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Signaling Pathways Regulating Hematopoietic Stem Cell and Progenitor Aging

  • Role of Classical Signaling Pathways in Stem Cell Maintenance (A Cardoso and N Carlesso, Section Editors)
  • Published:
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Abstract

Purpose of Review

The functional decline of hematopoiesis that occurs in the elderly, or in patients who receive therapies that trigger cellular senescence effects, results in a progressive reduction in the immune response and an increased incidence of myeloid malignancy. Intracellular signals in hematopoietic stem cells and progenitors (HSC/P) mediate systemic, microenvironment, and cell-intrinsic effector aging signals that induce their decline. This review intends to summarize and critically review our advances in the understanding of the intracellular signaling pathways responsible for HSC decline during aging and opportunities for intervention.

Recent Findings

For a long time, aging of HSC has been thought to be an irreversible process imprinted in stem cells due to the cell-intrinsic nature of aging. However, recent murine models and human correlative studies provide evidence that aging is associated with molecular signaling pathways, including oxidative stress, metabolic dysfunction, loss of polarity, and an altered epigenome. These signaling pathways provide potential targets for prevention or reversal of age-related changes.

Summary

Here, we review our current understanding of the signaling pathways that are differentially activated or repressed during HSC/P aging, focusing on the oxidative, metabolic, biochemical, and structural consequences downstream, and cell-intrinsic, systemic, and environmental influences.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Cheng J, Turkel N, Hemati N, Fuller MT, Hunt AJ, Yamashita YM. Centrosome misorientation reduces stem cell division during aging. Nature. 2008;456(7222):599–604. https://doi.org/10.1038/nature07386.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. • Bernitz JM, Kim HS, MacArthur B, Sieburg H, Moore K. Hematopoietic stem cells count and remember self-renewal divisions. Cell. 2016;167(5):1296–309 e10. https://doi.org/10.1016/j.cell.2016.10.022. This article provides evidence that demonstrates age-related phenotypic changes within the HSC compartment are divisional history dependent.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135(6):1118–29. https://doi.org/10.1016/j.cell.2008.10.048.

    Article  PubMed  CAS  Google Scholar 

  4. Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006;441(7097):1068–74. https://doi.org/10.1038/nature04956.

    Article  PubMed  CAS  Google Scholar 

  5. Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol. 2006;169(2):338–46. https://doi.org/10.2353/ajpath.2006.060312.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Liang Y, Van Zant G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood. 2005;106(4):1479–87. https://doi.org/10.1182/blood-2004-11-4282.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nat Med. 1996;2(9):1011–6.

    Article  PubMed  CAS  Google Scholar 

  8. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005;102(26):9194–9. https://doi.org/10.1073/pnas.0503280102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Xing Z, Ryan MA, Daria D, Nattamai KJ, Van Zant G, Wang L, et al. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2006;108(7):2190–7. https://doi.org/10.1182/blood-2005-12-010272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Geiger H, Rudolph KL. Aging in the lympho-hematopoietic stem cell compartment. Trends Immunol. 2009;30(7):360–5. https://doi.org/10.1016/j.it.2009.03.010.

    Article  PubMed  CAS  Google Scholar 

  11. de Haan G, Nijhof W, Van Zant G. Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood. 1997;89(5):1543–50.

    PubMed  Google Scholar 

  12. de Haan G, Van Zant G. Dynamic changes in mouse hematopoietic stem cell numbers during aging. Blood. 1999;93(10):3294–301.

    PubMed  Google Scholar 

  13. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127(2):265–75. https://doi.org/10.1016/j.cell.2006.10.003.

    Article  PubMed  CAS  Google Scholar 

  14. Rufini A, Tucci P, Celardo I, Melino G. Senescence and aging: the critical roles of p53. Oncogene. 2013;32(43):5129–43. https://doi.org/10.1038/onc.2012.640.

    Article  PubMed  CAS  Google Scholar 

  15. Geiger H, de Haan G, Florian MC. The aging haematopoietic stem cell compartment. Nat Rev Immunol. 2013;13(5):376–89. https://doi.org/10.1038/nri3433.

    Article  PubMed  CAS  Google Scholar 

  16. Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med. 2014;20(8):833–46. https://doi.org/10.1038/nm.3647.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, et al. Stem-cell aging modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443(7110):421–6. https://doi.org/10.1038/nature05159.

    Article  PubMed  CAS  Google Scholar 

  18. Jeck WR, Siebold AP, Sharpless NE. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell. 2012;11(5):727–31. https://doi.org/10.1111/j.1474-9726.2012.00871.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. • Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184–9. https://doi.org/10.1038/nature16932. This paper provides evidence of p16Ink4a positive cells accumulation with aging and it removal as an important therapeutic approach to extend longevity

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003;423(6937):302–5. https://doi.org/10.1038/nature01587.

