Ageing and rejuvenation of tissue stem cells and their niches

In the paper

“While clonal expansion during normal ageing has not yet been observed in mice, it has been reported in mouse models for disease61 and in physiologically aged macaques62.”

What the sources say

• Supported

  Citation 61 is attached to the mouse disease-model finding, not the separate claims about normal ageing in mice or macaques. The Results section ('Experimental validation of accelerated CH emergence in CVD'; page unavailable) reports significantly faster expansion of transplanted Tet2−/− cells in an atherosclerosis mouse model. (LLM, conf=0.92)

  cites [61] Heyde, A. et al. Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell 184, 1348–1361.e22 (2021). source
• Partly supported

  The Results report expanding clones in aged macaques but not young macaques. The expansions were observed after autologous transplantation, however, and the Discussion cautions that the finding may be specific to that setting rather than steady-state hematopoiesis. Thus the paper does not establish clonal expansion during unperturbed physiological ageing. (LLM, conf=0.84)

  cites [62] Yu, K. R. et al. The impact of aging on primate hematopoiesis as interrogated by clonal tracking. Blood 131, 1195–1205 (2018). sourceExperimental — accuracy not yet measured

In the paper

“fumarate affects young HSC function126, and might restore defects in aged HSCs.”

What the sources say

• Supported

  The Results section (‘Efficient fumarate metabolism is essential for HSC maintenance and multilineage hematopoiesis’; page not provided) states that HSCs must metabolize fumarate to sustain hematopoietic differentiation. The Discussion also describes fumarate’s detrimental impact on hematopoiesis. Citation 126 is attached to the clause about young HSC function; the suggestion about restoring defects in aged HSCs follows the citation and is not attributed to this source. (LLM, conf=0.90)

  cites [126] Guitart, A. V. et al. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions. J. Exp. Med. 214, 719–735 (2017). source

In the paper

“Cell composition of the bone marrow shifts with ageing, with the proportion of adipocytes markedly increasing, creating an inflammatory environment through secretion of soluble factors129.”

What the sources say

• Partly supported

  The Introduction and Results (‘The Adipocytic Lineage Responds to Diet and Aging’; page unavailable) support increased marrow adiposity with aging. The Results (‘DPP4 Released from MAT Inhibits Bone Healing’; page unavailable) show that adipogenic cells release DPP4, with greater release from old tibiae. The paper links this secreted factor to impaired bone healing, but does not establish that it creates an inflammatory environment. (LLM, conf=0.88)

  cites [129] Ambrosi, T. H. et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell 20, 771–784 e6 (2017). sourceExperimental — accuracy not yet measured

In the paper

“The number and function of most somatic stem cells decline with ageing, with the exception of HSCs.”

In the paper

“Ageing is characterized by a decline in all organ function and a striking increase in multi-organ diseases1.”

What the sources say

• Not checked yetcites [1] Rando, T. A. & Wyss-Coray, T. Asynchronous, contagious and digital aging. Nat. Aging 1, 29–35 (2021). source

In the paper

“The cell types that build each organ are subject to different turnover rates. Some differentiated cell types can last a lifetime, such as neurons in the brain or cardiomyocytes in the heart. Other differentiated cell types are continuously lost and replenished quickly, such as red blood cells, monocytes and epithelial cells of the skin and intestine2.”

What the sources say

• Not checked yetcites [2] Sender, R. & Milo, R. The distribution of cellular turnover in the human body. Nat. Med. 27, 45–48 (2021). source

In the paper

“The number of HSCs (defined by phenotype) increases but their function decreases with age.”

In the paper

“Stem cells can enter a state of senescence or excessive activation or can undergo aberrant differentiation (FIG. 2).”

In the paper

“For example, subpopulations of MuSCs become more ‘primed’ (that is, poised towards a myogenic fate) with ageing32, whereas others adopt a more fibrogenic state16.”

What the sources say

• Not checked yetcites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source
• Not checked yetcites [16] Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007). source

In the paper

“In the brain, old progenitors exhibit reduced differentiation dynamics during ageing45, and their fate potential is predominantly skewed towards astrocytes46.”

