Skip to main content

Plausible Links Between Metabolic Networks, Stem Cells, and Longevity

  • Chapter
  • First Online:
Book cover Stem Cells

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1201))

Abstract

Aging is an inevitable consequence of life, and all multicellular organisms undergo a decline in tissue and organ functions as they age. Several well-known risk factors, such as obesity, diabetes, and lack of physical activity that lead to the cardiovascular system, decline and impede the function of vital organs, ultimately limit overall life span. Over recent years, aging research has experienced an unparalleled growth, particularly with the discovery and recognition of genetic pathways and biochemical processes that control to some extent the rate of aging.

In this chapter, we focus on several aspects of stem cell biology and aging, beginning with major cellular hallmarks of aging, endocrine regulation of aging and its impact on stem cell compartment, and mechanisms of increased longevity. We then discuss the role of epigenetic modifications associated with aging and provide an overview on a most recent search of antiaging modalities.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621

    Article  CAS  PubMed  Google Scholar 

  2. Hayflick L (1976) The cell biology of human aging. N Engl J Med 295:1302–1308. https://doi.org/10.1056/NEJM197612022952308

    Article  CAS  PubMed  Google Scholar 

  3. Hayflick L (1980) The cell biology of human aging. Sci Am 242:58–65

    Article  CAS  PubMed  Google Scholar 

  4. Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233. https://doi.org/10.1016/j.cell.2007.07.003

    Article  CAS  PubMed  Google Scholar 

  5. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460. https://doi.org/10.1038/345458a0

    Article  CAS  PubMed  Google Scholar 

  6. Blasco MA (2005) Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6:611–622. https://doi.org/10.1038/nrg1656

    Article  CAS  PubMed  Google Scholar 

  7. de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110. https://doi.org/10.1101/gad.1346005

    Article  CAS  PubMed  Google Scholar 

  8. von Zglinicki T, Martin-Ruiz CM (2005) Telomeres as biomarkers for ageing and age-related diseases. Curr Mol Med 5:197–203

    Article  Google Scholar 

  9. Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301–334. https://doi.org/10.1146/annurev.genet.41.110306.130350

    Article  CAS  PubMed  Google Scholar 

  10. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Armanios M et al (2009) Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 85:823–832. https://doi.org/10.1016/j.ajhg.2009.10.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361:1475–1485. https://doi.org/10.1056/NEJMra0804615

    Article  CAS  PubMed  Google Scholar 

  13. Ratajczak MZ, Bartke A, Darzynkiewicz Z (2017) Prolonged growth hormone/insulin/insulin-like growth factor nutrient response signaling pathway as a silent killer of stem cells and a culprit in aging. Stem Cell Rev 13:443–453. https://doi.org/10.1007/s12015-017-9728-2

    Article  CAS  PubMed Central  Google Scholar 

  14. Darzynkiewicz Z, Balazs EA (2012) Genome integrity, stem cells and hyaluronan. Aging (Albany NY) 4:78–88. https://doi.org/10.18632/aging.100438

    Article  CAS  Google Scholar 

  15. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991. https://doi.org/10.1146/annurev.biochem.052308.114844

    Article  CAS  PubMed  Google Scholar 

  16. Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10:205–215. https://doi.org/10.1016/j.arr.2010.02.001

    Article  CAS  PubMed  Google Scholar 

  17. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075. https://doi.org/10.1038/nature06639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332. https://doi.org/10.1038/nature10317

    Article  CAS  PubMed  Google Scholar 

  19. Morrow G, Samson M, Michaud S, Tanguay RM (2004) Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J 18:598–599. https://doi.org/10.1096/fj.03-0860fje

    Article  CAS  PubMed  Google Scholar 

  20. Walker GA, Lithgow GJ (2003) Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2:131–139. https://doi.org/10.1046/j.1474-9728.2003.00045.x

    Article  CAS  PubMed  Google Scholar 

  21. Min JN et al (2008) CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 28:4018–4025. https://doi.org/10.1128/MCB.00296-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Swindell WR et al (2009) Endocrine regulation of heat shock protein mRNA levels in long-lived dwarf mice. Mech Ageing Dev 130:393–400. https://doi.org/10.1016/j.mad.2009.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schultz MB, Sinclair DA (2016) When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development 143:3–14. https://doi.org/10.1242/dev.130633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Smith JA, Daniel R (2012) Stem cells and aging: a chicken-or-the-egg issue? Aging Dis 3:260–268

    PubMed  PubMed Central  Google Scholar 

  25. Liu L, Rando TA (2011) Manifestations and mechanisms of stem cell aging. J Cell Biol 193:257–266. https://doi.org/10.1083/jcb.201010131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133–139. https://doi.org/10.1038/ni1033

    Article  CAS  PubMed  Google Scholar 

  27. Beghe C, Wilson A, Ershler WB (2004) Prevalence and outcomes of anemia in geriatrics: a systematic review of the literature. Am J Med 116(Suppl 7A):3S–10S. https://doi.org/10.1016/j.amjmed.2003.12.009

    Article  PubMed  Google Scholar 

  28. Lichtman MA, Rowe JM (2004) The relationship of patient age to the pathobiology of the clonal myeloid diseases. Semin Oncol 31:185–197

    Article  PubMed  Google Scholar 

  29. Rossi DJ, Jamieson CH, Weissman IL (2008) Stems cells and the pathways to aging and cancer. Cell 132:681–696. https://doi.org/10.1016/j.cell.2008.01.036

    Article  CAS  PubMed  Google Scholar 

  30. Metcalf D, Moore AS (1971) Embryonic aspects of haemopoiesis. In: Neuberger A, Tatum EL (eds) Frontiers of biology, vol. 24: hematopoietic cells, pp 172–271. North Holland Publishers, Amsterdam

    Google Scholar 

  31. Broxmeyer HE et al (1989) Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A 86:3828–3832. https://doi.org/10.1073/pnas.86.10.3828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lansdorp PM, Dragowska W, Mayani H (1993) Ontogeny-related changes in proliferative potential of human hematopoietic cells. J Exp Med 178:787–791. https://doi.org/10.1084/jem.178.3.787

    Article  CAS  PubMed  Google Scholar 

  33. Kollman C et al (2001) Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98:2043–2051. https://doi.org/10.1182/blood.v98.7.2043

    Article  CAS  PubMed  Google Scholar 

  34. Sudo K, Ema H, Morita Y, Nakauchi H (2000) Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192:1273–1280. https://doi.org/10.1084/jem.192.9.1273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rossi DJ et al (2005) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102:9194–9199. https://doi.org/10.1073/pnas.0503280102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cho RH, Sieburg HB, Muller-Sieburg CE (2008) A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood 111:5553–5561. https://doi.org/10.1182/blood-2007-11-123547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Challen GA, Boles NC, Chambers SM, Goodell MA (2010) Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell 6:265–278. https://doi.org/10.1016/j.stem.2010.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Beerman I et al (2010) Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 107:5465–5470. https://doi.org/10.1073/pnas.1000834107

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kim M, Moon HB, Spangrude GJ (2003) Major age-related changes of mouse hematopoietic stem/progenitor cells. Ann N Y Acad Sci 996:195–208. https://doi.org/10.1111/j.1749-6632.2003.tb03247.x

