compounds for their therapeutic potential. One such naturally occurring compound acetophenone derivative polyphenolic compound 2, 6-Dihydroxyacetophenone (DHAP) inhibits cell growth in different conditions. We investigated anticancer properties of both Torin2 and DHAP against colorectal cancer in HCT8 cell lines. Both Torin2 and DHAP inhibited growth of CRC cells at different concentrations by restricting multiple cellular functions e.g., cell cycle progression, cell migration and induced apoptosis. Treatment of HCT8 cells with natural compound DHAP resulted in reduced expression of mTOR pathway specific genes p70S6K1 and AKT1. In silico docking studies showed affinity of DHAP to mTOR kinase like Torin2. Taken together, our result vouches for role of Torin2 in CRC therapy and recommends DHAP an mTOR inhibitor, as a potential lead in the development of new therapeutic regimes against colorectal cancer.
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Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.
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The Leiden Longevity Study consists of families that express extended survival across generations, decreased morbidity in middle-age, and beneficial metabolic profiles. To identify which pathways drive this complex phenotype of familial longevity and healthy aging, we performed a genome-wide gene expression study within this cohort to screen for mRNAs whose expression changes with age and associates with longevity. We first compared gene expression profiles from whole blood samples between 50 nonagenarians and 50 middle-aged controls, resulting in identification of 2,953 probes that associated with age. Next, we determined which of these probes associated with longevity by comparing the offspring of the nonagenarians (50 subjects) and the middle-aged controls. The expression of 360 probes was found to change differentially with age in members of the long-lived families. In a RT-qPCR replication experiment utilizing 312 controls, 332 offspring and 79 nonagenarians, we confirmed a nonagenarian specific expression profile for 21 genes out of 25 tested. Since only some of the offspring will have inherited the beneficial longevity profile from their long-lived parents, the contrast between offspring and controls is expected to be weak. Despite this dilution of the longevity effects, reduced expression levels of two genes, ASF1A and IL7R, involved in maintenance of chromatin structure and the immune system, associated with familial longevity already in middle-age. The size of this association increased when controls were compared to a subfraction of the offspring that had the highest probability to age healthily and become long-lived according to beneficial metabolic parameters. In conclusion, an "aging-signature" formed of 21 genes was identified, of which reduced expression of ASF1A and IL7R marked familial longevity already in middle-age. This indicates that expression changes of genes involved in metabolism, epigenetic control and immune function occur as a function of age, and some of these, like ASF1A and IL7R, represent early features of familial longevity and healthy ageing.
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Androgen receptor (AR) plays a central role in prostate cancer (PCa) growth, with androgen deprivation or AR down-regulation causing cell-cycle arrest and accumulation of the p27 cyclin-dependent kinase inhibitor. The molecular basis for this AR regulation of cell-cycle progression remains unclear. Here we demonstrate that androgen can rapidly reduce p27 protein in PCa cells by increasing its proteasome-mediated degradation. This rapid androgen-stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157. Significantly, androgen increased TORC2-mediated AKT S473 phosphorylation without affecting the PDK1-mediated AKT T308 phosphorylation or TORC1 activity. The TORC2 activation was further supported by enhanced mTOR/RICTOR association and increased phosphorylation of additional TORC2 substrates, SGK1 and PKCα. The androgen-stimulated nuclear translocation of AR was associated with markedly-increased nuclear SIN1, a critical component of TORC2. Finally, the androgen-mediated TORC2/AKT activation targets a subset of AKT substrates including p27 and FOXO1, but not PRAS40. This study reveals a pathway linking AR to a selective activation of TORC2, the subsequent activation of AKT, and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival. These findings establish that TORC2 can function as a central regulator of growth in response to signals that are distinct from those regulating TORC1, and support efforts to target TORC2 for cancer therapy.
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In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity. Electronic supplementary material The online version of this article (doi:10.1007/s11357-011-9340-3) contains supplementary material, which is available to authorized users.