What the sources say

• Not checked yetcites [45] Zhao, X. et al. 4D imaging analysis of the aging mouse neural stem cell niche reveals a dramatic loss of progenitor cell dynamism regulated by the RHO-ROCK pathway. Stem Cell Rep. 17, 245–258 (2022). source
• Not checked yetcites [46] White, C. W. III et al. Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation. Proc. Natl Acad. Sci. USA 117, 22214–22224 (2020). source

In the paper

“Consistent with this possibility, machine learning models of HSC division as a function of increasing age suggested that HSC division is intrinsically regulated in young adults and old adults, but is more extrinsically regulated in middle age47.”

What the sources say

• Not checked yetcites [47] Arai, F. et al. Machine learning of hematopoietic stem cell divisions from paired daughter cell expression profiles reveals effects of aging on self-renewal. Cell Syst. 11, 640–652.e5 (2020). source

In the paper

“Thus, stem cells pools are heterogeneous, and different subpopulations arise with increasing age (FIG. 2).”

In the paper

“In muscle, MuSCs also exist as a heterogeneous quiescent population in adult mice30–33, with changes in heterogeneity with ageing32,34,35.”

What the sources say

• Not checked yetcites [30] Kuang, S., Kuroda, K., Le Grand, F. & Rudnicki, M. A. Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999–1010 (2007). source
• Not checked yetcites [31] Rocheteau, P., Gayraud-Morel, B., Siegl-Cachedenier, I., Blasco, M. A. & Tajbakhsh, S. A subpopulation of adult skeletal muscle stem cells retains all template DNA strands after cell division. Cell 148, 112–125 (2012). source
• Not checked yetcites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source
• Not checked yetcites [33] Evano, B. et al. Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation. PLoS Genet. 16, e1009022 (2020). source
• Not checked yetcites [34] Brett, J. O. et al. Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of cyclin D1. Nat. Metab. 2, 307–317 (2020). source

In the paper

“This phenomenon is ubiquitous in aged individuals, and it is probably the result of variant stem cells having a survival and proliferation advantage.”

In the paper

“Another subset of MuSCs (identified by inducible Mx1–Cre lineage tracing) is particularly resistant to stress36, perhaps also representing a population that is protected from ageing37.”

What the sources say

• Not checked yetcites [36] Scaramozza, A. et al. Lineage tracing reveals a subset of reserve muscle stem cells capable of clonal expansion under stress. Cell Stem Cell 24, 944–957.e5 (2019). source
• Not checked yetcites [37] Collins, C. A., Zammit, P. S., Ruiz, A. P., Morgan, J. E. & Partridge, T. A. A population of myogenic stem cells that survives skeletal muscle aging. Stem Cell 25, 885–894 (2007). source

In the paper

“In the brain, old age is accompanied by an increase in the number of quiescent NSCs and a decrease in their ability to activate6–8.”

What the sources say

• Not checked yetcites [6] Artegiani, B. et al. A single-cell RNA sequencing study reveals cellular and molecular dynamics of the hippocampal neurogenic niche. Cell Rep. 21, 3271–3284 (2017). source
• Not checked yetcites [7] Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019). source
• Not checked yetcites [8] Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176, 1407–1419.e14 (2019). source

In the paper

“In muscle, clonal expansion of MuSCs has been reported during tissue regeneration in response to acute injury55, but has not yet been thoroughly examined during ageing.”

What the sources say

• Not checked yetcites [55] Tierney, M. T., Stec, M. J., Rulands, S., Simons, B. D. & Sacco, A. Muscle stem cells exhibit distinct clonal dynamics in response to tissue repair and homeostatic aging. Cell Stem Cell 22, 119–127.e3 (2018). source

In the paper

“Clonal haematopoiesis is associated with a tenfold increased risk of malignancy development, thus underlying the increase in the incidence of blood cancer with ageing in humans.”

In the paper

“Niche cells in many tissues also experience drastic transcriptomic changes with ageing69, which could indirectly impair stem cell function.”

What the sources say

• Not checked yetcites [69] Tabula Muris, C. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source

In the paper

“Upregulation of cell adhesion markers in HSCs may be a direct indicator of their inflammatory state and may correlate with the bias towards myeloid cell production68.”

What the sources say

• Not checked yetcites [68] Svendsen, A. F. et al. A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood 138, 439–451 (2021). source

In the paper

“Clonal expansion has also been found in other human tissues, including skin, colon and oesophagus52–54, and is thought to be a normal, possibly ubiquitous, process that is associated with ageing in all tissues, in particular those that experience significant cellular turnover.”