    Article  PubMed  CAS  Google Scholar 

  21. Attema JL, Pronk CJ, Norddahl GL, Nygren JM, Bryder D. Hematopoietic stem cell aging is uncoupled from p16 INK4A-mediated senescence. Oncogene. 2009;28(22):2238–43. https://doi.org/10.1038/onc.2009.94.

    Article  PubMed  CAS  Google Scholar 

  22. • Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016;22(1):78–83. https://doi.org/10.1038/nm.4010. This article shows that selective clearance of senescent cells rejuvenate aged stem cells.

    Article  PubMed  CAS  Google Scholar 

  23. •• Zhang H, Ryu D. Wu Y, Gariani K, Wang X, Luan P et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436–43. https://doi.org/10.1126/science.aaf2693. This article demonstrates that NAD+ supplemantation delays senescence and rejuvanate aged HSC through induction of mitochondrial unfolded protein response and synthesis of prohibitin proteins.

    Article  PubMed  CAS  Google Scholar 

  24. Alers S, Loffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012;32(1):2–11. https://doi.org/10.1128/MCB.06159-11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Kennedy BK, Lamming DW. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab. 2016;23(6):990–1003. https://doi.org/10.1016/j.cmet.2016.05.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Florian MC, Dorr K, Niebel A, Daria D, Schrezenmeier H, Rojewski M, et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell. 2012;10(5):520–30. https://doi.org/10.1016/j.stem.2012.04.007.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446–51. https://doi.org/10.1038/nm1388.

    Article  PubMed  CAS  Google Scholar 

  28. Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007;110(8):3056–63. https://doi.org/10.1182/blood-2007-05-087759.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Lopez-Otin C, Galluzzi L, Freije JMP, Madeo F, Kroemer G. Metabolic control of longevity. Cell. 2016;166(4):802–21. https://doi.org/10.1016/j.cell.2016.07.031.

    Article  PubMed  CAS  Google Scholar 

  30. Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14(6):810–23. https://doi.org/10.1016/j.stem.2014.04.014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of aging and age-related disease. Nature. 2013;493(7432):338–45. https://doi.org/10.1038/nature11861.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Satoh Y, Yokota T, Sudo T, Kondo M, Lai A, Kincade PW, et al. The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. Immunity. 2013;38(6):1105–15. https://doi.org/10.1016/j.immuni.2013.05.014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Brown K, Xie S, Qiu X, Mohrin M, Shin J, Liu Y, et al. SIRT3 reverses aging-associated degeneration. Cell Rep. 2013;3(2):319–27. https://doi.org/10.1016/j.celrep.2013.01.005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. •• Mohrin M, Shin J, Liu Y, Brown K, Luo H, Xi Y, et al. Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science. 2015;347(6228):1374–7. https://doi.org/10.1126/science.aaa2361. This study identified SIRT7-NRF1 as a regulator of mitochondrial unfolded protein response and define its significance in rejuvanation of aged HSC.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, et al. p16(Ink4a) and senescence-associated beta-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging (Albany NY). 2017;9(8):1867–84. https://doi.org/10.18632/aging.101268.

    Article  Google Scholar 

  36. Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, et al. Aging of mice is associated with p16(Ink4a)- and beta-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY). 2016;8(7):1294–315. https://doi.org/10.18632/aging.100991.

    Article  CAS  Google Scholar 

  37. Carrasco-Garcia E, Moreno M, Moreno-Cugnon L, Matheu A. Increased Arf/p53 activity in stem cells, aging and cancer. Aging Cell. 2017;16(2):219–25. https://doi.org/10.1111/acel.12574.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, et al. p53 mutant mice that display early aging-associated phenotypes. Nature. 2002;415(6867):45–53. https://doi.org/10.1038/415045a.

    Article  PubMed  CAS  Google Scholar 

  39. Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 2004;18(3):306–19. https://doi.org/10.1101/gad.1162404.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Dumble M, Moore L, Chambers SM, Geiger H, Van Zant G, Goodell MA, et al. The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood. 2007;109(4):1736–42. https://doi.org/10.1182/blood-2006-03-010413.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, et al. Delayed aging through damage protection by the Arf/p53 pathway. Nature. 2007;448(7151):375–9. https://doi.org/10.1038/nature05949.

    Article  PubMed  CAS  Google Scholar 

  42. Armata HL, Garlick DS, Sluss HK. The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression. Cancer Res. 2007;67(24):11696–703. https://doi.org/10.1158/0008-5472.CAN-07-1610.