    Article  PubMed  Google Scholar 

  40. Liang Y, Van Zant G, Szilvassy SJ (2005) Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106:1479–1487. https://doi.org/10.1182/blood-2004-11-4282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Signer RA, Montecino-Rodriguez E, Witte ON, McLaughlin J, Dorshkind K (2007) Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia. Blood 110:1831–1839. https://doi.org/10.1182/blood-2007-01-069401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Eriksson PS et al (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317. https://doi.org/10.1038/3305

    Article  CAS  PubMed  Google Scholar 

  43. Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult Hippocampus. Cold Spring Harb Perspect Biol 7:a018812. https://doi.org/10.1101/cshperspect.a018812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Palmer TD, Takahashi J, Gage FH (1997) The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8:389–404. https://doi.org/10.1006/mcne.1996.0595

    Article  CAS  PubMed  Google Scholar 

  45. Andersen B et al (1995) The Ames dwarf gene is required for Pit-1 gene activation. Dev Biol 172:495–503

    Article  CAS  PubMed  Google Scholar 

  46. Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027–2033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Maslov AY, Barone TA, Plunkett RJ, Pruitt SC (2004) Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J Neurosci 24:1726–1733. https://doi.org/10.1523/JNEUROSCI.4608-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Seki T, Arai Y (1995) Age-related production of new granule cells in the adult dentate gyrus. Neuroreport 6:2479–2482

    Article  CAS  PubMed  Google Scholar 

  49. Tropepe V, Craig CG, Morshead CM, van der Kooy D (1997) Transforming growth factor-alpha null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J Neurosci 17:7850–7859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bondolfi L, Ermini F, Long JM, Ingram DK, Jucker M (2004) Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice. Neurobiol Aging 25:333–340. https://doi.org/10.1016/S0197-4580(03)00083-6

    Article  CAS  PubMed  Google Scholar 

  51. Renault VM et al (2009) FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5:527–539. https://doi.org/10.1016/j.stem.2009.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bailey KJ, Maslov AY, Pruitt SC (2004) Accumulation of mutations and somatic selection in aging neural stem/progenitor cells. Aging Cell 3:391–397. https://doi.org/10.1111/j.1474-9728.2004.00128.x

    Article  CAS  PubMed  Google Scholar 

  53. Molofsky AV et al (2006) Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443:448–452. https://doi.org/10.1038/nature05091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nishino J, Kim I, Chada K, Morrison SJ (2008) Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell 135:227–239. https://doi.org/10.1016/j.cell.2008.09.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Murphy CT et al (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424:277–283. https://doi.org/10.1038/nature01789

    Article  CAS  PubMed  Google Scholar 

  56. Lee S, Dong HH (2017) FoxO integration of insulin signaling with glucose and lipid metabolism. J Endocrinol 233:R67–R79. https://doi.org/10.1530/JOE-17-0002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Paik JH et al (2009) FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5:540–553. https://doi.org/10.1016/j.stem.2009.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Santo EE, Paik J (2018) FOXO in neural cells and diseases of the nervous system. Curr Top Dev Biol 127:105–118. https://doi.org/10.1016/bs.ctdb.2017.10.002

    Article  PubMed  PubMed Central  Google Scholar 

  59. Willcox BJ et al (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A 105:13987–13992. https://doi.org/10.1073/pnas.0801030105

    Article  PubMed  PubMed Central  Google Scholar 

  60. Donlon TA, Davy PMC, Willcox BJ (1890) Analysis of FOXO3 gene polymorphisms associated with human longevity. Methods Mol Biol:251–257. https://doi.org/10.1007/978-1-4939-8900-3_21

    Google Scholar 

  61. Flachsbart F et al (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A 106:2700–2705. https://doi.org/10.1073/pnas.0809594106

    Article  PubMed  PubMed Central  Google Scholar 

  62. van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241–260. https://doi.org/10.1146/annurev.physiol.010908.163145

    Article  CAS  PubMed  Google Scholar 

  63. Heath JP (1996) Epithelial cell migration in the intestine. Cell Biol Int 20:139–146. https://doi.org/10.1006/cbir.1996.0018

    Article  CAS  PubMed  Google Scholar 

  64. Booth C, Potten CS (2000) Gut instincts: thoughts on intestinal epithelial stem cells. J Clin Invest 105:1493–1499. https://doi.org/10.1172/JCI10229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Marshman E, Booth C, Potten CS (2002) The intestinal epithelial stem cell. BioEssays 24:91–98. https://doi.org/10.1002/bies.10028

    Article  PubMed  Google Scholar 

  66. Bjerknes M, Cheng H (2006) Intestinal epithelial stem cells and progenitors. Methods Enzymol 419:337–383. https://doi.org/10.1016/S0076-6879(06)19014-X

    Article  CAS  PubMed  Google Scholar 

  67. Barker N et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007. https://doi.org/10.1038/nature06196

    Article  CAS  PubMed  Google Scholar 

  68. van der Flier LG et al (2009) Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136:903–912. https://doi.org/10.1016/j.cell.2009.01.031

    Article  CAS  PubMed  Google Scholar 

  69. Martin K, Kirkwood TB, Potten CS (1998) Age changes in stem cells of murine small intestinal crypts. Exp Cell Res 241:316–323. https://doi.org/10.1006/excr.1998.4001

    Article  CAS  PubMed  Google Scholar 

  70. Martin K, Potten CS, Roberts SA, Kirkwood TB (1998) Altered stem cell regeneration in irradiated intestinal crypts of senescent mice. J Cell Sci 111(Pt 16):2297–2303

    CAS  PubMed  Google Scholar 

  71. Yatabe Y, Tavare S, Shibata D (2001) Investigating stem cells in human colon by using methylation patterns. Proc Natl Acad Sci U S A 98:10839–10844. https://doi.org/10.1073/pnas.191225998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim JY, Siegmund KD, Tavare S, Shibata D (2005) Age-related human small intestine methylation: evidence for stem cell niches. BMC Med 3:10. https://doi.org/10.1186/1741-7015-3-10

    Article  PubMed  PubMed Central  Google Scholar 

  73. Tian D, Mitchell I, Kreeger PK (2016) Quantitative analysis of insulin-like growth factor 2 receptor and insulin-like growth factor binding proteins to identify control mechanisms for insulin-like growth factor 1 receptor phosphorylation. BMC Syst Biol 10:15. https://doi.org/10.1186/s12918-016-0263-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yakar S, Adamo ML (2012) Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinol Metab Clin North Am 41:231–247, v. https://doi.org/10.1016/j.ecl.2012.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Adamo ML, Neuenschwander S, LeRoith D, Roberts CT Jr (1993) Structure, expression, and regulation of the IGF-I gene. Adv Exp Med Biol 343:1–11. https://doi.org/10.1007/978-1-4615-2988-0_1

    Article  CAS  PubMed  Google Scholar 

  76. Frystyk J, Skjaerbaek C, Dinesen B, Orskov H (1994) Free insulin-like growth factors (IGF-I and IGF-II) in human serum. FEBS Lett 348:185–191. https://doi.org/10.1016/0014-5793(94)00602-4

    Article  CAS  PubMed  Google Scholar 

  77. Delaval K, Feil R (2004) Epigenetic regulation of mammalian genomic imprinting. Curr Opin Genet Dev 14:188–195. https://doi.org/10.1016/j.gde.2004.01.005

