Skip to main content

Advertisement

SpringerLink
Log in

Amino acids and amino acid sensing: implication for aging and diseases

  • Research Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Biogerontological research indicates nutrition as one of the major determinants of healthy aging, due to the role of nutrients in maintaining the dynamic-homeostasis of the organism. In this frame, the importance of proteins and constitutive amino acids (AAs), and in particular of functional AAs is emerging. The ability to sense and respond to changes in AAs availability is mediated by a complex network of dynamic players, crucial for an efficient regulation of their downstream effects. Here, we reviewed the current knowledge about the involvement of AA sensing mechanisms in aging and age-related diseases, focusing our attention on mTORC1 and AA transporters. In this context it is of note that alterations in AA sensors have been reported to be directly implicated in age-related phenotypes, suggesting that their modulation can represent a possible strategy for modulating (and possibly delaying) aging decline. Furthermore, these alterations may influence the effects of AA supplementation, by influencing the individual answer to AA availability. On the whole, evidences support the hypothesis that the efficiency of components of AA sensing network may have important implications for therapy, and their knowledge may be crucial for programming AA supplementation for contrasting age-related phenotypes, opening new opportunities for therapeutic interventions aimed to promote human health span.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Allen NE, Appleby PN, Key TJ, Bueno-de-Mesquita HB, Ros MM, Kiemeney LA, Tjonneland A, Roswall N, Overvad K, Weikert S, Boeing H, Chang-Claude J, Teucher B, Panico S, Sacerdote C, Tumino R, Palli D, Sieri S, Peeters P, Quiros JR, Jakszyn P, Molina-Montes E, Chirlaque MD, Ardanaz E, Dorronsoro M, Khaw KT, Wareham N, Ljungberg B, Hallmans G, Ehrnstrom R, Ericson U, Gram IT, Parr CL, Trichopoulou A, Karapetyan T, Dilis V, Clavel-Chapelon F, Boutron-Ruault MC, Fagherrazzi G, Romieu I, Gunter MJ, Riboli E (2013) Macronutrient intake and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition. Int J Cancer 132:635–644

    Article  CAS  PubMed  Google Scholar 

  • Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, Boschi F, Arcidiaco P, Viglio S (2005) Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil 86:1729–1735

    Article  PubMed  Google Scholar 

  • Aquilani R, Boselli M, Boschi F, Viglio S, Iadarola P, Dossena M, Pastoris O, Verri M (2008) Branched-chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: a pilot study. Arch Phys Med Rehabil 89:1642–1647

    Article  PubMed  Google Scholar 

  • Aquilani R, Zuccarelli GC, Dioguardi FS, Baiardi P, Frustaglia A, Rutili C, Comi E, Catani M, Iadarola P, Viglio S, Barbieri A, D’Agostino L, Verri M, Pasini E, Boschi F (2011) Effects of oral amino acid supplementation on long-term-care-acquired infections in elderly patients. Arch Gerontol Geriatr 52:e123–e128

    Article  CAS  PubMed  Google Scholar 

  • Averous J, Lambert-Langlais S, Mesclon F, Carraro V, Parry L, Jousse C, Bruhat A, Maurin AC, Pierre P, Proud CG, Fafournoux P (2016) GCN2 contributes to mTORC1 inhibition by leucine deprivation through an ATF4 independent mechanism. Sci Rep 6:27698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayala V, Naudì A, Sanz A, Caro P, Portero-Otin M, Barja G, Pamplona R (2007) Dietary protein restriction decrease oxidative protein damage, peroxidizability index, and mitochondrial complex I content in rat liver. J Gerontol 62A:352–360

    Article  CAS  Google Scholar 

  • Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM (2013) A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340:1100–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Battu S, Minhas G, Mishra A, Khan N (2017) Amino acid sensing via general control nonderepressible-2 kinase and immunological programming. Front Immunol 8:1719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beugnet A, Tee AR, Taylor PM, Proud CG (2003) Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular AA availability. Biochem J 372:555–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhutia YD, Babu E, Ramachandran S, Ganapathy V (2015) Amino acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs. Cancer Res 75:1782–1788