    Article  PubMed  CAS  Google Scholar 

  43. Liu D, Ou L, Clemenson GD Jr, Chao C, Lutske ME, Zambetti GP, et al. Puma is required for p53-induced depletion of adult stem cells. Nat Cell Biol. 2010;12(10):993–8. https://doi.org/10.1038/ncb2100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Domen J, Cheshier SH, Weissman IL. The role of apoptosis in the regulation of hematopoietic stem cells: Overexpression of Bcl-2 increases both their number and repopulation potential. J Exp Med. 2000;191(2):253–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. •• Kirschner K, Chandra T, Kiselev V, Flores-Santa Cruz D, Macaulay IC, Park HJ, et al. Proliferation drives aging-related functional decline in a subpopulation of the hematopoietic stem cell compartment. Cell Rep. 2017;19(8):1503–11. https://doi.org/10.1016/j.celrep.2017.04.074. This article defines cellular heterogeneity in HSC aging, and highlighted the significance of JAK/STAT signaling in stem cell exhaustion.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Kim HN, Chang J, Shao L, Han L, Iyer S, Manolagas SC, et al. DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age. Aging Cell. 2017;16(4):693–703. https://doi.org/10.1111/acel.12597.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A. 2010;107(12):5465–70. https://doi.org/10.1073/pnas.1000834107.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Dykstra B, Olthof S, Schreuder J, Ritsema M, de Haan G. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J Exp Med. 2011;208(13):2691–703. https://doi.org/10.1084/jem.20111490.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner SM, et al. Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature. 2015;518(7540):542–6. https://doi.org/10.1038/nature14242.

    Article  PubMed  CAS  Google Scholar 

  50. Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514(7522):322–7. https://doi.org/10.1038/nature13824.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Verovskaya E, Broekhuis MJ, Zwart E, Ritsema M, van Os R, de Haan G, et al. Heterogeneity of young and aged murine hematopoietic stem cells revealed by quantitative clonal analysis using cellular barcoding. Blood. 2013;122(4):523–32. https://doi.org/10.1182/blood-2013-01-481135.

    Article  PubMed  CAS  Google Scholar 

  52. •• Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87. https://doi.org/10.1056/NEJMoa1409405. This article preformed whole exome sequencing on a large cohort and reveiled detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. •• Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98. https://doi.org/10.1056/NEJMoa1408617. This article highlights that detectable somatic mutations, partcularly in DNMT3A, TET2, and ASXL1, were rare in persons younger than 40 years of age but rose appreciably in frequency with age and was associated with an increase in the risk of hematologic cancer, an increase in all-cause mortality, with increases in the risks of incident coronary heart disease and ischemic stroke.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. •• McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J, et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10(8):1239–45. https://doi.org/10.1016/j.celrep.2015.02.005. This paper indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. •• Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16. https://doi.org/10.1182/blood-2015-03-631747. This article highlights the acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell. 2014;15(1):37–50. https://doi.org/10.1016/j.stem.2014.04.016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Rossi DJ, Seita J, Czechowicz A, Bhattacharya D, Bryder D, Weissman IL. Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle. 2007;6(19):2371–6. https://doi.org/10.4161/cc.6.19.4759.

    Article  PubMed  CAS  Google Scholar 

  58. Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, et al. Replication stress is a potent driver of functional decline in aging haematopoietic stem cells. Nature. 2014;512(7513):198–202. https://doi.org/10.1038/nature13619.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. •• Walter D, Lier A, Geiselhart A, Thalheimer FB, Huntscha S, Sobotta MC, et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature. 2015;520(7548):549–52. https://doi.org/10.1038/nature14131. This article establishes a novel link between physiological stress and DNA damage in normal HSC while providing a mechanistic explanation for the accumulation of DNA damage in HSC during aging and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.

    Article  PubMed  CAS  Google Scholar 

  60. Seita J, Rossi DJ, Weissman IL. Differential DNA damage response in stem and progenitor cells. Cell Stem Cell. 2010;7(2):145–7. https://doi.org/10.1016/j.stem.2010.07.006.

    Article  PubMed  CAS  Google Scholar 

  61. Capper R, Britt-Compton B, Tankimanova M, Rowson J, Letsolo B, Man S, et al. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev. 2007;21(19):2495–508. https://doi.org/10.1101/gad.439107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Wahlestedt M, Norddahl GL, Sten G, Ugale A, Frisk MA, Mattsson R, et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood. 2013;121(21):4257–64. https://doi.org/10.1182/blood-2012-11-469080.