    Article  CAS  PubMed  Google Scholar 

  78. Reik W, Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21–32. https://doi.org/10.1038/35047554

    Article  CAS  PubMed  Google Scholar 

  79. Werner H, Weinstein D, Bentov I (2008) Similarities and differences between insulin and IGF-I: structures, receptors, and signalling pathways. Arch Physiol Biochem 114:17–22. https://doi.org/10.1080/13813450801900694

    Article  CAS  PubMed  Google Scholar 

  80. Kornfeld S (1992) Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. Annu Rev Biochem 61:307–330. https://doi.org/10.1146/annurev.bi.61.070192.001515

    Article  CAS  PubMed  Google Scholar 

  81. Oka Y, Rozek LM, Czech MP (1985) Direct demonstration of rapid insulin-like growth factor II receptor internalization and recycling in rat adipocytes. Insulin stimulates 125I-insulin-like growth factor II degradation by modulating the IGF-II receptor recycling process. J Biol Chem 260:9435–9442

    CAS  PubMed  Google Scholar 

  82. Baxter RC (2014) IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer 14:329–341. https://doi.org/10.1038/nrc3720

    Article  CAS  PubMed  Google Scholar 

  83. Baxter RC (2000) Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab 278:E967–E976. https://doi.org/10.1152/ajpendo.2000.278.6.E967

    Article  CAS  PubMed  Google Scholar 

  84. Mohan S, Baylink DJ (2002) IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol 175:19–31

    Article  CAS  PubMed  Google Scholar 

  85. Wakai K et al (2009) Time spent walking or exercising and blood levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3): a large-scale cross-sectional study in the Japan Collaborative Cohort study. Asian Pac J Cancer Prev 10(Suppl):23–27

    PubMed  Google Scholar 

  86. Forbes K, Westwood M (2008) The IGF axis and placental function. A mini review. Horm Res 69:129–137. https://doi.org/10.1159/000112585

    Article  CAS  PubMed  Google Scholar 

  87. Frystyk J (2005) Aging somatotropic axis: mechanisms and implications of insulin-like growth factor-related binding protein adaptation. Endocrinol Metab Clin North Am 34:865–876, viii. https://doi.org/10.1016/j.ecl.2005.07.001

    Article  CAS  PubMed  Google Scholar 

  88. Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ (2013) The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol 9:366–376. https://doi.org/10.1038/nrendo.2013.67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Moller N, Jorgensen JO (2009) Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev 30:152–177. https://doi.org/10.1210/er.2008-0027

    Article  CAS  PubMed  Google Scholar 

  90. Zadik Z, Chalew SA, McCarter RJ Jr, Meistas M, Kowarski AA (1985) The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab 60:513–516. https://doi.org/10.1210/jcem-60-3-513

    Article  CAS  PubMed  Google Scholar 

  91. Bartke A (2008) Growth hormone and aging: a challenging controversy. Clin Interv Aging 3:659–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Snell GD (1929) Dwarf, a new mendelian recessive character of the house mouse. Proc Natl Acad Sci U S A 15:733–734. https://doi.org/10.1073/pnas.15.9.733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Eicher EM, Beamer WG (1980) New mouse dw allele: genetic location and effects on lifespan and growth hormone levels. J Hered 71:187–190. https://doi.org/10.1093/oxfordjournals.jhered.a109344

    Article  CAS  PubMed  Google Scholar 

  94. Li S et al (1990) Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 347:528–533. https://doi.org/10.1038/347528a0

    Article  CAS  PubMed  Google Scholar 

  95. Flurkey K, Papaconstantinou J, Harrison DE (2002) The Snell dwarf mutation Pit1(dw) can increase life span in mice. Mech Ageing Dev 123:121–130

    Article  CAS  PubMed  Google Scholar 

  96. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A 98:6736–6741. https://doi.org/10.1073/pnas.111158898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Fang Q et al (2016) Genetics of combined pituitary hormone deficiency: roadmap into the genome era. Endocr Rev 37:636–675. https://doi.org/10.1210/er.2016-1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Turton JP et al (2005) Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab 90:4762–4770. https://doi.org/10.1210/jc.2005-0570

    Article  CAS  PubMed  Google Scholar 

  99. Brooks NL et al (2007) Low utilization of circulating glucose after food withdrawal in Snell dwarf mice. J Biol Chem 282:35069–35077. https://doi.org/10.1074/jbc.M700484200

    Article  CAS  PubMed  Google Scholar 

  100. Koks S et al (2016) Mouse models of ageing and their relevance to disease. Mech Ageing Dev 160:41–53. https://doi.org/10.1016/j.mad.2016.10.001

    Article  CAS  PubMed  Google Scholar 

  101. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33. https://doi.org/10.1038/384033a0

    Article  CAS  PubMed  Google Scholar 

  102. Bartke A, Sun LY, Longo V (2013) Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev 93:571–598. https://doi.org/10.1152/physrev.00006.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bartke A et al (2001) Extending the lifespan of long-lived mice. Nature 414:412. https://doi.org/10.1038/35106646

    Article  CAS  PubMed  Google Scholar 

  104. Sornson MW et al (1996) Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 384:327–333. https://doi.org/10.1038/384327a0

    Article  CAS  PubMed  Google Scholar 

  105. Bartke A, Brown-Borg H (2004) Life extension in the dwarf mouse. Curr Top Dev Biol 63:189–225. https://doi.org/10.1016/S0070-2153(04)63006-7

    Article  CAS  PubMed  Google Scholar 

  106. Fluck C et al (1998) Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C). J Clin Endocrinol Metab 83:3727–3734. https://doi.org/10.1210/jcem.83.10.5172

    Article  CAS  PubMed  Google Scholar 

  107. Cohen LE, Radovick S, Wondisford FE (1999) Transcription factors and hypopituitarism. Trends Endocrinol Metab 10:326–332

    Article  CAS  PubMed  Google Scholar 

  108. Bartke A (2011) Single-gene mutations and healthy ageing in mammals. Philos Trans R Soc Lond Ser B Biol Sci 366:28–34. https://doi.org/10.1098/rstb.2010.0281

    Article  CAS  Google Scholar 

  109. Brown-Borg HM (2011) Handbook of the biology of aging, 7th edn. pp 25–46. Academic press, Cambridge, Massachusetts, USA

    Chapter  Google Scholar 

  110. Eicher EM, Beamer WG (1976) Inherited ateliotic dwarfism in mice. Characteristics of the mutation, little, on chromosome 6. J Hered 67:87–91. https://doi.org/10.1093/oxfordjournals.jhered.a108682

    Article  CAS  PubMed  Google Scholar 

  111. Godfrey P et al (1993) GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet 4:227–232. https://doi.org/10.1038/ng0793-227

    Article  CAS  PubMed  Google Scholar 

  112. Donahue LR, Beamer WG (1993) Growth hormone deficiency in ‘little’ mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factor-binding protein-3 (IGFBP-3), but does not affect IGFBP-2, −1 or −4. J Endocrinol 136:91–104. https://doi.org/10.1677/joe.0.1360091

    Article  CAS  PubMed  Google Scholar 

  113. Zhou Y et al (1997) A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A 94:13215–13220. https://doi.org/10.1073/pnas.94.24.13215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Laron Z, Kopchick J (eds) (2011) Laron syndrome – from man to mouse. Springer Academic press, Cambridge, Massachusetts, USA