    Article  CAS  PubMed  Google Scholar 

  • Bifari F, Nisoli E (2017) Branched-chain amino acids differently modulate catabolic and anabolic states in mammals: a pharmacological point of view. Br J Pharmacol 174:1366–1377

    Article  CAS  PubMed  Google Scholar 

  • Bifari F, Ruocco C, Decimo I, Fumagalli G, Valerio A, Nisoli E (2017) Amino acid supplements and metabolic health: a potential interplay between intestinal microbiota and systems control. Genes Nutr 12:27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bolasco P, Caria S, Cupisti A, Secci R, Saverio Dioguardi F (2011) A novel amino acids oral supplementation in hemodialysis patients: a pilot study. Ren Fail 33:1–5

    Article  CAS  PubMed  Google Scholar 

  • Bröer S (2018) Amino acid transporters as disease modifiers and drug targets. SLAS Discov 23:303–320

    PubMed  Google Scholar 

  • Bröer S, Palacín M (2011) The role of amino acid transporters in inherited and acquired diseases. Biochem J 436:193–211

    Article  CAS  PubMed  Google Scholar 

  • Caccamo A, Magrì A, Medina DX, Wisely EV, López-Aranda MF, Silva AJ, Oddo S (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12:370–380

    Article  CAS  PubMed  Google Scholar 

  • Chen R, Zou Y, Mao D, Sun D, Gao G, Shi J, Liu X, Zhu C, Yang M, Ye W, Hao Q, Li R, Yu L (2014) The general AA control pathway regulates mTOR and autophagy during serum/glutamine starvation. J Cell Biol 206:173–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen KB, Xuan Y, Shi WJ, Chi F, Xing R, Zeng YC (2016) Sestrin2 expression is a favorable prognostic factor in patients with non-small cell lung cancer. Am J Transl Res 8:1903–1909

    CAS  PubMed  PubMed Central  Google Scholar 

  • Christie GR, Hajduch E, Hundal HS, Proud CG, Taylor PM (2002) Intracellular sensing of AAs in Xenopus laevis oocytes stimulates p70 S6 kinase in a target of rapamycin-dependent manner. J Biol Chem 277:9952–9957

    Article  CAS  PubMed  Google Scholar 

  • Contrusciere AV, Paradisi S, Matteucci A, Malchiodi-Albedi F (2010) Branched-chain amino acids induce neurotoxicity in rat cortical culture. Neurotox Res 17:392–398

    Article  CAS  PubMed  Google Scholar 

  • Coothankandaswamy V, Cao S, Xu Y, Prasad PD, Singh PK, Reynolds CP, Yang S, Ogura J, Ganapathy V, Bhutia YD (2016) Amino acid transporter SLC6A14 is a novel and effective drug target for pancreatic cancer. Br J Pharmacol 173:3292–3306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cormerais Y, Giuliano S, LeFloch R, Front B, Durivault J, Tambutté E, Massard PA, de la Ballina LR, Endou H, Wempe MF, Palacin M, Parks SK, Pouyssegur J (2016) Genetic disruption of the multifunctional CD98/LAT1 Complex Demonstrates the Key Role of essential amino acid transport in the control of mTORC1 and tumor growth. Cancer Res 76:4481–4492

    Article  CAS  PubMed  Google Scholar 

  • Crocco P, Hoxha E, Dato S, De Rango F, Montesanto A, Rose G, Passarino G (2018) Physical decline and survival in the elderly are affected by the genetic variability of amino acid transporter genes. Aging (Albany NY) 10:658–673

    Article  CAS  Google Scholar 

  • Cuervo AM (2008) Autophagy and aging: keeping that old broom working. Trends Genet 24:604–612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Curi R, Newsholme P, Procopio J, Lagranha C, Gorjão R, Pithon-Curi TC (2007) Glutamine, gene expression, and cell function. Front Biosci 12:344–357