What the sources say

• Not checked yetcites [52] Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019). source
• Not checked yetcites [53] Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018). source
• Not checked yetcites [54] Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015). source

In the paper

“Conversely, other types of immune cells, such as regulatory T cells, are reduced in number in aged skin11, and this might contribute to the unbalance in tissue regulation for this regenerative niche.”

What the sources say

• Not checked yetcites [11] Ge, Y. et al. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020). source

In the paper

“In humans, several stem cell types, including those of the colon and liver, have been shown to acquire somatic mutations at a steady rate during ageing60; this feature is likely universal.”

What the sources say

• Not checked yetcites [60] Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016). source

In the paper

“These ageing-dependent changes in the composition of the stem cell niche and infiltration of immune cells influence the extracellular milieu, but also impact the ageing of stem cells in a non-cell-autonomous manner (see later).”

In the paper

“In the bone marrow, ageing HSCs display increased transcriptional heterogeneity, but a set of markers is consistently upregulated with ageing (for example, the cell adhesion molecule P-selectin).”

In the paper

“The infiltration of clonally expanded T cells and B cells is also observed in the brain and other tissues with ageing in mice and humans69,71–73, and it is accentuated in age-related diseases74,75.”

What the sources say

• Not checked yetcites [69] Tabula Muris, C. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583, 590–595 (2020). source
• Not checked yetcites [71] Gross, K. M. et al. Loss of slug compromises dna damage repair and accelerates stem cell aging in mammary epithelium. Cell Rep. 28, 394–407.e6 (2019). source
• Not checked yetcites [72] Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115.e12 (2021). source
• Not checked yetcites [73] Groh, J. et al. Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat. Aging 1, 357–367 (2021). source
• Not checked yetcites [74] Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020). source

In the paper

“However, the specific changes in proliferative and differentiation capacity, the timing of decline and the type of molecular defects with ageing may differ depending on tissue and age time points.”

In the paper

“These types of analysis have revealed profound changes in the composition of the niche (that is, the proportion of different cell types other than the stem cells themselves) as well as transcriptomic shifts in specific niche cells during ageing (FIG. 2).”

In the paper

“Other signalling pathways and transcription factors implicated in inflammation signalling may also function downstream of systemic factors in stem cell niches during ageing.”

In the paper

“FOXO factors are also activated by oxidative stress and can induce interferon production in NSCs via the STING pathway93.”

What the sources say

• Not checked yetcites [93] Hwang, I. et al. Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification. Nat. Commun. 12, 640 (2021). source

In the paper

“Thus, FOXO factors may integrate systemic or paracrine signals to orchestrate transcriptional changes that maintain stem cell quiescence during ageing and regulate inflammation.”

In the paper

“Cell death is also increased in ageing HSCs, and this is dependent on the DNA-damage signalling pathway ATM96.”

What the sources say

• Not checked yetcites [96] Gutierrez-Martinez, P. et al. Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage. Nat. Cell Biol. 20, 413–421 (2018). source

In the paper

“In muscle, DNA methylation changes with ageing in MuSCs, with increased heterogeneity (accompanied by transcriptional heterogeneity), suggesting an epigenetic drift with ageing33,67.”

What the sources say

• Not checked yetcites [33] Evano, B. et al. Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation. PLoS Genet. 16, e1009022 (2020). source
• Not checked yetcites [67] Hernando-Herraez, I. et al. Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat. Commun. 10, 4361 (2019). source

In the paper

“However, the transcription factors that induce stem cell rejuvenation remain largely unknown.”

In the paper

“In the brain, expression of TET2, the enzyme responsible for the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, decreases during ageing in the hippocampal neurogenic niche97, and Tet2 knockout mimics aspects of ageing, whereas its overexpression prevents the decline in neuronal differentiation during ageing97.”

What the sources say

• Not checked yetcites [97] Gontier, G. et al. Tet2 rescues age-related regenerative decline and enhances cognitive function in the adult mouse brain. Cell Rep. 22, 1974–1981 (2018). source

In the paper

“For example, FOXO transcription factors integrate growth factors and stress signal transduction pathways, and may represent a ‘hub’ for the action of various systemic factors in stem cells in ageing brain, muscle, blood and intestine32,85–90.”