    Google Scholar 

  115. List EO et al (2011) Endocrine parameters and phenotypes of the growth hormone receptor gene disrupted (GHR−/−) mouse. Endocr Rev 32:356–386. https://doi.org/10.1210/er.2010-0009

    Article  CAS  PubMed  Google Scholar 

  116. Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141:2608–2613. https://doi.org/10.1210/endo.141.7.7586

    Article  CAS  PubMed  Google Scholar 

  117. Coschigano KT et al (2003) Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144:3799–3810. https://doi.org/10.1210/en.2003-0374

    Article  CAS  PubMed  Google Scholar 

  118. Fundation. M (2013) Latest Mprize winner (online), http://www.mprize.org/?pn=mj mprize record

  119. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD (2001) Regulation of longevity and stress resistance by Sch9 in yeast. Science 292:288–290. https://doi.org/10.1126/science.1059497

    Article  CAS  PubMed  Google Scholar 

  120. Fabrizio P et al (2003) SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163:35–46

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Fontana L, Partridge L, Longo VD (2010) Extending healthy life span – from yeast to humans. Science 328:321–326. https://doi.org/10.1126/science.1172539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. De Benedictis G et al (2000) Does a retrograde response in human aging and longevity exist? Exp Gerontol 35:795–801

    Article  PubMed  Google Scholar 

  123. Itier JM et al (1998) Imprinted gene in postnatal growth role. Nature 393:125–126. https://doi.org/10.1038/30120

    Article  CAS  PubMed  Google Scholar 

  124. Borras C et al (2011) RasGrf1 deficiency delays aging in mice. Aging (Albany NY) 3:262–276. https://doi.org/10.18632/aging.100279

    Article  CAS  Google Scholar 

  125. Kapahi P et al (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14:885–890. https://doi.org/10.1016/j.cub.2004.03.059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Heintz C et al (2017) Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541:102–106. https://doi.org/10.1038/nature20789

    Article  CAS  PubMed  Google Scholar 

  127. Calvert S et al (2016) A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans. Aging Cell 15:256–266. https://doi.org/10.1111/acel.12432

    Article  CAS  PubMed  Google Scholar 

  128. Robida-Stubbs S et al (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15:713–724. https://doi.org/10.1016/j.cmet.2012.04.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lapierre LR, Hansen M (2012) Lessons from C. elegans: signaling pathways for longevity. Trends Endocrinol Metab 23:637–644. https://doi.org/10.1016/j.tem.2012.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Erdogan CS, Hansen BW, Vang O (2016) Are invertebrates relevant models in ageing research? Focus on the effects of rapamycin on TOR. Mech Ageing Dev 153:22–29. https://doi.org/10.1016/j.mad.2015.12.004

    Article  CAS  PubMed  Google Scholar 

  131. Sun X et al (2012) Nutrient-dependent requirement for SOD1 in lifespan extension by protein restriction in Drosophila melanogaster. Aging Cell 11:783–793. https://doi.org/10.1111/j.1474-9726.2012.00842.x

    Article  CAS  PubMed  Google Scholar 

  132. Selman C et al (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326:140–144. https://doi.org/10.1126/science.1177221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Fang Y et al (2018) Effects of rapamycin on growth hormone receptor knockout mice. Proc Natl Acad Sci U S A 115:E1495–E1503. https://doi.org/10.1073/pnas.1717065115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Martinez-Cisuelo V et al (2016) Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice. Exp Gerontol 83:130–138. https://doi.org/10.1016/j.exger.2016.08.002

    Article  CAS  PubMed  Google Scholar 

  135. Ito TK et al (2017) Hepatic S6K1 partially regulates lifespan of mice with mitochondrial complex I deficiency. Front Genet 8:113. https://doi.org/10.3389/fgene.2017.00113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72

    CAS  PubMed  Google Scholar 

  137. Holzenberger M et al (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187. https://doi.org/10.1038/nature01298

    Article  CAS  PubMed  Google Scholar 

  138. Bokov AF et al (2011) Does reduced IGF-1R signaling in Igf1r+/− mice alter aging? PLoS One 6:e26891. https://doi.org/10.1371/journal.pone.0026891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kappeler L et al (2008) Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 6:e254. https://doi.org/10.1371/journal.pbio.0060254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Swindell WR, Masternak MM, Bartke A (2010) In vivo analysis of gene expression in long-lived mice lacking the pregnancy-associated plasma protein A (PappA) gene. Exp Gerontol 45:366–374. https://doi.org/10.1016/j.exger.2010.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Conover CA, Mason MA, Levine JA, Novak CM (2008) Metabolic consequences of pregnancy-associated plasma protein-A deficiency in mice: exploring possible relationship to the longevity phenotype. J Endocrinol 198:599–605. https://doi.org/10.1677/JOE-08-0179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Vallejo AN et al (2009) Resistance to age-dependent thymic atrophy in long-lived mice that are deficient in pregnancy-associated plasma protein A. Proc Natl Acad Sci U S A 106:11252–11257. https://doi.org/10.1073/pnas.0807025106

    Article  PubMed  PubMed Central  Google Scholar 

  143. Conover CA, Oxvig C (2017) PAPP-A: a promising therapeutic target for healthy longevity. Aging Cell 16:205–209. https://doi.org/10.1111/acel.12564

    Article  CAS  PubMed  Google Scholar 

  144. Lawrence JB et al (1999) The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A 96:3149–3153. https://doi.org/10.1073/pnas.96.6.3149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Conover CA et al (2004) Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development 131:1187–1194. https://doi.org/10.1242/dev.00997

    Article  CAS  PubMed  Google Scholar 

  146. Oxvig C (2015) The role of PAPP-A in the IGF system: location, location, location. J Cell Commun Signal 9:177–187. https://doi.org/10.1007/s12079-015-0259-9

    Article  PubMed  PubMed Central  Google Scholar 

  147. Hoeflich A, David R, Hjortebjerg R (2018) Current IGFBP-related biomarker research in cardiovascular disease-we need more structural and functional information in clinical studies. Front Endocrinol (Lausanne) 9:388. https://doi.org/10.3389/fendo.2018.00388

    Article  Google Scholar 

  148. Conover CA et al (2010) Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A. J Gerontol A Biol Sci Med Sci 65:590–599. https://doi.org/10.1093/gerona/glq032

    Article  CAS  PubMed  Google Scholar 

  149. Argente J, Chowen JA, Perez-Jurado LA, Frystyk J, Oxvig C (2017) One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology. EMBO Mol Med 9:1338–1345. https://doi.org/10.15252/emmm.201707950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. White MF, Maron R, Kahn CR (1985) Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature 318:183–186. https://doi.org/10.1038/318183a0

    Article  CAS  PubMed  Google Scholar 

  151. Sun XJ et al (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77. https://doi.org/10.1038/352073a0

    Article  CAS  PubMed  Google Scholar 

  152. Araki E et al (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372:186–190. https://doi.org/10.1038/372186a0

    Article  CAS  PubMed  Google Scholar 

  153. Sun XJ et al (1995) Role of IRS-2 in insulin and cytokine signalling. Nature 377:173–177. https://doi.org/10.1038/377173a0