    Article  CAS  PubMed  Google Scholar 

  • Cuthbertson D, Smith K, Babraj J, Leese G, Waddell T, Atherton P, Wackerhage H, Taylor PM, Rennie MJ (2005) Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J 19:422–424

    Article  CAS  PubMed  Google Scholar 

  • D’Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F, Caliaro F, Corsetti G, Bottinelli R, Carruba MO, Valerio A, Nisoli E (2010) Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab 12:362–372

    Article  CAS  PubMed  Google Scholar 

  • D’Antona G, Tedesco L, Ruocco C, Corsetti G, Ragni M, Fossati A, Saba E, Fenaroli F, Montinaro M, Carruba MO, Valerio A, Nisoli E (2016) A peculiar formula of essential amino acids prevents rosuvastatin myopathy in mice. Antioxid Redox Signal 25:595–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dardevet D, Rémond D, Peyron MA, Papet I, Savary-Auzeloux I, Mosoni L (2012) Muscle wasting and resistance of muscle anabolism: the “anabolic threshold concept” for adapted nutritional strategies during sarcopenia. Sci World J 2012:269531

    Article  Google Scholar 

  • De Simone R, Vissicchio F, Mingarelli C, De Nuccio C, Visentin S, Ajmone-Cat MA, Minghetti L (2013) Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim Biophys Acta 1832:650–659

    Article  CAS  PubMed  Google Scholar 

  • Deutz NE, Pereira SL, Hays NP, Oliver JS, Edens NK, Evans CM, Wolfe RR (2013) Effect of β-hydroxy-β-methylbutyrate (HMB) on lean body mass during 10 days of bed rest in older adults. Clin Nutr 32:704–712

    Article  CAS  PubMed  Google Scholar 

  • Deutz NEP, Bauer JM, Barazzoni R, Biolo G, Boirie Y, Bosy-Westphal A, Cederholm T, Cruz-Jentoft A, Krznariç Z, Nair KS, Singer P, Teta D, Tipton K, Calder PC (2014) Protein intake and exercise for optimal muscle function with aging: Recommendations from the ESPEN Expert Group. Clin Nutr (Edinburgh, Scotland) 33:929–936

    Article  CAS  Google Scholar 

  • Dickinson JM, Drummond MJ, Coben JR, Volpi E, Rasmussen BB (2013) Aging differentially affects human skeletal muscle amino acid transporter expression when essential amino acids are ingested after exercise. Clin Nutr 32:273–280

    Article  CAS  PubMed  Google Scholar 

  • Dickinson JM, Gundermann DM, Walker DK, Reidy PT, Borack MS, Drummond MJ, Arora M, Volpi E, Rasmussen BB (2014) Leucine-enriched amino acid ingestion after resistance exercise prolongs myofibrillar protein synthesis and amino acid transporter expression in older men. J Nutr 144:1694–1702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dillon EL (2013) Nutritionally essential amino acids and metabolic signaling in aging. Amino Acids 45:431–441

    Article  CAS  PubMed  Google Scholar 

  • Drummond MJ, Glynn EL, Fry CS, Timmerman KL, Volpi E, Rasmussen BB (2010) An increase in essential amino acid availability upregulates amino acid transporter expression in human skeletal muscle. Am J Physiol Endocrinol Metab 298:e1011–e1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drummond MJ, Fry CS, Glynn EL, Timmerman KL, Dickinson JM, Walker DK, Gundermann DM, Volpi E, Rasmussen BB (2011) Skeletal muscle amino acid transporter expression is increased in young and older adults following resistance exercise. J Appl Physiol 111:135–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drummond MJ, Dickinson JM, Fry CS, Walker DK, Gundermann DM, Reidy PT, Timmerman KL, Markofski MM, Paddon-Jones D, Rasmussen BB, Volpi E (2012) Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults. Am J Physiol Endocrinol Metab 302:E1113–E1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Durand E, Boutin P, Meyre D, Charles MA, Clement K, Dina C, Froguel P (2004) Polymorphisms in the amino acid transporter solute carrier family 6 (neurotransmitter transporter) member 14 gene contribute to polygenic obesity in French Caucasians. Diabetes 53:2483–2486