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Activation of the PI3K pathway plays a pivotal role in regulating the inflammatory response. The loss of mTORC2 has been shown to abrogate the activation of Akt, a critical downstream component of PI3K signaling. However, the biological importance of mTORC2 in innate immunity is currently unknown. Here we demonstrate that rictor, a key component of mTORC2, plays a critical role in controlling the innate inflammatory response via its ability to regulate FoxO1. Upon LPS stimulation, both rictor-deficient mouse embryonic fibroblasts (MEFs) and rictor knockdown dendritic cells exhibited a hyperinflammatory phenotype. The hyperinflammatory phenotype was due to a defective Akt signaling axis, because both rictor-deficient MEFs and rictor knockdown dendritic cells exhibited attenuated Akt phosphorylation and kinase activity. Analysis of downstream Akt targets revealed that phosphorylation of FoxO1 was impaired in rictor-deficient cells, resulting in elevated nuclear FoxO1 levels and diminished nuclear export of FoxO1 upon LPS stimulation. Knockdown of FoxO1 attenuated the hyperinflammatory phenotype exhibited by rictor-deficient MEFs. Moreover, FoxO1 deletion in dendritic cells attenuated the capacity of LPS to induce inflammatory cytokine expression. These findings identify a novel signaling pathway by which mTORC2 regulates the TLR-mediated inflammatory response through its ability to regulate FoxO1.
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T cell-mediated immunity in elderly people is compromised in ways reflected in the composition of the peripheral T cell pool. The advent of polychromatic flow cytometry has made analysis of cell subsets feasible in unprecedented detail. Here we document shifts in subset distribution within naïve (N), central memory (CM) and effector memory (EM) cells defined by CD45RA and CCR7 expression in the elderly, additionally using the costimulatory receptors CD27 and CD28, as well as the coinhibitory receptors CD57 and KLRG-1, to further dissect these. Although differences between young and old were more marked in CD8 than in CD4 cells, a similar overall pattern prevailed in both. Thus, the use of all these markers together, and inclusion of assays of proliferation and cytokine secretion, may enable the construction of a differentiation scheme applicable to CD4 as well as CD8 cells, with the model (based on Romero et al.) suggesting the progression N-->CM-->EM1-->EM2-->pE1-->pE2-->EM4-->EM3-->E end-stage non-proliferative effector cells. Overall, the results suggest that both differences in subset distribution and differences between subsets are responsible for age-related changes in CD8 cells but that differences within rather than between subsets are more prominent for CD4 cells.
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By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P<1×10(-4) ) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR=0.71 (95% CI 0.65-0.77), P=3.39 × 10(-17) ]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P=0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found.
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Insulin resistance is a risk factor for various age-related diseases. In the Leiden Longevity study, we recruited long-lived siblings and their offspring. Previously, we showed that, compared to controls, the offspring of long-lived siblings had a better glucose tolerance. Here, we compared groups of offspring from long-lived siblings and controls for the relation between insulin and glucose in nonfasted serum (n = 1848 subjects) and for quantitation of insulin action using a two-step hyperinsulinemic-euglycemic clamp (n = 24 subjects). Groups of offspring and controls were similar with regard to sex distribution, age, and body mass index. We observed a positive bi-phasic linear relationship between ln (insulin) levels and nonfasted glucose with a steeper slope from 10.7mU L(-1) insulin onwards in controls compared to offspring (P = 0.02). During the clamp study, higher glucose infusion rate was required to maintain euglycemia during high-dose insulin infusion (P = 0.036) in offspring, reflecting higher whole-body insulin sensitivity. After adjustment for sex, age, and fat mass, the insulin-mediated glucose disposal rate (GDR) was higher in offspring than controls (42.5 ± 2.7 vs. 33.2 ± 2.7 micromol kg(-1) min(-1) , mean ± SE, P = 0.025). The insulin-mediated suppression of endogenous glucose production and lipolysis did not differ between groups (all P > 0.05). Furthermore, GDR was significantly correlated with the mean age of death of the parents. In conclusion, offspring from long-lived siblings are marked by enhanced peripheral glucose disposal. Future research will focus on identifying the underlying biomolecular mechanisms, with the aim to promote health in old age.
