Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms.

1.
Schaible R, Sussman M, Kramer BH: Aging and potential for self-renewal: hydra living in the age of aging - a mini-review. Gerontology 2014;60:548-556.
2.
Petralia RS, Mattson MP, Yao PJ: Aging and longevity in the simplest animals and the quest for immortality. Ageing Res Rev 2014;16:66-82.
3.
Gems D, Partridge L: Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol 2013;75:621-644.
4.
Biteau B, Karpac J, Supoyo S, Degennaro M, Lehmann R, Jasper H: Lifespan extension by preserving proliferative homeostasis in drosophila. PLoS Genet 2010;6:1001159.
5.
Austad SN: Is there a role for new invertebrate models for aging research? J Gerontol A Biol Sci Med Sci 2009;64:192-194.
6.
Pegoraro G, Misteli T: The central role of chromatin maintenance in aging. Aging (Albany) 2009;1:1017-1022.
7.
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D: Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 2013;497:211-216.
8.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM: Naturally occurring p16-positive cells shorten healthy lifespan. Nature 2016;530:184-189.
9.
Milo R, Phillips R: Cell Biology by the Numbers. New York, Garland Science, 2015.
10.
Florian MC, Dörr K, Niebel A, Daria D, Schrezenmeier H, Rojewski M, Filippi MD, Hasenberg A, Gunzer M, Scharffetter-Kochanek K, Zheng Y, Geiger H: CDC42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell 2012;10:520-530.
11.
Geiger H, de Haan G, Florian MC: The ageing haematopoietic stem cell compartment. Nat Rev Immunol 2013;13:376-389.
12.
Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE: Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 2011;333:218-221.
13.
Harrison DE, Astle CM: Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med 1982;156:1767-1779.
14.
Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, Hegland J, Kamani N, Kernan NA, King R, Ratanatharathorn V, Weisdorf D, Confer DL: Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001;98:2043-2051.
15.
Liang Y: Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 2005;106:1479-1487.
16.
Flach J, Bakker ST, Mohrin M, Conroy PC, Pietras EM, Reynaud D, Alvarez S, Diolaiti ME, Ugarte F, Forsberg EC, Le Beau MM, Stohr BA, Mendez J, Morrison CG, Passegue E: Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 2014;512:198-202.
17.
Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ, Schrier SL, Weissman IL: Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci USA 2011;108:20012-20017.
18.
Akunuru S, Geiger H: Aging, clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med 2016;22:701-712.
19.
Florian MC, Nattamai KJ, Dörr K, Marka G, Überle B, Vas V, Eckl C, Andrä I, Schiemann M, Oostendorp RAJ, Scharffetter-Kochanek K, Kestler HA, Zheng Y, Geiger H: A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature 2013;503:392-396.
20.
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;9:369-371.
21.
Mendez-Ferrer S, Lucas D, Battista M, Frenette PS: Haematopoietic stem cell release is regulated by circadian oscillations. Nature 2008;452:442-447.
22.
Ergen AV, Boles NC, Goodell MA: Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 2012;119:2500-2509.
23.
Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392-395.
24.
Chen C, Liu Y, Zheng P: mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2009;2:ra75-ra75.
25.
Arranz L, Sanchez-Aguilera A, Martin-Perez D, Isern J, Langa X, Tzankov A, Lundberg P, Muntion S, Tzeng YS, Lai DM, Schwaller J, Skoda RC, Mendez-Ferrer S: Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 2014;512:78-81.
26.
Boulais PE, Frenette PS: Making sense of hematopoietic stem cell niches. Blood 2015;125:2621-2629.
27.
Kamminga LM, van Os R, Ausema A, Noach EJ, Weersing E, Dontje B, Vellenga E, de Haan G: Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. Stem Cells 2005;23:82-92.
28.
Shen J, Tsai YT, Dimarco NM, Long MA, Sun X, Tang L: Transplantation of mesenchymal stem cells from young donors delays aging in mice. Sci Rep 2011;1:67.
29.
Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663-676.
30.
Studer L, Vera E, Cornacchia D: Programming and reprogramming cellular age in the era of induced pluripotency. Cell Stem Cell 2015;16:591-600.
31.
Eminli S, Foudi A, Stadtfeld M, Maherali N, Ahfeldt T, Mostoslavsky G, Hock H, Hochedlinger K: Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat Genet 2009;41:968-976.
32.
Kanherkar RR, Bhatia-Dey N, Makarev E, Csoka AB: Cellular reprogramming for understanding and treating human disease. Front Cell Dev Biol 2014;2:67.
33.
Larson K, Yan SJ, Tsurumi A, Liu J, Zhou J, Gaur K, Guo D, Eickbush TH, Li WX: Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet 2012;8:e1002473.
34.
Jin C, Li J, Green CD, Yu X, Tang X, Han D, Xian B, Wang D, Huang X, Cao X, Yan Z, Hou L, Liu J, Shukeir N, Khaitovich P, Chen CD, Zhang H, Jenuwein T, Han JD: Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metab 2011;14:161-172.
35.
Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, Kaeberlein M, Kennedy BK, Berger SL: Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 2009;459:802-807.
36.
Apostolou E, Hochedlinger K: Chromatin dynamics during cellular reprogramming. Nature 2013;502:462-471.
37.
Rohani L, Johnson AA, Arnold A, Stolzing A: The aging signature: a hallmark of induced pluripotent stem cells? Aging Cell 2014;13:2-7.
38.
Wahlestedt M, Norddahl GL, Sten G, Ugale A, Frisk MA, Mattsson R, Deierborg T, Sigvardsson M, Bryder D: An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood 2013;121:4257-4264.
39.
Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S, Taldone T, Fusaki N, Tomishima MJ, Krainc D, Milner TA, Rossi DJ, Studer L: Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 2013;13:691-705.
40.
Zhang J, Lian Q, Zhu G, Zhou F, Sui L, Tan C, Mutalif RA, Navasankari R, Zhang Y, Tse HF, Stewart CL, Colman A: A human iPSC model of Hutchinson Gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 2011;8:31-45.
41.
Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C, Thompson J, Boue S, Fung HL, Sancho-Martinez I, Zhang K, Yates J 3rd, Izpisua Belmonte JC: Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 2011;472:221-225.
42.
Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A, Yuan T, Yang J, Li Y, Shi L, Guan D, Pan H, Duan S, Ding Z, Li M, Yi F, Bai R, Wang Y, Chen C, Yang F, Li X, Wang Z, Aizawa E, Goebl A, Soligalla RD, Reddy P, Esteban CR, Tang F, Liu G-H, Belmonte JCI: Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 2015;348:1160-1163.
43.
Jung Y, Brack AS: Cellular mechanisms of somatic stem cell aging. Curr Top Dev Biol 2014;107:405-438.
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