During aging, stem cells accumulate several types of molecular damage and the stem cell environment (the stem cell niche and in the blood system) undergoes various alterations. Changes of the epigenome are induced in aging stem cells in response to these aging-associated cell intrinsic and cell extrinsic alterations. This results in the deregulation of developmental signaling pathways in aging stem cells. As a consequence, important processes that are regulated by developmental pathways in stem cells are disturbed, including the control of self-renewal, differentiation and overall stem cell capacity to regenerate and maintain tissues. Epigenetic modifications in response to cell intrinsic damages and cell extrinsic alterations start early during aging and lead to progressive impairments in stem cell function, which we propose to represent the first stage of stem cell aging. We hypothesize that reduced stem cell function in turn selects for growth of subpopulations of stem cells that acquire drifts in the epigenome or mutations in genes that increase epigenome plasticity. We propose that this “second stage of stem cell aging” represents a maladaptive change driven by selection, ultimately resulting in the production of aberrantly differentiated cells in tissues. According to this model, both stages of stem cells aging lead to progressive impairments in tissue maintenance, systemic side effects (for example, increased inflammatory immune cells deriving from mutant HSCs) and to the development of aging-associated diseases. Therapeutic interventions that target epigenetic alterations during these two stages of stem cell aging may have the potential to delay the development of age-associated diseases (with modification from Ermolaeva et al. NRMCB 2018).
- Leibniz SAW grant on DNA damage responses in aging (2015-2017)
- RTG2155 - Protein Modifications in Ageing
- RTG1715 - Molecular Signatures of Adaptive Stress Responses
The accumulation of DNA damage (including telomere dysfunction) can limit the function of adult stem cells and organ maintenance (for review see Sperka et al. 2012, Behrens et al. 2014). In recent years we identified new checkpoints responding to DNA damage in stem cells.
Telomerase abrogates aneuploidy-induced senescence by alleviating telomere replication stress.
Our work identified a new role of telomere replication stress in aneuploidy-induced senescence (AIS) – a checkpoint limiting the growth of aneuploidy cells, which mechanistically remained incompletely understood. The study showed that aneuploidy induction leads to replication stress at telomeres inducing p53-dependent senescence. This mechanism of AIS was alleviated in telomerase proficient cells. In murine hematopoietic stem and progenitor cells (HSPCs), endogenous expression of telomerase was sufficient to ameliorate replication stress in response to aneuploidy induction thus facilitating the in vivo expansion of aneuploid blood cells compared to telomerase-deficient HSCs (Meena et al. 2015). These findings suggest that stem cells have an increased sensitivity to undergo aneuploidy-induced transformation since stem cells in contrast to differentiated cells express telomerase in various tissues.
Developmental pathways influence the induction of DNA damage responses (DDRs) in stem cells.
Our study on intestinal stem cells (ISCs) provided experimental evidence that the level of Wnt-signaling, which depends on the topological position of individual ISCs in niches of the basal crypts, determines the sensitivity of ISCs to undergo p53-dependent apoptosis in response to DNA damage (Tao et al. 2015). These results could have implications for the selection of damaged stem cells during aging and carcinogenesis - two processes that are characterized by increases in DNA damage in stem cells.
Differentiation inducing DNA damage checkpoints limit HSC self-renewal.
Our group identified a Batf-dependent, differentiation-inducing checkpoint, which limits the maintenance of lymphoid-biased HSCs in response to DNA damage (Wang et al. 2012). Our study stands in line with the discoveries of other groups describing a differentiation-inducing checkpoint in melanocyte stem cells in response to DNA damage (Inomata et al. 2009) as well as in myeloid-biased HSCs in response to chronic infection (Matatall et al. 2016). Interestingly, the latter study identified another member of the Batf family of transcription factors (Batf2) being required for the induction of this differentiation-inducing checkpoint in myeloid biased HSCs. Together, these findings indicate that the induction of differentiation could represent a general mechanism limiting the maintenance of tissue stem cells in response to various stress factors across different tissues.
Our current work on the accumulation of molecular damages in stem cell aging focuses on the interactions between molecular damage accumulation, metabolism, and epigenetic remodeling.