    Article  PubMed  CAS  Google Scholar 

  63. Morrison SJ, Prowse KR, Ho P, Weissman IL. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity. 1996;5(3):207–16.

    Article  PubMed  CAS  Google Scholar 

  64. Allsopp RC, Cheshier S, Weissman IL. Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med. 2001;193(8):917–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Allsopp RC, Morin GB, Horner JW, DePinho R, Harley CB, Weissman IL. Effect of TERT over-expression on the long-term transplantation capacity of hematopoietic stem cells. Nat Med. 2003;9(4):369–71. https://doi.org/10.1038/nm0403-369.

    Article  PubMed  CAS  Google Scholar 

  66. Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 2007;5(8):e201. https://doi.org/10.1371/journal.pbio.0050201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, et al. DNA repair is limiting for haematopoietic stem cells during aging. Nature. 2007;447(7145):686–90. https://doi.org/10.1038/nature05875.

    Article  PubMed  CAS  Google Scholar 

  68. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447(7145):725–9. https://doi.org/10.1038/nature05862.

    Article  PubMed  CAS  Google Scholar 

  69. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461(7267):1071–8. https://doi.org/10.1038/nature08467.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Kenyon J, Gerson SL. The role of DNA damage repair in aging of adult stem cells. Nucleic Acids Res. 2007;35(22):7557–65. https://doi.org/10.1093/nar/gkm1064.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Qing Y, Wang Z, Bunting KD, Gerson SL. Bcl2 overexpression rescues the hematopoietic stem cell defects in Ku70-deficient mice by restoration of quiescence. Blood. 2014;123(7):1002–11. https://doi.org/10.1182/blood-2013-08-521716.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Prall WC, Czibere A, Jager M, Spentzos D, Libermann TA, Gattermann N, et al. Age-related transcription levels of KU70, MGST1 and BIK in CD34+ hematopoietic stem and progenitor cells. Mech Aging Dev. 2007;128(9):503–10. https://doi.org/10.1016/j.mad.2007.06.008.

    Article  PubMed  CAS  Google Scholar 

  73. Bender CF, Sikes ML, Sullivan R, Huye LE, Le Beau MM, Roth DB, et al. Cancer predisposition and hematopoietic failure in Rad50(S/S) mice. Genes Dev. 2002;16(17):2237–51. https://doi.org/10.1101/gad.1007902.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Prasher JM, Lalai AS, Heijmans-Antonissen C, Ploemacher RE, Hoeijmakers JH, Touw IP, et al. Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice. EMBO J. 2005;24(4):861–71. https://doi.org/10.1038/sj.emboj.7600542.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996;86(1):159–71.

    Article  PubMed  CAS  Google Scholar 

  76. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431(7011):997–1002. https://doi.org/10.1038/nature02989.

    Article  PubMed  CAS  Google Scholar 

  77. Moehrle BM, Nattamai K, Brown A, Florian MC, Ryan M, Vogel M, et al. Stem cell-specific mechanisms ensure genomic fidelity within HSCs and upon aging of HSCs. Cell Rep. 2015;13(11):2412–24. https://doi.org/10.1016/j.celrep.2015.11.030.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E, et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell. 2013;12(1):49–61. https://doi.org/10.1016/j.stem.2012.10.011.

    Article  PubMed  CAS  Google Scholar 

  79. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, et al. Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A. 2001;98(18):10469–74. https://doi.org/10.1073/pnas.171202698.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP. The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. Aging (Albany NY). 2012;4(10):686–94. https://doi.org/10.18632/aging.100493.

    Article  CAS  Google Scholar 

  81. Juntilla MM, Patil VD, Calamito M, Joshi RP, Birnbaum MJ, Koretzky GA. AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood. 2010;115(20):4030–8. https://doi.org/10.1182/blood-2009-09-241000.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205(10):2397–408. https://doi.org/10.1084/jem.20081297.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Borodkina A, Shatrova A, Abushik P, Nikolsky N, Burova E. Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells. Aging (Albany NY). 2014;6(6):481–95. https://doi.org/10.18632/aging.100673.

    Article  Google Scholar 

  84. Jung H, Kim DO, Byun JE, Kim WS, Kim MJ, Song HY, et al. Thioredoxin-interacting protein regulates haematopoietic stem cell aging and rejuvenation by inhibiting p38 kinase activity. Nat Commun. 2016;7:13674. https://doi.org/10.1038/ncomms13674.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Wang Y, Hekimi S. Mitochondrial dysfunction and longevity in animals: Untangling the knot. Science. 2015;350(6265):1204–7. https://doi.org/10.1126/science.aac4357.