    Article  CAS  PubMed  Google Scholar 

  154. Tamemoto H et al (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372:182–186. https://doi.org/10.1038/372182a0

    Article  CAS  PubMed  Google Scholar 

  155. Selman C, Partridge L, Withers DJ (2011) Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS One 6:e16144. https://doi.org/10.1371/journal.pone.0016144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Selman C et al (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22:807–818. https://doi.org/10.1096/fj.07-9261com

    Article  CAS  PubMed  Google Scholar 

  157. Previs SF, Withers DJ, Ren JM, White MF, Shulman GI (2000) Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem 275:38990–38994. https://doi.org/10.1074/jbc.M006490200

    Article  CAS  PubMed  Google Scholar 

  158. Withers DJ et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904. https://doi.org/10.1038/36116

    Article  CAS  PubMed  Google Scholar 

  159. Houtkooper RH, Williams RW, Auwerx J (2010) Metabolic networks of longevity. Cell 142:9–14. https://doi.org/10.1016/j.cell.2010.06.029

    Article  CAS  PubMed  Google Scholar 

  160. Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512. https://doi.org/10.1038/nature08980

    Article  CAS  PubMed  Google Scholar 

  161. Russell SJ, Kahn CR (2007) Endocrine regulation of ageing. Nat Rev Mol Cell Biol 8:681–691. https://doi.org/10.1038/nrm2234

    Article  CAS  PubMed  Google Scholar 

  162. Barzilai N, Huffman DM, Muzumdar RH, Bartke A (2012) The critical role of metabolic pathways in aging. Diabetes 61:1315–1322. https://doi.org/10.2337/db11-1300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Kenyon C (2010) A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Ann N Y Acad Sci 1204:156–162. https://doi.org/10.1111/j.1749-6632.2010.05640.x

    Article  CAS  PubMed  Google Scholar 

  164. Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals. Science 299:1346–1351. https://doi.org/10.1126/science.1081447

    Article  CAS  PubMed  Google Scholar 

  165. Hertweck M, Gobel C, Baumeister R (2004) C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell 6:577–588

    Article  CAS  PubMed  Google Scholar 

  166. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464. https://doi.org/10.1038/366461a0

    Article  CAS  PubMed  Google Scholar 

  167. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946. https://doi.org/10.1126/science.277.5328.942

    Article  CAS  PubMed  Google Scholar 

  168. Tatar M et al (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110. https://doi.org/10.1126/science.1057987

    Article  CAS  PubMed  Google Scholar 

  169. Pierce SB et al (2001) Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev 15:672–686. https://doi.org/10.1101/gad.867301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ratajczak MZ et al (2011) RasGrf1: genomic imprinting, VSELs, and aging. Aging (Albany NY) 3:692–697. https://doi.org/10.18632/aging.100354

    Article  CAS  Google Scholar 

  171. Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120:449–460. https://doi.org/10.1016/j.cell.2005.02.002

    Article  CAS  PubMed  Google Scholar 

  172. Lin K, Hsin H, Libina N, Kenyon C (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28:139–145. https://doi.org/10.1038/88850

    Article  CAS  PubMed  Google Scholar 

  173. Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429:562–566. https://doi.org/10.1038/nature02549

    Article  CAS  PubMed  Google Scholar 

  174. Johnson SC, Rabinovitch PS, Kaeberlein M (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493:338–345. https://doi.org/10.1038/nature11861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 169:361–371. https://doi.org/10.1016/j.cell.2017.03.035

    Article  CAS  PubMed  Google Scholar 

  176. Templeman NM, Murphy CT (2018) Regulation of reproduction and longevity by nutrient-sensing pathways. J Cell Biol 217:93–106. https://doi.org/10.1083/jcb.201707168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Vellai T et al (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426:620. https://doi.org/10.1038/426620a

    Article  CAS  PubMed  Google Scholar 

  178. Jia K, Chen D, Riddle DL (2004) The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131:3897–3906. https://doi.org/10.1242/dev.01255

    Article  CAS  PubMed  Google Scholar 

  179. Um SH et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205. https://doi.org/10.1038/nature02866

    Article  CAS  PubMed  Google Scholar 

  180. Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895–1908. https://doi.org/10.1101/gad.17420111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11:230–241. https://doi.org/10.1016/j.arr.2011.12.005

    Article  CAS  PubMed  Google Scholar 

  182. Hardie DG, Schaffer BE, Brunet A (2016) AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol 26:190–201. https://doi.org/10.1016/j.tcb.2015.10.013

    Article  CAS  PubMed  Google Scholar 

  183. Weir HJ et al (2017) Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab 26:884–896 e885. https://doi.org/10.1016/j.cmet.2017.09.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Cameron KO, Kurumbail RG (2016) Recent progress in the identification of adenosine monophosphate-activated protein kinase (AMPK) activators. Bioorg Med Chem Lett 26:5139–5148. https://doi.org/10.1016/j.bmcl.2016.09.065

    Article  CAS  PubMed  Google Scholar 

  185. Hardie DG (2013) AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes 62:2164–2172. https://doi.org/10.2337/db13-0368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Manio MC, Inoue K, Fujitani M, Matsumura S, Fushiki T (2016) Combined pharmacological activation of AMPK and PPARdelta potentiates the effects of exercise in trained mice. Physiol Rep 4. https://doi.org/10.14814/phy2.12625

    Article  PubMed  PubMed Central  Google Scholar 

  187. Martin-Montalvo A et al (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192. https://doi.org/10.1038/ncomms3192

    Article  CAS  PubMed  Google Scholar 

  188. Cabreiro F et al (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153:228–239. https://doi.org/10.1016/j.cell.2013.02.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS One 5:e8758. https://doi.org/10.1371/journal.pone.0008758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Derosa G, Maffioli P, Cicero AF (2012) Berberine on metabolic and cardiovascular risk factors: an analysis from preclinical evidences to clinical trials. Expert Opin Biol Ther 12:1113–1124. https://doi.org/10.1517/14712598.2012.704014

    Article  CAS  PubMed  Google Scholar 

  191. Harrison DE et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–395. https://doi.org/10.1038/nature08221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Blagosklonny MV (2013) Rapamycin extends life- and health span because it slows aging. Aging (Albany NY) 5:592–598. https://doi.org/10.18632/aging.100591

    Article  CAS  Google Scholar 

  193. Bridges HR, Sirvio VA, Agip AN, Hirst J (2016) Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase. BMC Biol 14:65. https://doi.org/10.1186/s12915-016-0287-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Houtkooper RH, Pirinen E, Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13:225–238. https://doi.org/10.1038/nrm3293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Haigis MC, Sinclair DA (2010) Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5:253–295. https://doi.org/10.1146/annurev.pathol.4.110807.092250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Zhong L, Mostoslavsky R (2011) Fine tuning our cellular factories: sirtuins in mitochondrial biology. Cell Metab 13:621–626. https://doi.org/10.1016/j.cmet.2011.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Verdin E, Hirschey MD, Finley LW, Haigis MC (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35:669–675. https://doi.org/10.1016/j.tibs.2010.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Canto C, Auwerx J (2012) Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol Rev 64:166–187. https://doi.org/10.1124/pr.110.003905