References (own publications in italics)
Behrens A, van Deursen JM, Rudolph KL, Schumacher B. Impact of genomic damage and ageing on stem cell function. Nat Cell Biol. 2014; 16:201-7. Review.
Inomata K, Aoto T, Binh NT, Okamoto N, Tanimura S, Wakayama T, Iseki S, Hara E, Masunaga T, Shimizu H, Nishimura EK. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell. 2009 Jun 12;137(6):1088-99.
Matatall KA, Jeong M, Chen S, Sun D, Chen F, Mo Q, Kimmel M, King KY. Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation. Cell Rep. 2016; 17:2584-2595.
Meena JK, Cerutti A, Beichler C, Morita Y, Bruhn C, Kumar M, Kraus JM, Speicher MR, Wang ZQ, Kestler HA, d'Adda di Fagagna F, Günes C, Rudolph KL. Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion. EMBO J. 2015; 34:1371-84.
Sperka T, Wang J, Rudolph KL. DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol. 2012; 13:579-90.
Tao S, Tang D, Morita Y, Sperka T, Omrani O, Lechel A, Sakk V, Kraus J, Kestler HA, Kühl M, Rudolph KL. Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage. EMBO J. 2015; 34:624-40
Wang J, Sun Q, Morita Y, Jiang H, Groß A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wüstefeld T, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL. Batf defines a differentiation checkpoint limiting hematopoietic stem cell self-renewal in response to DNA damage. Cell 2012, 148:1001-14.
Systemic acting factors as well as changes in metabolism and inflammatory signaling affect stem cell and organism aging but the contribution of systemic vs. intrinsic factors to stem cell aging and remains under debate (Brack and Munoz-Canovez 2016). The causes for aging-associated changes in systemic factors, metabolism and inflammation and its mechanistic consequences for aging of the organism remain incompletely understood.
Metabolism and aging.
In current studies we cooperate with Alessandro Ori and other groups from the institute to analyze the effects of dietary restriction (DR: 30% reduction) compared to ad libitum (AL) diet on the maintenance of functional stem cells during organism aging. Our initial study focused on 12 months old C57Bl-6J mice that were kept for 9 months on DR vs. AL diet (Tang et al. 2016). These experiments revealed that DR delayed early aging and improved maintenance of the repopulation capacity of HSCs, when applied to 3-12 month old mice compared to AL fed mice. However, DR impaired lymphopoiesis resulting in reduced immune function required for clearance of bacteria infections from mouse tissues (Tang et al. 2016). The observed adverse effect of DR could contribute to the limited effects of DR on lifespan extension of non-human primates despite clear evidences of improved health parameters in DR-fed primates compared to AL-fed controls (Vaughan et al. 2017).
Inflammation and aging.
Increases in inflammatory signaling have long been recognized as a hallmark of human aging and aging-associated diseases. Our previous work on aging of telomerase deficient mice revealed that telomere dysfunction elevates the expression of inflammatory cytokines and growth stimulatory factors in blood serum aging telomerase deficient mice (Ju et al. 2007). This in vivo phenotype resembled the senescence-associated secretory phenotype (SASP) of cultured cells (Coppé et al. 2008). In vivo, the induction of inflammatory signaling aggravates the myeloid skewing of hematopoiesis and impairs successful engraftment of transplanted HSCs (Ju et al. 2007).
Our future work aims to identify causal factors that may lead to changes in metabolism and in the expression of systemic acting factors/inflammatory signaling that influence metabolism and stem cell aging. Also we wish to investigate the influence of these factors on the accumulation of molecular damages and the selection of altered stem cells during aging.
References (own publications in italics)
Brack AS, Muñoz-Cánoves P. The ins and outs of muscle stem cell aging. Skelet Muscle. 2016; 6:1. Review.
Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6:2853-68.
Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007; 13:742-7.
Tang D, Tao S, Chen Z, Koliesnik IO, Gebert N, Calmes PG, Hörr V, Löffler B, Morita Y*, Rudolph KL*. * Co-Corresponding. Long-term dietary restriction improves repopulation but impairs lymphoid differentiation capacity of aging hematopoietic stem cells. J Ex Med J Exp Med. 2016; 213:535-53.