    Article  PubMed  CAS  Google Scholar 

  86. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217. https://doi.org/10.1016/j.cell.2013.05.039.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Norddahl GL, Pronk CJ, Wahlestedt M, Sten G, Nygren JM, Ugale A, et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell. 2011;8(5):499–510. https://doi.org/10.1016/j.stem.2011.03.009.

    Article  PubMed  CAS  Google Scholar 

  88. Liang R, Ghaffari S. Mitochondria and FOXO3 in stem cell homeostasis, a window into hematopoietic stem cell fate determination. J Bioenerg Biomembr. 2017;49(4):343–6. https://doi.org/10.1007/s10863-017-9719-7.

    Article  PubMed  CAS  Google Scholar 

  89. Kohli L, Passegue E. Surviving change: the metabolic journey of hematopoietic stem cells. Trends Cell Biol. 2014;24(8):479–87. https://doi.org/10.1016/j.tcb.2014.04.001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Luchsinger LL, de Almeida MJ, Corrigan DJ, Mumau M, Snoeck HW. Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature. 2016;529(7587):528–31. https://doi.org/10.1038/nature16500.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016;61(5):654–66. https://doi.org/10.1016/j.molcel.2016.01.028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, et al. Premature aging in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429(6990):417–23. https://doi.org/10.1038/nature02517.

    Article  PubMed  CAS  Google Scholar 

  93. Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nature Medicine. 2014;20(8):870–80. https://doi.org/10.1038/nm.3651.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, et al. NAD+ in aging: molecular mechanisms and translational implications. Trends in Mol Med. 2017;23(10):899–916. https://doi.org/10.1016/j.molmed.2017.08.001.

    Article  CAS  Google Scholar 

  95. Bernales S, Soto MM, McCullagh E. Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration. Front Aging Neurosci. 2012;4:5. https://doi.org/10.3389/fnagi.2012.00005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Shyh-Chang N, Daley GQ, Cantley LC. Stem cell metabolism in tissue development and aging. Development. 2013;140(12):2535–47. https://doi.org/10.1242/dev.091777.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Schreiber KH, Kennedy BK. When lamins go bad: nuclear structure and disease. Cell. 2013;152(6):1365–75. https://doi.org/10.1016/j.cell.2013.02.015.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009;326(5949):140–4. https://doi.org/10.1126/science.1177221.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Wu JJ, Liu J, Chen EB, Wang JJ, Cao L, Narayan N, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep. 2013;4(5):913–20. https://doi.org/10.1016/j.celrep.2013.07.030.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335(6076):1638–43. https://doi.org/10.1126/science.1215135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Rimmele P, Bigarella CL, Liang R, Izac B, Dieguez-Gonzalez R, Barbet G, et al. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Reports. 2014;3(1):44–59. https://doi.org/10.1016/j.stemcr.2014.04.015.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. O'Callaghan C, Vassilopoulos A. Sirtuins at the crossroads of stemness, aging, and cancer. Aging Cell. 2017;16(6):1208–18. https://doi.org/10.1111/acel.12685.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. •• Wang H, Diao D, Shi Z, Zhu X, Gao Y, Gao S, et al. SIRT6 controls hematopoietic stem cell homeostasis through epigenetic regulation of Wnt signaling. Cell Stem Cell. 2016;18(4):495–507. https://doi.org/10.1016/j.stem.2016.03.005. This study for the first time shows the link between SIRT6 and Wnt signaling in the regulation of HSC homeostasis and self-renewal.

    Article  PubMed  CAS  Google Scholar 

  104. Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17(1):41–52. https://doi.org/10.1016/j.ccr.2009.11.023.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Wrighton KH. Stem cells:SIRT7, the UPR and HSC aging. Nat Rev Mol Cell Biol. 2015;16(5):266–7. https://doi.org/10.1038/nrm3981.

    Article  PubMed  CAS  Google Scholar 

  106. Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624–38. https://doi.org/10.1016/j.cell.2013.11.037.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124(2):315–29. https://doi.org/10.1016/j.cell.2005.11.044.

    Article  PubMed  CAS  Google Scholar 

  108. Tothova Z, Gilliland DG. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell. 2007;1(2):140–52. https://doi.org/10.1016/j.stem.2007.07.017.

    Article  PubMed  CAS  Google Scholar 

  109. Mohrin M, Chen D. The mitochondrial metabolic checkpoint and aging of hematopoietic stem cells. Curr Opin Hematol. 2016;23(4):318–24. https://doi.org/10.1097/MOH.0000000000000244.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol. 2014;15(4):243–56. https://doi.org/10.1038/nrm3772.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Bigarella CL, Li J, Rimmele P, Liang R, Sobol RW, Ghaffari S. FOXO3 transcription factor is essential for protecting hematopoietic stem and progenitor cells from oxidative DNA damage. J Biol Chem. 2017;292(7):3005–15. https://doi.org/10.1074/jbc.M116.769455.