What the sources say

• Not checked yetcites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source
• Not checked yetcites [85] Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009). source
• Not checked yetcites [86] Gopinath, S. D., Webb, A. E., Brunet, A. & Rando, T. A. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Rep. 2, 414–426 (2014). source
• Not checked yetcites [87] Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009). source
• Not checked yetcites [88] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). source
• Not checked yetcites [89] Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007). source
• Not checked yetcites [90] Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008). source

In the paper

“Consistent with previous reports of the role of FOXO factors in HSC, MuSC and NSC quiescence85–90, constitutive deletion of three of the FOXO genes (FOXO1, FOXO3 and FOXO4) in the MuSC lineage during development results in the impairment of postnatal establishment of the MuSC population and a more rapid MuSC depletion with age32.”

What the sources say

• Not checked yetcites [32] Garcia-Prat, L. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat. Cell Biol. 22, 1307–1318 (2020). source
• Not checked yetcites [85] Renault, V. M. et al. FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell 5, 527–539 (2009). source
• Not checked yetcites [86] Gopinath, S. D., Webb, A. E., Brunet, A. & Rando, T. A. FOXO3 promotes quiescence in adult muscle stem cells during the process of self-renewal. Stem Cell Rep. 2, 414–426 (2014). source
• Not checked yetcites [87] Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009). source
• Not checked yetcites [88] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007). source
• Not checked yetcites [89] Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007). source
• Not checked yetcites [90] Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008). source

In the paper

“STAT3 is modified by O-linked β-N-acetylglucosamine, and this post-translational modification is lost during ageing, contributing to the ageing-dependent bias towards glia46.”

What the sources say

• Not checked yetcites [46] White, C. W. III et al. Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation. Proc. Natl Acad. Sci. USA 117, 22214–22224 (2020). source

In the paper

“The ageing skin is characterized by niche stiffening and hair shaft miniaturization, which are accompanied by defects in hair follicle stem cells (HFSCs)83,84.”

What the sources say

• Not checked yetcites [83] Xie, Y. et al. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis. Cell Stem Cell 29, 70–85.e6 (2022). source
• Not checked yetcites [84] Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021). source

In the paper

“Stem cell niches become stiffer during ageing, and they exhibit drastic changes in ECM composition.”

In the paper

“Hence, the general milieu of the niche may become more inflamed and stiffer, which may contribute to stem cell defects.”

In the paper

“Interestingly, age-dependent NSC decline can be reversed by expression of the master transcription factor for lysosomes TFEB and by nutrient deprivation64.”

What the sources say

• Not checked yetcites [64] Leeman, D. S. et al. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359, 1277–1283 (2018). source

In the paper

“Glucose metabolism is critical for MuSCs and influences histone acetylation124.”

What the sources say

• Not checked yetcites [124] Yucel, N. et al. Glucose metabolism drives histone acetylation landscape transitions that dictate muscle stem cell function. Cell Rep. 27, 3939–3955.e6 (2019). source

In the paper

“Autophagy is also required for activation out of quiescence109, and defects in autophagic activity with ageing lead to increased cell death during activation110.”

What the sources say

• Not checked yetcites [109] Tang, A. H. & Rando, T. A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 33, 2782–2797 (2014). source
• Not checked yetcites [110] White, J. P. et al. The AMPK/p27Kip1 axis regulates autophagy/apoptosis decisions in aged skeletal muscle stem cells. Stem Cell Rep. 11, 425–439 (2018). source

In the paper

“Indeed, the protein chaperone network is entirely rewired when NSCs give rise to differentiated progeny, and this rewiring is impaired during ageing112.”

What the sources say

• Not checked yetcites [112] Vonk, W. I. M. et al. Differentiation drives widespread rewiring of the neural stem cell chaperone network. Mol. Cell 78, 329–345 e9 (2020). source

In the paper

“SIRT2, another member of the sirtuin family, is necessary to prevent ageing in HSCs, and can inhibit the inflammation (inflammasome) response that occurs in old HSCs119.”

What the sources say

• Not checked yetcites [119] Luo, H. et al. Mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome regulates the functional deterioration of hematopoietic stem cell aging. Cell Rep. 26, 945–954.e4 (2019). source

In the paper

“In old quiescent MuSCs, the repressive mark trimethylated histone H3 at lysine 27 (H3K27me3) increases, whereas the activating mark trimethylated histone H3 at lysine 4 (H3K4me3) decreases65.”

What the sources say

• Not checked yetcites [65] Liu, L. et al. Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. Cell Rep. 4, 189–204 (2013). source

In the paper

“Together, these results illustrate the critical nature of chromatin regulators for long-lasting changes during ageing, and their potential to integrate extrinsic stimuli.”