    Article  CAS  PubMed  Google Scholar 

  • Efeyan A, Comb WC, Sabatini DM (2015) Nutrient sensing mechanisms and pathways. Nature 517:302–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El Ansari R, Craze ML, Miligy I, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA, Green AR (2018a) The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours. Breast Cancer Res 20:21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El Ansari R, Craze ML, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA, Green AR (2018b) The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes. Br J Cancer 118:1115–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan SJ, Snell C, Turley H, Li JL, McCormick R, Perera SM, Heublein S, Kazi S, Azad A, Wilson C, Harris AL, Goberdhan DC (2016) PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer. Oncogene 35:3004–3015

    Article  CAS  PubMed  Google Scholar 

  • Fiorentino A, Sharp SI, McQuillin A (2015) Association of rare variation in the glutamate receptor gene SLC1A2 with susceptibility to bipolar disorder and schizophrenia. Eur J Hum Genet 23:1200–1206

    Article  CAS  PubMed  Google Scholar 

  • Fontana L, Partridge L (2015) Promoting health and longevity through diet: from model organisms to humans. Cell 161:106–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, Cava E, Spelta F, Tosti V, Syed FA, Baar EL, Veronese N, Cottrell SE, Fenske RJ, Bertozzi B, Brar HK, Pietka T, Bullock AD, Figenshau RS, Andriole GL, Merrins MJ, Alexander CM, Kimple ME, Lamming DW (2016) Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep 16:520–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • GBD 2016 SDG Collaborators (2017) Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016. Lancet 390:1423–1459

    Article  Google Scholar 

  • Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA (2003) M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ 10:1165–1177

    Article  CAS  PubMed  Google Scholar 

  • Goberdhan DC (2010) Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target? Curr Opin Investig Drugs 11:1360–1367

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goberdhan DCI, Wilson C, Harris AL (2016) Amino acid sensing by mTORC1: intracellular transporters mark the spot. Cell Metab 23:580–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grohmann U, Bronte V (2010) Control of immune response by amino acid metabolism. Immunol Rev 236:243–264

    Article  CAS  PubMed  Google Scholar 

  • Gu Y, Chen T, Fu S, Sun X, Wang L, Wang J, Lu Y, Ding S, Ruan G, Teng L, Wang M (2015) Perioperative dynamics and significance of amino acid profiles in patients with cancer. J Transl Med 13:35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi K, Anzai N (2017) Novel therapeutic approaches targeting L-type amino acid transporters for cancer treatment. World J Gastrointest Oncol 9:21–29

    Article  PubMed  PubMed Central  Google Scholar 

  • Heffernan KS, Fahs CA, Ranadive SM, Patvardhan EA (2010) l-Arginine as a nutritional prophylaxis against vascular endothelial dysfunction with aging. J Cardiovasc Pharmacol Ther 15:17–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, Tagliabracci VS, Guan KL (2015) Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 347:194–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Y, Rose AJ, Sijmonsma TP, Bröer A, Pfenninger A, Herzig S, Schmoll D, Bröer S (2015) Mice lacking neutral amino acid transporter B(0)AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control. Mol Metab 4:406–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall VZ, Gagnidze A, Oh K, Wasko BM, Ramos FJ, Palmiter RD, Rabinovitch PS, Morgan PG, Sedensky MM, Kaeberlein M (2013) mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342:1524–1528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones RG, Pearce EJ (2017) MenTORing immunity: mTOR signaling in the development and function of tissue-resident immune cells. Immunity 46:730–742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jung J, Genau HM, Behrends C (2015) AA dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol Cell Biol 35:2479–2494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR (2005) Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. Am J Clin Nutr 82:1065–1073

    Article  CAS  PubMed  Google Scholar 

  • Kim CH, Park KJ, Park JR, Kanai Y, Endou H, Park JC, Kim DK (2006) The RNA interference of amino acid transporter LAT1 inhibits the growth of KB human oral cancer cells. Anticancer Res 26(4B):2943–2948