    Article  PubMed  CAS  Google Scholar 

  112. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325–39. https://doi.org/10.1016/j.cell.2007.01.003.

    Article  PubMed  CAS  Google Scholar 

  113. Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1(1):101–12. https://doi.org/10.1016/j.stem.2007.02.001.

    Article  PubMed  CAS  Google Scholar 

  114. Rimmele P, Liang R, Bigarella CL, Kocabas F, Xie J, Serasinghe MN, et al. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3. EMBO Rep. 2015;16(9):1164–76. https://doi.org/10.15252/embr.201439704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. •• Ho TT, Warr MR, Adelman ER, Lansinger OM, Flach J, Verovskaya EV, et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature. 2017;543(7644):205–10. https://doi.org/10.1038/nature21388. This study demonstrate that autophagy is necessary to preserve the regenerative capacity of old HSC by clearing active, healthy mitochondria and convincingly shows that about 30% of old HSC exhibit high autophagy and retain stemness like yong one.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Mortensen M, Soilleux EJ, Djordjevic G, Tripp R, Lutteropp M, Sadighi-Akha E, et al. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med. 2011;208(3):455–67. https://doi.org/10.1084/jem.20101145.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Mortensen M, Watson AS, Simon AK. Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation. Autophagy. 2011;7(9):1069–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity? Nat Cell Biol. 2010;12(9):842–6. https://doi.org/10.1038/ncb0910-842.

    Article  PubMed  CAS  Google Scholar 

  119. Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature. 2013;494(7437):323–7. https://doi.org/10.1038/nature11895.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Ito K, Turcotte R, Cui J, Zimmerman SE, Pinho S, Mizoguchi T, et al. Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science. 2016;354(6316):1156–60. https://doi.org/10.1126/science.aaf5530.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Kohler A, Schmithorst V, Filippi MD, Ryan MA, Daria D, Gunzer M, et al. Altered cellular dynamics and endosteal location of aged early hematopoietic progenitor cells revealed by time-lapse intravital imaging in long bones. Blood. 2009;114(2):290–8. https://doi.org/10.1182/blood-2008-12-195644.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science. 2003;299(5613):1751–3. https://doi.org/10.1126/science.1080418.

    Article  PubMed  CAS  Google Scholar 

  123. Erjavec N, Larsson L, Grantham J, Nystrom T. Accelerated aging and failure to segregate damaged proteins in Sir2 mutants can be suppressed by overproducing the protein aggregation-remodeling factor Hsp104p. Genes Dev. 2007;21(19):2410–21. https://doi.org/10.1101/gad.439307.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Liu B, Larsson L, Caballero A, Hao X, Oling D, Grantham J, et al. The polarisome is required for segregation and retrograde transport of protein aggregates. Cell. 2010;140(2):257–67. https://doi.org/10.1016/j.cell.2009.12.031.

    Article  PubMed  CAS  Google Scholar 

  125. Shcheprova Z, Baldi S, Frei SB, Gonnet G, Barral Y. A mechanism for asymmetric segregation of age during yeast budding. Nature. 2008;454(7205):728–34. https://doi.org/10.1038/nature07212.

    Article  PubMed  CAS  Google Scholar 

  126. Sengupta A, Duran A, Ishikawa E, Florian MC, Dunn SK, Ficker AM, et al. Atypical protein kinase C (aPKCzeta and aPKClambda) is dispensable for mammalian hematopoietic stem cell activity and blood formation. Proc Natl Acad Sci U S A. 2011;108(24):9957–62. https://doi.org/10.1073/pnas.1103132108.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Wilson A, Ardiet DL, Saner C, Vilain N, Beermann F, Aguet M, et al. Normal hemopoiesis and lymphopoiesis in the combined absence of numb and numblike. J Immunol. 2007;178(11):6746–51.

    Article  PubMed  CAS  Google Scholar 

  128. •• Florian MC, Nattamai KJ, Dorr K, Marka G, Uberle B, Vas V, et al. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell aging. Nature. 2013;503(7476):392–6. https://doi.org/10.1038/nature12631. This paper highlights that Wnt5a treatment of young HSC induces aging-associated stem-cell apolarity, reduction of regenerative capacity and an aging-like myeloid-lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. They also identify that Wnt5a haploinsufficiency attenuates HSC aging, and stem-cell-intrinsic reduction of Wnt5a expression results in functionally rejuvenated aged HSC.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013;12(4):413–25. https://doi.org/10.1016/j.stem.2013.01.017.