In the paper

“Hence, lysosomes and autophagy, which clear damaged proteins and organelles, are both critical to maintain stem cells and ameliorate their function during ageing.”

In the paper

“In MuSCs, autophagy is essential for the maintenance of MuSC quiescence, via the process of mitophagy (degradation of damaged mitochondria), and this declines with ageing108.”

What the sources say

• Not checked yetcites [108] Garcia-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016). source

In the paper

“A comprehensive analysis of murine HSC ageing has found increased chromatin accessibility and an overall increase in transcription68.”

What the sources say

• Not checked yetcites [68] Svendsen, A. F. et al. A comprehensive transcriptome signature of murine hematopoietic stem cell aging. Blood 138, 439–451 (2021). source

In the paper

“Glycolysis and mitochondrial function also decline during ageing.”

What the sources say

• Not checked yetcites [121] Poisa-Beiro, L. et al. Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells. Sci. Rep. 10, 11597 (2020). source
• Not checked yetcites [122] Pala, F. et al. Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977 (2018). source
• Not checked yetcites [123] Hennrich, M. L. et al. Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nat. Commun. 9, 4004 (2018). source

In the paper

“Primary cultures of old quiescent NSCs also exhibit increased chromatin accessibility at genes involved in quiescence, a potential mechanism underlying deep quiescence during ageing98.”

What the sources say

• Not checked yetcites [98] Maybury-Lewis, S. Y. et al. Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age. Aging Cell 20, e13499 (2021). source

In the paper

“These age-dependent chromatin changes in HFSCs are affected by stiffening of the niche84, and could mediate the impact of external and biophysical properties on stem cells during ageing.”

What the sources say

• Not checked yetcites [84] Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021). source

In the paper

“HSC maintenance by autophagy is mediated at least in part by a membrane ubiquitin ligase called ‘MAEA’ (macrophage–erythroblast attacher), although it is not yet clear whether this mechanism contributes to HSC ageing107.”

What the sources say

• Not checked yetcites [107] Wei, Q. et al. MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells. Nat. Commun. 12, 2522 (2021). source

In the paper

“Protein homeostasis is influenced by the external milieu, and could connect cell–cell interaction and systemic factors to key cellular function for stem cells (FIG. 3).”

In the paper

“Finally, expression of lamin B1, a key component of the nuclear architecture involved in epigenomic maintenance103, declines in old NSCs, and restoration of lamin B1 expression is sufficient to increase old NSC proliferation and neurogenesis104.”

What the sources say

• Not checked yetcites [103] Guerreiro, I. & Kind, J. Spatial chromatin organization and gene regulation at the nuclear lamina. Curr. Opin. Genet. Dev. 55, 19–25 (2019). source
• Not checked yetcites [104] Bin Imtiaz, M. K. et al. Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. Cell Stem Cell 28, 967–977.e8 (2021). source

In the paper

“Quiescent MuSCs exhibit reduced energetic demands and perturbed oxidative phosphorylation during ageing122.”

What the sources say

• Not checked yetcites [122] Pala, F. et al. Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977 (2018). source

In the paper

“Finally, a particular form of autophagy — chaperone-mediated autophagy — is essential to preserve HSCs throughout the lifespan, not only by clearing proteins but also by altering lipid metabolism111.”

What the sources say

• Not checked yetcites [111] Dong, S. et al. Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature (2021). source

In the paper

“Aged MuSCs and HSCs have increased glucose use and higher levels of glycolysis121–123.”

What the sources say

• Not checked yetcites [121] Poisa-Beiro, L. et al. Glycogen accumulation, central carbon metabolism, and aging of hematopoietic stem and progenitor cells. Sci. Rep. 10, 11597 (2020). source
• Not checked yetcites [122] Pala, F. et al. Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977 (2018). source
• Not checked yetcites [123] Hennrich, M. L. et al. Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nat. Commun. 9, 4004 (2018). source

In the paper

“SIRT1 was also found to promote autophagy in quiescent MuSCs, and in this case, a loss of SIRT1 leads to a delay in MuSC activation out of quiescence — similar to what is observed in aged muscles109.”

What the sources say

• Not checked yetcites [109] Tang, A. H. & Rando, T. A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 33, 2782–2797 (2014). source

In the paper

“Other protein homeostasis mechanisms (for example, protein chaperones) play a role in stem cell ageing and could respond to changes in the external milieu.”