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Seropositivity for CMV is one of the parameters of the "immune risk profile" associated with mortality in longitudinal studies of the very elderly and may accelerate immunosenescence. Thus, any genetic factors influencing human longevity may be associated with susceptibility to CMV and CMV-accelerated immunosenescence. To test this, we analyzed long-lived families in the Leiden Longevity Study (LLS) in which offspring enjoy a 30% reduced standardized mortality rate, possibly owing to genetic enrichment. Serum C-reactive protein levels and the frequency of different T cell subsets were compared between 97 LLS offspring and 97 controls (their partners, representing the normal population). We also determined the capacity of T cells to respond against immunodominant Ags from CMV in a smaller group of LLS subjects and controls. CMV infection was strongly associated with an age-related reduction in the frequency of naive T cells and an accumulation of CD45RA-re-expressing and late-differentiated effector memory T cells in the general population, but not in members of long-lived families. The latter also had significantly lower C-reactive protein levels, indicating a lower proinflammatory status compared with CMV-infected controls. Finally, T cells from a higher proportion of offspring mounted a proliferative response against CMV Ags, which was also of greater magnitude and broader specificity than controls. Our data suggest that these rare individuals genetically enriched for longevity are less susceptible to the characteristic CMV-associated age-driven immune alterations commonly considered to be hallmarks of immunosenescence, which might reflect better immunological control of the virus and contribute to their decreased mortality rate.
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Recently, we have shown that compared to controls, long-lived familial nonagenarians (mean age: 93.4 years) from the Leiden Longevity Study displayed a lower mortality rate, and their middle-aged offspring displayed a lower prevalence of cardio-metabolic diseases, including diabetes mellitus. The evolutionarily conserved insulin/IGF-1 signaling (IIS) pathway has been implicated in longevity in model organisms, but its relevance for human longevity has generated much controversy. Here, we show that compared to their partners, the offspring of familial nonagenarians displayed similar non-fasted serum levels of IGF-1, IGFBP3 and insulin but lower non-fasted serum levels of glucose, indicating that familial longevity is associated with differences in insulin sensitivity.
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Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
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Rictor is a component of the target of rapamycin complex 2 (TORC2). While TORC2 has been implicated in insulin and other growth factor signaling pathways, the key inputs and outputs of this kinase complex remain unknown. We identified mutations in the Caenorhabditis elegans homolog of rictor in a forward genetic screen for increased body fat. Despite high body fat, rictor mutants are developmentally delayed, small in body size, lay an attenuated brood, and are short-lived, indicating that Rictor plays a critical role in appropriately partitioning calories between long-term energy stores and vital organismal processes. Rictor is also necessary to maintain normal feeding on nutrient-rich food sources. In contrast to wild-type animals, which grow more rapidly on nutrient-rich bacterial strains, rictor mutants display even slower growth, a further reduced body size, decreased energy expenditure, and a dramatically extended life span, apparently through inappropriate, decreased consumption of nutrient-rich food. Rictor acts directly in the intestine to regulate fat mass and whole-animal growth. Further, the high-fat phenotype of rictor mutants is genetically dependent on akt-1, akt-2, and serum and glucocorticoid-induced kinase-1 (sgk-1). Alternatively, the life span, growth, and reproductive phenotypes of rictor mutants are mediated predominantly by sgk-1. These data indicate that Rictor/TORC2 is a nutrient-sensitive complex with outputs to AKT and SGK to modulate the assessment of food quality and signal to fat metabolism, growth, feeding behavior, reproduction, and life span.
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The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1alpha-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.
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The group of enzymes known as TOR (for 'target of rapamycin') kinases regulates cell growth and proliferation in response to nutrients and hormone-dependent mitogenic signals. Here we show that TOR deficiency in the nematode Caenorhabditis elegans more than doubles its natural lifespan. This new function for TOR signalling in ageing control may represent a link between nutrition, metabolism and longevity.