    Article  PubMed  CAS  Google Scholar 

  130. Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014;14(5):673–88. https://doi.org/10.1016/j.stem.2014.03.002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Fraga MF, Esteller M. Epigenetics and aging: the targets and the marks. Trends Genet. 2007;23(8):413–8. https://doi.org/10.1016/j.tig.2007.05.008.

    Article  PubMed  CAS  Google Scholar 

  132. Han S, Brunet A. Histone methylation makes its mark on longevity. Trends Cell Biol. 2012;22(1):42–9. https://doi.org/10.1016/j.tcb.2011.11.001.

    Article  PubMed  CAS  Google Scholar 

  133. • Burman B, Zhang ZZ, Pegoraro G, Lieb JD, Misteli T. Histone modifications predispose genome regions to breakage and translocation. Genes Dev. 2015;29(13):1393–402. https://doi.org/10.1101/gad.262170.115. This article identifies specific histone modifications as facilitators of chromosome breakage and translocations using a combination of bioinformatics, biochemical analysis, and cell-based assays.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Burke B, Stewart CL. Functional architecture of the cell’s nucleus in development, aging, and disease. Curr Top Dev Biol. 2014;109:1–52. https://doi.org/10.1016/B978-0-12-397920-9.00006-8.

    Article  PubMed  Google Scholar 

  135. • Ugarte F, Sousae R, Cinquin B, Martin EW, Krietsch J, Sanchez G, et al. Progressive chromatin condensation and H3K9 methylation regulate the differentiation of embryonic and hematopoietic stem cells. Stem Cell Reports. 2015;5(5):728–40. https://doi.org/10.1016/j.stemcr.2015.09.009. This article identifies global chromatin rearrangements during stem cell differentiation and that heterochromatin formation by H3K9methylation regulates HSC differentiation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Vas V, Senger K, Dorr K, Niebel A, Geiger H. Aging of the microenvironment influences clonality in hematopoiesis. PLoS One. 2012;7(8):e42080. https://doi.org/10.1371/journal.pone.0042080.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Vas V, Wandhoff C, Dorr K, Niebel A, Geiger H. Contribution of an aged microenvironment to aging-associated myeloproliferative disease. PLoS One. 2012;7(2):e31523. https://doi.org/10.1371/journal.pone.0031523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Siclari VA, Zhu J, Akiyama K, Liu F, Zhang X, Chandra A, et al. Mesenchymal progenitors residing close to the bone surface are functionally distinct from those in the central bone marrow. Bone. 2013;53(2):575–86. https://doi.org/10.1016/j.bone.2012.12.013.

    Article  PubMed  Google Scholar 

  139. •• Kusumbe AP, Ramasamy SK, Itkin T, Mae MA, Langen UH, Betsholtz C, et al. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature. 2016;532(7599):380–4. https://doi.org/10.1038/nature17638. This article demonstrated the role of vascular niches and niche forming vessels in HSC aging, and highlighted the significance of endothelial cells Notch signalling in niche expansion.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Zhang Y, Depond M, He L, Foudi A, Kwarteng EO, Lauret E, et al. CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress. Sci Rep. 2016;6:37827. https://doi.org/10.1038/srep37827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Tuljapurkar SR, McGuire TR, Brusnahan SK, Jackson JD, Garvin KL, Kessinger MA, et al. Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging. J Anat. 2011;219(5):574–81. https://doi.org/10.1111/j.1469-7580.2011.01423.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Ergen AV, Boles NC, Goodell MA. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood. 2012;119(11):2500–9. https://doi.org/10.1182/blood-2011-11-391730.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Chang KH, Sengupta A, Nayak RC, Duran A, Lee SJ, Pratt RG, et al. p62 is required for stem cell/progenitor retention through inhibition of IKK/NF-kappaB/Ccl4 signaling at the bone marrow macrophage-osteoblast niche. Cell Rep. 2014;9(6):2084–97. https://doi.org/10.1016/j.celrep.2014.11.031.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. •• Guidi N, Sacma M, Standker L, Soller K, Marka G, Eiwen K, et al. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J. 2017;36(7):840–53. https://doi.org/10.15252/embj.201694969. This paper convincingly shows that reduced expression of osteopoetin upon aging limits HSC regeneation, and identified thrombin-cleaved osteopoetin as a novel rejuvenation approach.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Quere R, Saint-Paul L, Carmignac V, Martin RZ, Chretien ML, Largeot A, et al. Tif1gamma regulates the TGF-beta1 receptor and promotes physiological aging of hematopoietic stem cells. Proc Natl Acad Sci U S A. 2014;111(29):10592–7. https://doi.org/10.1073/pnas.1405546111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Blank U, Karlsson S. TGF-beta signaling in the control of hematopoietic stem cells. Blood. 2015;125(23):3542–50. https://doi.org/10.1182/blood-2014-12-618090.