Vaughan KL, Kaiser T, Peaden R, Anson RM, de Cabo R, Mattison JA. Caloric Restriction Study Design Limitations in Rodent and Nonhuman Primate Studies. J Gerontol A Biol Sci Med Sci. 2017 Dec 12;73(1):48-53.
- EU-Adv-ERC: StemCellGerontogenes (2013-2018),
- HaematoOpt consortium of the BMBF (2015-2018),
- Leibniz SAW grant to establish a “PostdocsNetwork - Aging induced impairments of regeneration and stem cell functionality”
Epigenetic stress responses.
Our collaborative work with Julia von Maltzahn, group leader on “Stem Cells in Regeneration of Skeletal Muscle” at FLI, revealed that aging-associated epigenetic alterations contribute to the activation of developmental pathways and impairments of muscle stem cell (MuSC) self-renewal and regenerative potential during aging (Schwörer et al. 2016). We propose that aging-associated accumulation of cell intrinsic damages as well as alteration in stem cell niches and the circulatory environment lead to impairments in stem cell function that are mediated by alterations in epigenetic stress responses (e.g. after tissue injury). These constrains on stem cell function in turn promote the clonal selection of altered stem cells that gain advantages in self-renewal and proliferation in the adverse environment of an aging organism (for review of our concept see: Ermolaeva et al. 2018). Our studies showed that the epigenetic stress response of aged MuSCs is characterized by overshooting modifications leading to an enhanced opening of the chromatin and aberrant activation of Hoxa9 dependent developmental signaling pathways that have previously been implicate in MuSC aging.
Clonal selection of mutant stem cells during aging.
At age seventy, 30-50% of humans exhibit clonal hematopoiesis – originating from mutant stem or progenitor cells. This parallels with increased risk of aging-associated diseases and mortality (for review see Adams et al. 2015). There is evidence that mutant clones in blood contribute to disease development by changing immune functions. Interestingly, aging-associated clonal mutations in blood predominantly affect regulators of the epigenome. We propose that epigenetic alterations impair the functionality of stem cells during aging and thereby select for mutations that increase epigenetic plasticity and re-adaptation of stem cells to the adverse environment of aging tissues.
Our aim within the ERC project is to analyze the function of longevity and aging-associated genes in regulating stem cell aging. Several projects employed in vivo and cell culture based RNAi screens to identify genes and molecular mechanisms that affect the function of stem cells in aging mice.
Our future work concentrates on the identification of causal mechanisms that lead to the induction and/or selection of epi-/genetic changes in stem cells during aging and how this impairs the maintenance of tissues and the development of disease conditions in the aging of the organism. We will explore the possibility to improve tissue aging by altering the activity of epigenome regulators that contribute to epigenetic alterations/drifts in aging stem cells.
Adams PD, Jasper H, Rudolph KL. Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell. 2015; 16:601-12. Review.
Ermolaeva M, Ori A, Neri F, Rudolph KL. Cellular and epigenetic drivers of stem cell ageing. Nat Rev Mol Cell Biol 2018, in press. Review.
Schwoerer S, Becker F, Feller C, Baig AH, Koeber U, Henze H, Kraus JM, Xin B, Lechel A, Lipka DB, Varghese CS, Schmidt M, Rohs R, Aebersold R, Medina KL, Kestler HA, Neri F, von Maltzahn J, Tuempel S and Rudolph KL. Epigenetic stress responses induce muscle stem cell aging by Hoxa9 developmental signals. Nature. 2016; 540:428-432.
|Karl Lenhard Rudolph||+49 3641 656818||lenhard.rudolph@~@leibniz-fli.de||Group Leader|
|Friedrich Becker||+49 3641 656844||friedrich.becker@~@leibniz-fli.de||Postdoc|
|Yulin Chen||+49 3641 656844||yulin.chen@~@leibniz-fli.de||Postdoc|
|Thomas André||---||thomas.andre@~@leibniz-fli.de||Doctoral Candidate|
|Louis Charles Nabineau||+49 3641 656844||louis.nabineau@~@leibniz-fli.de||Doctoral Candidate|
|Melanie Kettering||+49 3641 656814||melanie.kettering@~@leibniz-fli.de||Research Engineer|
|Imaz Khalid||---||imaz.khalid@~@leibniz-fli.de||Master Student|
* incomplete due to Data protection