In the paper

“Sirtuin activity and NAD levels both decline with age116,117.”

What the sources say

• Not checked yetcites [116] Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014). source
• Not checked yetcites [117] Schultz, M. B. & Sinclair, D. A. Why NAD+ declines during aging: it’s destroyed. Cell Metab. 23, 965–966 (2016). source

In the paper

“Consistently, the H3K27me3 demethylase UTX helps maintain a youthful phenotype in HSCs, with UTX-deficient HSCs acquiring an early-ageing phenotype100.”

What the sources say

• Not checked yetcites [100] Sera, Y. et al. UTX maintains functional integrity of murine hematopoietic system by globally regulating aging-associated genes. Blood 137, 908–922 (2020). source

In the paper

“During ageing, SDF1 signalling (via CXCR4 receptors in NSCs) is reduced, and this decline is in part responsible for impaired NSC proliferation during ageing135.”

What the sources say

• Not checked yetcites [135] Zhu, C., Mahesula, S., Temple, S. & Kokovay, E. Heterogeneous expression of SDF1 retains actively proliferating neural progenitors in the capillary compartment of the niche. Stem Cell Rep. 12, 6–13 (2019). source

In the paper

“In the bone marrow, TNF (likely produced by niche cells) induces the expression of IL-27 receptor, and ablation of IL-27 receptor blunts the negative impact of ageing on HSCs76.”

What the sources say

• Not checked yetcites [76] He, H. et al. Aging-induced IL27Ra signaling impairs hematopoietic stem cells. Blood 136, 183–198 (2020). source

In the paper

“In the skin, niche stiffening and persistent hair shaft miniaturization during ageing can also contribute to HFSC ageing via a reduction in promoter bivalency in HFSCs84 and via a PIEZO1–TNF mechanism83.”

What the sources say

• Not checked yetcites [84] Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021). source
• Not checked yetcites [83] Xie, Y. et al. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-alpha axis. Cell Stem Cell 29, 70–85.e6 (2022). source

In the paper

“Although IFNγ can also have positive effects, IFNα has an overall negative impact on the brain137. Chronic inflammation and IFNα convert αNSCs into ΩNSCs, which are more quiescent138.”

What the sources say

• Not checked yetcites [137] Baruch, K. et al. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014). source
• Not checked yetcites [138] Martin-Suarez, S., Valero, J., Muro-Garcia, T. & Encinas, J. M. Phenotypical and functional heterogeneity of neural stem cells in the aged hippocampus. Aging Cell 18, e12958 (2019). source

In the paper

“Paracrine signalling is altered during ageing, and this change contributes to stem cell defects in a non-cell-autonomous manner (FIG. 3).”

In the paper

“In the central nervous system, transplantation experiments in rats indicate that ECM stiffness has a strong effect on OPC proliferation and differentiation during ageing80. OPC niche stiffness drastically increased with age, as determined by atomic force microscopy in the prefrontal cortex80. A softer niche is sufficient to restore OPC proliferation. Interestingly, niche stiffness is mediated by”

What the sources say

• Not checked yetcites [80] Segel, M. et al. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 573, 130–134 (2019). source

In the paper

“In muscle, ECM stiffness also increases with age and is associated with decreased collagen tortuosity82. These ECM changes induce MuSCs to adopt a more fibrogenic fate, thereby diminishing their myogenic potential.”

What the sources say

• Not checked yetcites [82] Stearns-Reider, K. M. et al. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16, 518–528 (2017). source

In the paper

“In the bone marrow, skeletal stem cells become inflammatory with ageing, which impedes HSC function in old mice128.”

What the sources say

• Not checked yetcites [128] Ambrosi, T. H. et al. Aged skeletal stem cells generate an inflammatory degenerative niche. Nature 597, 256–262 (2021). source

In the paper

“In the bone marrow, a specialized periarteriolar niche supports lymphoid progenitors and osteogenesis. The niche is maintained by mechanosensation, is transduced via PIEZO1 and is responsive to exercise. This niche is depleted with ageing, likely contributing to a reduced immune response81.”

What the sources say

• Not checked yetcites [81] Shen, B. et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 591, 438–444 (2021). source

In the paper

“In the skin, HFSCs exhibit significant transcriptomic changes in ECM proteins, and this is correlated with structural defects in the ageing stem cell niche11.”