    Article  PubMed  CAS  Google Scholar 

  147. Taniguchi Ishikawa E, Gonzalez-Nieto D, Ghiaur G, Dunn SK, Ficker AM, Murali B, et al. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci U S A. 2012;109(23):9071–6. https://doi.org/10.1073/pnas.1120358109.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Gonzalez-Nieto D, Li L, Kohler A, Ghiaur G, Ishikawa E, Sengupta A, et al. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood. 2012;119(22):5144–54. https://doi.org/10.1182/blood-2011-07-368506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Howcroft TK, Campisi J, Louis GB, Smith MT, Wise B, Wyss-Coray T, et al. The role of inflammation in age-related disease. Aging (Albany NY). 2013;5(1):84–93. https://doi.org/10.18632/aging.100531.

    Article  CAS  Google Scholar 

  150. De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflamm-aging and lifelong antigenic load as major determinants of aging rate and longevity. FEBS Lett. 2005;579(10):2035–9. https://doi.org/10.1016/j.febslet.2005.02.055.

    Article  PubMed  CAS  Google Scholar 

  151. Kovtonyuk LV, Fritsch K, Feng X, Manz MG, Takizawa H. Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment. Front Immunol. 2016;7:502. https://doi.org/10.3389/fimmu.2016.00502.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Bersenev A, Rozenova K, Balcerek J, Jiang J, Wu C, Tong W. Lnk deficiency partially mitigates hematopoietic stem cell aging. Aging Cell. 2012;11(6):949–59. https://doi.org/10.1111/j.1474-9726.2012.00862.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Norddahl GL, Wahlestedt M, Gisler S, Sigvardsson M, Bryder D. Reduced repression of cytokine signaling ameliorates age-induced decline in hematopoietic stem cell function. Aging Cell. 2012;11(6):1128–31. https://doi.org/10.1111/j.1474-9726.2012.00863.x.

    Article  PubMed  CAS  Google Scholar 

  154. Pietras EM. Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. Blood. 2017;130(15):1693–8. https://doi.org/10.1182/blood-2017-06-780882.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  155. • Josefsdottir KS, Baldridge MT, Kadmon CS, King KY. Antibiotics impair murine hematopoiesis by depleting the intestinal microbiota. Blood. 2017;129(6):729–39. https://doi.org/10.1182/blood-2016-03-708594. This paper demonstrated that microbiota sustain steady-state hematopoiesis through activation of Stat1 signaling.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Khosravi A, Yanez A, Price JG, Chow A, Merad M, Goodridge HS, et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe. 2014;15(3):374–81. https://doi.org/10.1016/j.chom.2014.02.006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Heintz C, Mair W. You are what you host: microbiome modulation of the aging process. Cell. 2014;156(3):408–11. https://doi.org/10.1016/j.cell.2014.01.025.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. •• Han B, Sivaramakrishnan P, Lin CJ, Neve IAA, He J, Tay LWR, et al. Microbial genetic composition tunes host longevity. Cell. 2017;169(7):1249–62 e13. https://doi.org/10.1016/j.cell.2017.05.036. This study highlighted the significance of bacterial genes on host aging and identified mTOR, JNK, Insulin signaling, and caloric restriction as a novel molecular targets.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

The authors want to thank Ms. Margaret O’Leary for editing this manuscript.

The authors also want to thank the Cincinnati Children’s Hospital Medical Center and Hoxworth Blood Center for their continued support.

Funding

This study has been partly supported by the National Institutes of Health F31HL1324801 (M.J.A.), R01GM110628 (J.A.C), Leukemia and Lymphoma Society of North America (J.A.C.), and Williams Lawrence & Blanche Hughes Foundation (J.A.C.)

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  1. Abhishek K. Singh and Mark J. Althoff contributed equally to this work.

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA

    Abhishek K. Singh, Mark J. Althoff & Jose A. Cancelas

  2. Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Abhishek K. Singh, Mark J. Althoff & Jose A. Cancelas

  3. Cancer & Cell Biology Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Mark J. Althoff & Jose A. Cancelas

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Singh, A.K., Althoff, M.J. & Cancelas, J.A. Signaling Pathways Regulating Hematopoietic Stem Cell and Progenitor Aging. Curr Stem Cell Rep 4, 166–181 (2018). https://doi.org/10.1007/s40778-018-0128-6

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