    CAS  PubMed  Google Scholar 

  • Kim HJ, Jang SH, Ryu JS, Lee JE, Kim YC, Lee MK, Jang TW, Lee SY, Nakamura H, Nishikata N, Mori M, Noguchi Y, Miyano H, Lee KY (2015) The performance of a novel amino acid multivariate index for detecting lung cancer: a case control study in Korea. Lung Cancer 90:522–527

    Article  PubMed  Google Scholar 

  • Kobayashi T, Shimabukuro-Demoto S, Yoshida-Sugitani R, Furuyama-Tanaka K, Karyu H, Sugiura Y, Shimizu Y, Hosaka T, Goto M, Kato N (2014) The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 41:375–388

    Article  CAS  PubMed  Google Scholar 

  • Laplante M, Sabatini DM (2012) mTOR signalling in growth control and disease. Cell 149:274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le Floc’h N, Melchior D, Obled C (2004) Modifications of protein and amino acid metabolism during inflammation and immune system activation. Livest Prod Sci 87:37–45

    Article  Google Scholar 

  • Lee JY, Kim JH, Lee DC (2014) Urine melatonin levels are inversely associated with sarcopenia in postmenopausal women. Menopause 21:39–44

    Article  PubMed  Google Scholar 

  • Lee BC, Kaya A, Gladyshev VN (2016) Methionine restriction and lifespan control. Ann N Y Acad Sci 1363:116–124

    Article  CAS  PubMed  Google Scholar 

  • Leite JSM, Cruzat VF, Krause MS, Homem de Bittencourt PI (2016) Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions. Nutrire 41:17

    Article  CAS  Google Scholar 

  • Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD (2014) Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19:407–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin C-LG, Kong Q, Cuny GD, Glicksman MA (2012) Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases. Fut Med Chem 4:1689–1700

    Article  CAS  Google Scholar 

  • Longo VD, Mattson MP (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinet W, De Loof H, De Meyer GR (2014) mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. Atherosclerosis 233:601–607

    Article  CAS  PubMed  Google Scholar 

  • Matsui T, Fukuda M (2013) Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4. EMBO Rep 14:450–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mirzaei H, Suarez JA, Longo VD (2014) Protein and amino acid restriction, aging and disease: from yeast to humans. TEM 25:558–566

    CAS  PubMed  Google Scholar 

  • Moro T, Ebert SM, Adams CM, Rasmussen BB (2016) Amino acid sensing in skeletal muscle. Trends Endocrinol Metab 27:796–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, Blonska M, Lin X, Sun SC (2014) Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40:692–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of AAs regulates mTOR and autophagy. Cell 136:521–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishitani S, Matsumura T, Fujitani S, Sonaka I, Miura Y, Yagasaki K (2002) Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun 299:693–696

    Article  CAS  PubMed  Google Scholar 

  • Norton LE, Wilson GJ, Moulton CJ, Layman DK (2017) Meal distribution of dietary protein and leucine influences long-term muscle mass and body composition in adult rats. J Nutr 147:195–201

    Article  CAS  PubMed  Google Scholar 

  • Ögmundsdóttir MH, Heublein S, Kazi S, Reynolds B, Visvalingam SM, Shaw MK, Goberdhan DC (2012) Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes. PLoS ONE 7:e36616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’ Neill C (2013) PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp Gerontol 48:647–653

    Article  CAS  PubMed  Google Scholar 

  • Pinilla J, Aledo JC, Cwiklinski E, Hyde R, Taylor PM, Hundal HS (2011) SNAT2 transceptor signalling via mTOR: a role in cell growth and proliferation? Front Biosci 3:1289–1299