    Article  CAS  PubMed  Google Scholar 

  199. Feige JN, Auwerx J (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20:303–309. https://doi.org/10.1016/j.ceb.2008.03.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Jing E, Gesta S, Kahn CR (2007) SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab 6:105–114. https://doi.org/10.1016/j.cmet.2007.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11:437–444

    Article  CAS  PubMed  Google Scholar 

  202. Beirowski B et al (2011) Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling. Proc Natl Acad Sci U S A 108:E952–E961. https://doi.org/10.1073/pnas.1104969108

    Article  PubMed  PubMed Central  Google Scholar 

  203. Someya S et al (2010) Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143:802–812. https://doi.org/10.1016/j.cell.2010.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 12:662–667. https://doi.org/10.1016/j.cmet.2010.11.015

    Article  CAS  PubMed  Google Scholar 

  205. Jing E et al (2011) Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci U S A 108:14608–14613. https://doi.org/10.1073/pnas.1111308108

    Article  PubMed  PubMed Central  Google Scholar 

  206. Haigis MC et al (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126:941–954. https://doi.org/10.1016/j.cell.2006.06.057

    Article  CAS  PubMed  Google Scholar 

  207. Nasrin N et al (2010) SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 285:31995–32002. https://doi.org/10.1074/jbc.M110.124164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Nakagawa T, Lomb DJ, Haigis MC, Guarente L (2009) SIRT5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137:560–570. https://doi.org/10.1016/j.cell.2009.02.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Mostoslavsky R et al (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124:315–329. https://doi.org/10.1016/j.cell.2005.11.044

    Article  CAS  PubMed  Google Scholar 

  210. Ford E et al (2006) Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev 20:1075–1080. https://doi.org/10.1101/gad.1399706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Kane AE, Sinclair DA (2018) Sirtuins and NAD(+) in the development and treatment of metabolic and cardiovascular diseases. Circ Res 123:868–885. https://doi.org/10.1161/CIRCRESAHA.118.312498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Schemies J, Uciechowska U, Sippl W, Jung M (2010) NAD(+) -dependent histone deacetylases (sirtuins) as novel therapeutic targets. Med Res Rev 30:861–889. https://doi.org/10.1002/med.20178

    Article  CAS  PubMed  Google Scholar 

  213. Bitterman KJ, Medvedik O, Sinclair DA (2003) Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin. Microbiol Mol Biol Rev 67:376–399, table of contents. https://doi.org/10.1128/mmbr.67.3.376-399.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO (2010) SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci 123:4251–4258. https://doi.org/10.1242/jcs.073783

    Article  CAS  PubMed  Google Scholar 

  215. Huang H, Tindall DJ (2007) Dynamic FoxO transcription factors. J Cell Sci 120:2479–2487. https://doi.org/10.1242/jcs.001222

    Article  CAS  PubMed  Google Scholar 

  216. Bordone L et al (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4:e31. https://doi.org/10.1371/journal.pbio.0040031

    Article  CAS  PubMed  Google Scholar 

  217. Hou X et al (2008) SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 283:20015–20026. https://doi.org/10.1074/jbc.M802187200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Sanokawa-Akakura R, Akakura S, Tabibzadeh S (2016) Replicative senescence in human fibroblasts is delayed by hydrogen sulfide in a NAMPT/SIRT1 dependent manner. PLoS One 11:e0164710. https://doi.org/10.1371/journal.pone.0164710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Romeo-Guitart D et al (2018) SIRT1 activation with neuroheal is neuroprotective but SIRT2 inhibition with AK7 is detrimental for disconnected motoneurons. Cell Death Dis 9:531. https://doi.org/10.1038/s41419-018-0553-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Watanabe H et al (2018) Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein. Nat Commun 9:30. https://doi.org/10.1038/s41467-017-02537-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13:2570–2580. https://doi.org/10.1101/gad.13.19.2570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Berdichevsky A, Viswanathan M, Horvitz HR, Guarente LC (2006) Elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125:1165–1177. https://doi.org/10.1016/j.cell.2006.04.036

    Article  CAS  PubMed  Google Scholar 

  223. Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A 101:15998–16003. https://doi.org/10.1073/pnas.0404184101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Rascon B, Hubbard BP, Sinclair DA, Amdam GV (2012) The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging (Albany NY) 4:499–508. https://doi.org/10.18632/aging.100474

    Article  CAS  Google Scholar 

  225. Wang C et al (2013) The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster. Age (Dordr) 35:69–81. https://doi.org/10.1007/s11357-011-9332-3

    Article  CAS  Google Scholar 

  226. Gehm BD, McAndrews JM, Chien PY, Jameson JL (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A 94:14138–14143. https://doi.org/10.1073/pnas.94.25.14138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Chung JH, Manganiello V, Dyck JR (2012) Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 22:546–554. https://doi.org/10.1016/j.tcb.2012.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Baur JA et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342. https://doi.org/10.1038/nature05354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Minor RK et al (2011) SRT1720 improves survival and healthspan of obese mice. Sci Rep 1:70. https://doi.org/10.1038/srep00070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Mitchell SJ et al (2014) The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep 6:836–843. https://doi.org/10.1016/j.celrep.2014.01.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Singh SK et al (2013) Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance. J Exp Med 210:987–1001. https://doi.org/10.1084/jem.20121608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Kucia M et al (2006) A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia 20:857–869. https://doi.org/10.1038/sj.leu.2404171

    Article  CAS  PubMed  Google Scholar 

  233. Kucia M et al (2007) Morphological and molecular characterization of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood: preliminary report. Leukemia 21:297–303. https://doi.org/10.1038/sj.leu.2404470

    Article  CAS  PubMed  Google Scholar 

  234. Ratajczak MZ et al (2010) Epiblast/germ line hypothesis of cancer development revisited: lesson from the presence of Oct-4+ cells in adult tissues. Stem Cell Rev 6:307–316. https://doi.org/10.1007/s12015-010-9143-4

    Article  PubMed Central  Google Scholar 

  235. Shin DM et al (2010) Molecular signature of adult bone marrow-purified very small embryonic-like stem cells supports their developmental epiblast/germ line origin. Leukemia 24:1450–1461. https://doi.org/10.1038/leu.2010.121

    Article  CAS  PubMed  Google Scholar 

  236. Shin DM et al (2010) Molecular characterization of isolated from murine adult tissues very small embryonic/epiblast like stem cells (VSELs). Mol Cells 29:533–538. https://doi.org/10.1007/s10059-010-0081-4

    Article  CAS  PubMed  Google Scholar 

  237. Shin DM et al (2012) Global gene expression analysis of very small embryonic-like stem cells reveals that the Ezh2-dependent bivalent domain mechanism contributes to their pluripotent state. Stem Cells Dev 21:1639–1652. https://doi.org/10.1089/scd.2011.0389

    Article  CAS  PubMed  Google Scholar 

  238. Shin DM et al (2009) Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4(+) very small embryonic-like stem cells. Leukemia 23:2042–2051. https://doi.org/10.1038/leu.2009.153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Ratajczak MZ, Shin DM, Schneider G, Ratajczak J, Kucia M (2013) Parental imprinting regulates insulin-like growth factor signaling: a Rosetta stone for understanding the biology of pluripotent stem cells, aging and cancerogenesis. Leukemia 27:773–779. https://doi.org/10.1038/leu.2012.322