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A recent surge of interest in survival as the primary clinical endpoint of microarray studies has called for an extension of the Global Test methodology to survival. We present a score test for association of the expression profile of one or more groups of genes with a (possibly censored) survival time. Groups of genes may be pathways, areas of the genome, clusters from a cluster analysis or all genes on a chip. The test allows one to test hypotheses about the influence of these groups of genes on survival directly, without the intermediary of single gene testing. The test is based on the Cox proportional hazards model and is calculated using martingale residuals. It is possible to adjust the test for the presence of covariates. We also present a diagnostic graph to assist in the interpretation of the test result, visualizing the influence of genes. The test is applied to a tumor dataset, revealing pathways from the gene ontology database that are associated with survival of patients. The Global Test for survival has been incorporated into the R-package globaltest (version 3.0), available at http://www.bioconductor.org
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We conducted a sib pair study in very old subjects for the purpose of mapping longevity loci. In the present analysis, we explore whether our recruitment strategy has resulted in a population enriched for a heritable component for exceptional longevity. Our study includes families with at least two long-living siblings (men aged 89 years or above; women aged 91 years or above). Data were collected on date of birth and, if applicable, date of death of parents, brothers and sisters, offspring, and spouses of the long-living participants. Standardised mortality ratios (SMRs) compared with the general Dutch population, were calculated. The SMR for all siblings of the long-living participants was 0.66 (95% CI 0.60-0.73). A similar survival benefit was also observed in the parents (SMR=0.76, 95% CI 0.66-0.87) and in the offspring of the long-living subjects (SMR=0.65, 95% CI 0.51-0.80). The SMR of the spouses of the long-living subjects was 0.95 (95% CI 0.82-1.12). The familial clustering of extended survival is unlikely to be caused by ascertainment bias, because in all analyses the long-living participants were excluded. Moreover, it is also unlikely to be caused by environmental factors, because the spouses of the long-living participants had a mortality risk comparable with the general Dutch population, whereas they share the same environment. We conclude that our sample is genetically enriched for extreme survival.
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Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene–deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.
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Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population. NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10(-3)) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007). Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.
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The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid-induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m(2)) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia (approximately 450 pmol/l, 180-360 min). Glucose turnover was assessed using d-[6,6-(2)H(2)]glucose infusion (n = 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia (n = 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% (R(d 300-360 min), 75 +/- 5 vs. 64 +/- 5 micromol x kg(-1) x min(-1), P = 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway.
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Rictor is an essential component of mTOR (mammalian target of rapamycin) complex 2 (mTORC2), a kinase complex that phosphorylates Akt at Ser473 upon activation of phosphatidylinositol 3-kinase (PI-3 kinase). Since little is known about the role of either rictor or mTORC2 in PI-3 kinase-mediated physiological processes in adult animals, we generated muscle-specific rictor knockout mice. Muscle from male rictor knockout mice exhibited decreased insulin-stimulated glucose uptake, and the mice showed glucose intolerance. In muscle lacking rictor, the phosphorylation of Akt at Ser473 was reduced dramatically in response to insulin. Furthermore, insulin-stimulated phosphorylation of the Akt substrate AS160 at Thr642 was reduced in rictor knockout muscle, indicating a defect in insulin signaling to stimulate glucose transport. However, the phosphorylation of Akt at Thr308 was normal and sufficient to mediate the phosphorylation of glycogen synthase kinase 3 (GSK-3). Basal glycogen synthase activity in muscle lacking rictor was increased to that of insulin-stimulated controls. Consistent with this, we observed a decrease in basal levels of phosphorylated glycogen synthase at a GSK-3/protein phosphatase 1 (PP1)-regulated site in rictor knockout muscle. This change in glycogen synthase phosphorylation was associated with an increase in the catalytic activity of glycogen-associated PP1 but not increased GSK-3 inactivation. Thus, rictor in muscle tissue contributes to glucose homeostasis by positively regulating insulin-stimulated glucose uptake and negatively regulating basal glycogen synthase activity.
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Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.
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