    Google Scholar 

  • Ravindran R, Loebbermann J, Nakaya HI, Khan N, Ma H, Gama L, Machiah DK, Lawson B, Hakimpour P, Wang YC, Li S, Sharma P, Kaufman RJ, Martinez J, Pulendran B (2016) The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 531:523–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rebsamen M, Pochini L, Stasyk T, de Araùjo MEG, Galluccio M, Kandasamy RK, Snijder B, Fauster A, Rudashevskaya EL, Bruckner M, Scorzoni S, Filipek PA, Huber KVM, Bigenzahn J, Heinz LX, Kraft C, Bennett KL, Indiveri C, Huber LA, Superti-Furga G (2015) SLC38A9 is a component of the lysosomal AA-sensing machinery that controls mTORC1. Nature 519:477–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reddy K, Cusack CL, Nnah IC, Khayati K, Saqcena C, Huynh TB, Noggle SA, Ballabio A, Dobrowolski R (2016) Dysregulation of nutrient sensing and CLEARance in presenilin deficiency. Cell Rep 14:2166–2179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reidy PT, Borack MS, Markofski MM, Dickinson JM, Deer RR, Husaini SH, Walker DK, Igbinigie S, Robertson SM, Cope MB, Mukherjea R, Hall-Porter JM, Jennings K, Volpi E, Rasmussen BB (2016) Protein supplementation has minimal effects on muscle adaptations during resistance exercise training in young men: a double-blind randomized clinical trial. J Nutr 146:1660–1669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren W, Liu G, Yin J, Tan B, Wu G, Bazer FW, Peng Y, Yin Y (2017) Amino-acid transporters in T-cell activation and differentiation. Cell Death Dis 8: e2655. Erratum in: Cell Death Dis 8: e2757

  • Rondanelli M, Faliva M, Monteferrario F, Peroni G, Repaci E, Allieri F, Perna S (2015) Novel insights on nutrient management of sarcopenia in elderly. Biomed Res Int 2015:524948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–1501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santoro A, Pini E, Scurti M, Palmas G, Berendsen A, Brzozowska A, Pietruszka B, Szczecinska A, Cano N, Meunier N, de Groot CP, Feskens E, Fairweather-Tait S, Salvioli S, Capri M, Brigidi P, Franceschi C, NU-AGEConsortium (2014) Combating inflammaging through a Mediterranean whole diet approach: the NU-AGE project’s conceptual framework and design. Mech Ageing Dev 136–137:3–13

    Article  PubMed  Google Scholar 

  • Seol SY, Lee SY, Kim YD, Do EJ, Kwon JA, Kim SI, Chu IS, Leem SH (2008) Minisatellite polymorphisms of the SLC6A19: susceptibility in hypertension. Biochem Biophys Res Commun 374(4):714–719

    Article  CAS  PubMed  Google Scholar 

  • Shanware NP, Mullen AR, DeBerardinis RJ, Abraham RT (2011) Glutamine: pleiotropic roles in tumor growth and stress resistance. J Mol Med 89:229–236

    Article  CAS  PubMed  Google Scholar 

  • Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA (2013) Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14:500–508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solon-Biet SM, Mitchell SJ, de Cabo R, Raubenheimer D, Le Couteur DG, Simpson SJ (2015) Macronutrients and caloric intake in health and longevity. J Endocrinol 226:R17–R28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK (2009) The TOR pathway comes of age. Biochem Biophys Acta 1790:1067–1074

    Article  CAS  PubMed  Google Scholar 

  • Suviolahti E, Oksanen LJ, Ohman M, Cantor RM, Ridderstrale M, Tuomi T, Kaprio J, Rissanen A, Mustajoki P, Jousilahti P, Vartiainen E, Silander K, Kilpikari R, Salomaa V, Groop L, Kontula K, Peltonen L, Pajukanta P (2003) The SLC6A14 gene shows evidence of association with obesity. J Clin Invest 112:1762–1772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tărlungeanu DC, Deliu E, Dotter CP, Kara M, Janiesch PC, Scalise M, Galluccio M, Tesulov M, Morelli E, Sonmez FM, Bilguvar K, Ohgaki R, Kanai Y, Johansen A, Esharif S, Ben-Omran T, Topcu M, Schlessinger A, Indiveri C, Duncan KE, Caglayan AO, Gunel M, Gleeson JG, Novarino G (2016) Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell 167:1481–1494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tattoli I, Sorbara MT, Vuckovic D, Ling A, Soares F, Carneiro LA (2012) Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 11(563–75):10