    Article  CAS  PubMed  Google Scholar 

  240. Yamazaki Y et al (2003) Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proc Natl Acad Sci U S A 100:12207–12212. https://doi.org/10.1073/pnas.2035119100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Horii T, Kimura M, Morita S, Nagao Y, Hatada I (2008) Loss of genomic imprinting in mouse parthenogenetic embryonic stem cells. Stem Cells 26:79–88. https://doi.org/10.1634/stemcells.2006-0635

    Article  CAS  PubMed  Google Scholar 

  242. Pannetier M, Feil R (2007) Epigenetic stability of embryonic stem cells and developmental potential. Trends Biotechnol 25:556–562. https://doi.org/10.1016/j.tibtech.2007.09.003

    Article  CAS  PubMed  Google Scholar 

  243. Hajkova P et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23

    Article  CAS  PubMed  Google Scholar 

  244. Shovlin TC, Durcova-Hills G, Surani A, McLaren A (2008) Heterogeneity in imprinted methylation patterns of pluripotent embryonic germ cells derived from pre-migratory mouse germ cells. Dev Biol 313:674–681. https://doi.org/10.1016/j.ydbio.2007.11.007

    Article  CAS  PubMed  Google Scholar 

  245. Lopes S et al (2003) Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions. Hum Mol Genet 12:295–305. https://doi.org/10.1093/hmg/ddg022

    Article  CAS  PubMed  Google Scholar 

  246. Kobayashi H et al (2006) Bisulfite sequencing and dinucleotide content analysis of 15 imprinted mouse differentially methylated regions (DMRs): paternally methylated DMRs contain less CpGs than maternally methylated DMRs. Cytogenet Genome Res 113:130–137. https://doi.org/10.1159/000090824

    Article  CAS  PubMed  Google Scholar 

  247. Mierzejewska K et al (2013) Genome-wide analysis of murine bone marrowderived very small embryonic-like stem cells reveals that mitogenic growth factor signaling pathways play a crucial role in the quiescence and ageing of these cells. Int J Mol Med 32:281–290. https://doi.org/10.3892/ijmm.2013.1389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Maj M et al (2015) The cell cycle- and insulin-signaling-inhibiting miRNA expression pattern of very small embryonic-like stem cells contributes to their quiescent state. Exp Biol Med (Maywood) 240:1107–1111. https://doi.org/10.1177/1535370215584940

    Article  CAS  Google Scholar 

  249. Keniry A et al (2012) The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat Cell Biol 14:659–665. https://doi.org/10.1038/ncb2521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Tarnowski M et al (2015) 5Azacytidine inhibits human rhabdomyosarcoma cell growth by downregulating insulinlike growth factor 2 expression and reactivating the H19 gene product miR675, which negatively affects insulinlike growth factors and insulin signaling. Int J Oncol 46:2241–2250. https://doi.org/10.3892/ijo.2015.2906

    Article  CAS  PubMed  Google Scholar 

  251. Ge Y, Sun Y, Chen J (2011) IGF-II is regulated by microRNA-125b in skeletal myogenesis. J Cell Biol 192:69–81. https://doi.org/10.1083/jcb.201007165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Ma N, Zhou L, Zhang Y, Jiang Y, Gao X (2014) Intragenic microRNA and long non-coding RNA: novel potential regulator of IGF2-H19 imprinting region. Evol Dev 16:1–2. https://doi.org/10.1111/ede.12057

    Article  CAS  PubMed  Google Scholar 

  253. Ratajczak MZ et al (2012) Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation--an update and comparison to other primitive small stem cells isolated from adult tissues. Aging (Albany NY) 4:235–246. https://doi.org/10.18632/aging.100449

    Article  CAS  Google Scholar 

  254. Ratajczak J et al (2011) Higher number of stem cells in the bone marrow of circulating low Igf-1 level Laron dwarf mice--novel view on Igf-1, stem cells and aging. Leukemia 25:729–733. https://doi.org/10.1038/leu.2010.314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Kucia M et al (2013) The negative effect of prolonged somatotrophic/insulin signaling on an adult bone marrow-residing population of pluripotent very small embryonic-like stem cells (VSELs). Age (Dordr) 35:315–330. https://doi.org/10.1007/s11357-011-9364-8

    Article  CAS  Google Scholar 

  256. Kucia M et al (2011) Reduced number of VSELs in the bone marrow of growth hormone transgenic mice indicates that chronically elevated Igf1 level accelerates age-dependent exhaustion of pluripotent stem cell pool: a novel view on aging. Leukemia 25:1370–1374. https://doi.org/10.1038/leu.2011.98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Bartke A, Westbrook R, Sun L, Ratajczak M (2013) Links between growth hormone and aging. Endokrynol Pol 64:46–52

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Grymula K et al (2014) Positive effects of prolonged caloric restriction on the population of very small embryonic-like stem cells - hematopoietic and ovarian implications. J Ovarian Res 7:68. https://doi.org/10.1186/1757-2215-7-68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Marycz K et al (2016) Endurance exercise mobilizes developmentally early stem cells into peripheral blood and increases their number in bone marrow: implications for tissue regeneration. Stem Cells Int:5756901. https://doi.org/10.1155/2016/5756901

    Article  Google Scholar 

  260. Bazgir B, Fathi R, Rezazadeh Valojerdi M, Mozdziak P, Asgari A (2017) Satellite cells contribution to exercise mediated muscle hypertrophy and repair. Cell J 18:473–484

    PubMed  Google Scholar 

  261. Zhao H, Halicka HD, Li J, Darzynkiewicz Z (2013) Berberine suppresses gero-conversion from cell cycle arrest to senescence. Aging (Albany NY) 5:623–636. https://doi.org/10.18632/aging.100593

    Article  CAS  Google Scholar 

  262. Zhang QS et al (2015) The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. Stem Cell Res 15:130–140. https://doi.org/10.1016/j.scr.2015.05.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Peled T et al (2012) Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Exp Hematol 40:342–355 e341. https://doi.org/10.1016/j.exphem.2011.12.005

    Article  CAS  PubMed  Google Scholar 

  264. Chaurasia P, Gajzer DC, Schaniel C, D'Souza S, Hoffman R (2014) Epigenetic reprogramming induces the expansion of cord blood stem cells. J Clin Invest 124:2378–2395. https://doi.org/10.1172/JCI70313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Horwitz ME et al (2014) Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest 124:3121–3128. https://doi.org/10.1172/JCI74556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Broxmeyer H, Inhibiting E (2014) HDAC for human hematopoietic stem cell expansion. J Clin Invest 124:2365–2368. https://doi.org/10.1172/JCI75803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–922. https://doi.org/10.1016/j.mad.2005.03.012

    Article  CAS  PubMed  Google Scholar 

  268. Osborne TB, Mendel LB, Ferry EL (1917) The effect of retardation of growth upon the breeding period and duration of life of rats. Science 45:294–295. https://doi.org/10.1126/science.45.1160.294

    Article  CAS  PubMed  Google Scholar 

  269. McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. J Nutr 10:63–79

    Article  CAS  Google Scholar 

  270. Fontana L, Klein S (2007) Aging, adiposity, and calorie restriction. JAMA 297:986–994. https://doi.org/10.1001/jama.297.9.986

    Article  CAS  PubMed  Google Scholar 

  271. Weindruch R, Sohal RS (1997) Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med 337:986–994. https://doi.org/10.1056/NEJM199710023371407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Weindruch R, Naylor PH, Goldstein AL, Walford RL (1988) Influences of aging and dietary restriction on serum thymosin alpha 1 levels in mice. J Gerontol 43:B40–B42

    Article  CAS  PubMed  Google Scholar 

  273. Weindruch R, Walford RL (1982) Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215:1415–1418. https://doi.org/10.1126/science.7063854

    Article  CAS  PubMed  Google Scholar 

  274. Anderson RM, Weindruch R (2010) Metabolic reprogramming, caloric restriction and aging. Trends Endocrinol Metab 21:134–141. https://doi.org/10.1016/j.tem.2009.11.005

    Article  CAS  PubMed  Google Scholar 

  275. Harper JM, Leathers CW, Austad SN (2006) Does caloric restriction extend life in wild mice? Aging Cell 5:441–449. https://doi.org/10.1111/j.1474-9726.2006.00236.x

    Article  CAS  PubMed  Google Scholar 

  276. Gallinetti J, Harputlugil E, Mitchell JR (2013) Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. Biochem J 449:1–10. https://doi.org/10.1042/BJ20121098

    Article  CAS  PubMed  Google Scholar 

  277. Miller RA et al (2005) Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4:119–125. https://doi.org/10.1111/j.1474-9726.2005.00152.x

    Article  CAS  PubMed  Google Scholar 

  278. Maeda H et al (1985) Nutritional influences on aging of Fischer 344 rats: II. Pathology. J Gerontol 40:671–688

    Article  CAS  PubMed  Google Scholar 

  279. Bronson RT, Lipman RD (1991) Reduction in rate of occurrence of age related lesions in dietary restricted laboratory mice. Growth Dev Aging 55:169–184

    CAS  PubMed  Google Scholar 

  280. Hursting SD, Lavigne JA, Berrigan D, Perkins SN, Barrett JC (2003) Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med 54:131–152. https://doi.org/10.1146/annurev.med.54.101601.152156

    Article  CAS  PubMed  Google Scholar 

  281. Heilbronn LK et al (2006) Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 295:1539–1548. https://doi.org/10.1001/jama.295.13.1539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Larson-Meyer DE et al (2006) Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care 29:1337–1344. https://doi.org/10.2337/dc05-2565

    Article  PubMed  Google Scholar 

  283. Redman LM et al (2007) Effect of calorie restriction with or without exercise on body composition and fat distribution. J Clin Endocrinol Metab 92:865–872. https://doi.org/10.1210/jc.2006-2184

    Article  CAS  PubMed  Google Scholar 

  284. Racette SB et al (2006) One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue. J Gerontol A Biol Sci Med Sci 61:943–950. https://doi.org/10.1093/gerona/61.9.943

    Article  PubMed  Google Scholar 

  285. Weiss EP et al (2006) Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. Am J Clin Nutr 84:1033–1042. https://doi.org/10.1093/ajcn/84.5.1033

    Article  CAS  PubMed  Google Scholar 

  286. Demetrius L (2006) Aging in mouse and human systems: a comparative study. Ann N Y Acad Sci 1067:66–82. https://doi.org/10.1196/annals.1354.010

    Article  CAS  PubMed  Google Scholar 

  287. Phelan JP, Rose MR (2006) Caloric restriction increases longevity substantially only when the reaction norm is steep. Biogerontology 7:161–164. https://doi.org/10.1007/s10522-006-9005-2

    Article  PubMed  Google Scholar 

  288. Kennedy MA, Rakoczy SG, Brown-Borg HM (2003) Long-living Ames dwarf mouse hepatocytes readily undergo apoptosis. Exp Gerontol 38:997–1008

    Article  CAS  PubMed  Google Scholar 

  289. Buckwalter MS, Katz RW, Camper SA (1991) Localization of the panhypopituitary dwarf mutation (df) on mouse chromosome 11 in an intersubspecific backcross. Genomics 10:515–526

    Article  CAS  PubMed  Google Scholar 

  290. Murakami S (2006) Stress resistance in long-lived mouse models. Exp Gerontol 41:1014–1019. https://doi.org/10.1016/j.exger.2006.06.061

    Article  CAS  PubMed  Google Scholar 

  291. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A (2003) Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci 58:291–296. https://doi.org/10.1093/gerona/58.4.b291

    Article  PubMed  Google Scholar 

  292. Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA (2004) Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. J Gerontol A Biol Sci Med Sci 59:1244–1250. https://doi.org/10.1093/gerona/59.12.1244

    Article  PubMed  Google Scholar 

  293. Majeed N et al (2005) A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. Oncogene 24:4736–4740. https://doi.org/10.1038/sj.onc.1208572

    Article  CAS  PubMed  Google Scholar 

  294. Amador-Noguez D et al (2007) Alterations in xenobiotic metabolism in the long-lived Little mice. Aging Cell 6:453–470. https://doi.org/10.1111/j.1474-9726.2007.00300.x

    Article  CAS  PubMed  Google Scholar 

  295. Berryman DE et al (2004) Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res 14:309–318. https://doi.org/10.1016/j.ghir.2004.02.005

    Article  CAS  PubMed  Google Scholar 

  296. Berryman DE et al (2010) Two-year body composition analyses of long-lived GHR null mice. J Gerontol A Biol Sci Med Sci 65:31–40. https://doi.org/10.1093/gerona/glp175

    Article  CAS  PubMed  Google Scholar 

  297. Wang M, Miller RA (2012) Augmented autophagy pathways and MTOR modulation in fibroblasts from long-lived mutant mice. Autophagy 8:1273–1274. https://doi.org/10.4161/auto.20917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Conover CA, Bale LK (2007) Loss of pregnancy-associated plasma protein a extends lifespan in mice. Aging Cell 6:727–729. https://doi.org/10.1111/j.1474-9726.2007.00328.x

    Article  CAS  PubMed  Google Scholar 

  299. Bartke A (2003) Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology 78:210–216. https://doi.org/10.1159/000073704

    Article  CAS  PubMed  Google Scholar 

  300. Palmer AJ et al (2009) Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology 150:1353–1360. https://doi.org/10.1210/en.2008-1199

    Article  CAS  PubMed  Google Scholar 

  301. Kurosu H et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833. https://doi.org/10.1126/science.1112766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382:536–539. https://doi.org/10.1038/382536a0

    Article  CAS  PubMed  Google Scholar 

  303. Lee SS, Kennedy S (2003) Tolonen, A. C. & Ruvkun, G. DAF-16 target genes that control C. elegans life-span and metabolism. Science 300:644–647. https://doi.org/10.1126/science.1083614

    Article  CAS  PubMed  Google Scholar 

  304. Oh SW et al (2006) Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat Genet 38:251–257. https://doi.org/10.1038/ng1723

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Magdalena Kucia .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kucia, M., Ratajczak, M.Z. (2019). Plausible Links Between Metabolic Networks, Stem Cells, and Longevity. In: Ratajczak, M. (eds) Stem Cells. Advances in Experimental Medicine and Biology, vol 1201. Springer, Cham. https://doi.org/10.1007/978-3-030-31206-0_15

Download citation

Publish with us

Policies and ethics