    Google Scholar 

  • Taylor PM (2014) Role of amino acid transporters in amino acid sensing. Am J Clin Nutr 99:223S–230S

    Article  CAS  PubMed  Google Scholar 

  • Valerio A, D’Antona G, Nisoli E (2011) Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective. Aging (Albany NY) 3:464–478

    Article  CAS  Google Scholar 

  • Wang Q, Holst J (2015) L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am J Cancer Res 5:1281–1294

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Bailey CG, Ng C, Tiffen J, Thoeng A, Minhas V, Lehman ML, Hendy SC, Buchanan G, Nelson CC, Rasko JE, Holst J (2011) Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res 71:7525–7536

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Ning Y, Alam GN, Jankowski BM, Dong Z, Nor JE, Polverini PJ (2013) Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway. Neoplasia. 15:989–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W (2015) Metabolism. Lysosomal AA transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347:188–194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu G (2013) Functional amino acids in nutrition and health. Amino Acids 45:407–411

    Article  CAS  PubMed  Google Scholar 

  • Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl JA, Ron D, Koumenis C (2010) The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 29:2082–2096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye J, Palm W, Peng M, King B, Lindsten T, Li MO, Koumenis C, Thompson CB (2015) GCN2 sustains mTORC1 suppression upon AA deprivation by inducing Sestrin2. Genes Dev 29:2331–2336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Han Q, Liu Y, Sun C, Gang X, Wang G (2016) The relationship between branched-chain amino acid related metabolomic signature and insulin resistance: a systematic review. J Diabetes Res 16:2794591

    Google Scholar 

  • Zheng L, Zhang W, Zhou Y, Li F, Wei H, Peng J (2016) Recent advances in understanding AA sensing mechanisms that regulate mTORC1. Int J Mol Sci 17:E1636

    Article  CAS  PubMed  Google Scholar 

  • Zhenyukh O, Civantos E, Ruiz-Ortega M, Sánchez MS, Vázquez C, Peiró C, Egido J, Mas S (2017) High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. Free Radic Biol Med 104:165–177

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Danbolt NC (2014) Glutamate as a neurotransmitter in the healthy brain. J Neural Transm 121(8):799–817

    Article  CAS  PubMed  Google Scholar 

  • Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal AAs through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334:678–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work has been made possible by the collaboration with the nursing homes of Sadel Spa, Sadel San Teodoro srl, Sadel CS srl, Casa di Cura Madonna dello Scoglio, AGI srl, Casa di Cura Villa del Rosario srl, Savelli Hospital srl, Casa di Cura Villa Ermelinda, in the frame of the agreement “SOLUZIONI INNOVATIVE PER L’INNALZAMENTO DELLA SALUTE E DELLA SICUREZZA DELLA POPOLAZIONE” with the University of Calabria.

Funding

This study was supported by grants from the Italian Ministry of University and Research (PRIN: Progetti di Ricerca di rilevante Interesse Nazionale – 2015, Prot. 20157ATSLF) to GR.

Author information

Authors and Affiliations

  1. Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036, Rende, Italy

    Serena Dato, Eneida Hoxha, Paolina Crocco, Francesca Iannone, Giuseppe Passarino & Giuseppina Rose

Authors
  1. Serena Dato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eneida Hoxha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paolina Crocco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesca Iannone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giuseppe Passarino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giuseppina Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giuseppina Rose.

Ethics declarations

Conflict of interest

Dato, S., Hohxa, E., Crocco, P., Iannone, F., Passarino, G. and Rose, G., declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dato, S., Hoxha, E., Crocco, P. et al. Amino acids and amino acid sensing: implication for aging and diseases. Biogerontology 20, 17–31 (2019). https://doi.org/10.1007/s10522-018-9770-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-018-9770-8

Keywords

Search

Navigation