What the sources say

• Not checked yetcites [11] Ge, Y. et al. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020). source

In the paper

“Thus, the deterioration and inflammation of niche cells and the lack of production of growth factors negatively impact stem cell function during ageing.”

In the paper

“Extrinsic signals from old niches appear to dominate over intrinsic function of young stem cells in transplantation experiments143,144. By contrast, signals from young niches may have only limited rejuvenation effects on old stem cells, at least for HSCs145.”

What the sources say

• Not checked yetcites [143] Carlson, B. M. & Faulkner, J. A. Muscle transplantation between young and old rats: age of host determines recovery. Am. J. Physiol. 256, C1262–C1266 (1989). source
• Not checked yetcites [144] Popplewell, L. L. & Forman, S. J. Is there an upper age limit for bone marrow transplantation? Bone Marrow Transpl. 29, 277–284 (2002). source
• Not checked yetcites [145] Kuribayashi, W. et al. Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche. J. Exp. Med. 218 (2021). source

In the paper

“During ageing, the number the of fibroadipogenic progenitors declines, and so does their ability to produce paracrine factors such as WNT1-inducible signalling pathway protein 1 (WISP1), a non-structural protein of the ECM10. This leads to diminished MuSC support and contributes to the decline in MuSC function during ageing10.”

What the sources say

• Not checked yetcites [10] Lukjanenko, L. et al. Aging disrupts muscle stem cell function by impairing matricellular WISP1 secretion from fibro-adipogenic progenitors. Cell Stem Cell 24, 433–446.e7 (2019). source

In the paper

“In muscle, quantitative proteomic studies also reveal striking remodelling in ECM during ageing66,82, and those changes can influence MuSC function.”

What the sources say

• Not checked yetcites [66] Schuler, S. C. et al. Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality. Cell Rep. 35, 109223 (2021). source
• Not checked yetcites [82] Stearns-Reider, K. M. et al. Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16, 518–528 (2017). source

In the paper

“In the bone marrow, megakaryocytes appear to show increased production of the inflammatory cytokine IL-6 (REF.78), which is modulated by both β-adrenergic signalling (from sympathetic nerves) and inducible nitric oxide synthase signalling78. Indeed, β3-adrenergic receptor agonist treatment reduces the myeloid shift of HSCs in prematurely aged mice, caused by germ line mutations in lamin A78.”

What the sources say

• Not checked yetcites [78] Ho, Y. H. et al. Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging. Cell Stem Cell 25, e6 (2019). source

In the paper

“In the brain SVZ neurogenic region, T cells can secrete interferon-γ (IFNγ), and IFNγ signalling is increased in the entire neurogenic region. NSCs respond to IFNγ by decreased proliferation, which is restored (at least in vitro) by blocking antibodies to IFNγ7.”

What the sources say

• Not checked yetcites [7] Dulken, B. W. et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571, 205–210 (2019). source

In the paper

“In the intestine, old Paneth cells, which are niche cells, can secrete increased amounts of NOTUM, which in turn attenuates WNT signalling in ISCs and contributes to stem cell dysfunction and intestinal decline132.”

What the sources say

• Not checked yetcites [132] Pentinmikko, N. et al. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature 571, 398–402 (2019). source

In the paper

“during ageing, expression of collagen type XVII α1 chain (COL17A1) decreases owing to genomic stress (UV) in a heterogeneous manner in some epithelial stem cells (epidermal stem cells) but not others141. This results in competition and advantage of the subpopulation of COL17A1-positive stem cells during ageing and expansion of these cells141.”

What the sources say

• Not checked yetcites [141] Liu, N. et al. Stem cell competition orchestrates skin homeostasis and ageing. Nature 568, 344–350 (2019). source

In the paper

“In a reconstituted slice system, increased fluid flow promotes proliferation of NSCs, and this is dependent on a sodium channel142. Thus, fluid flow could be an important component, at least in some stem cell niches, to integrate environmental changes.”

What the sources say

• Not checked yetcites [142] Petrik, D. et al. Epithelial sodium channel regulates adult neural stem cell proliferation in a flow-dependent manner. Cell Stem Cell 22, 865–878.e8 (2018). source

In the paper

“Knockout of Tfam (a central transcription factor for mitochondria) mimics ageing in NSCs, whereas enhancement of mitochondrial function by piracetam boosts neurogenesis in aged mice125.”

What the sources say

• Not checked yetcites [125] Beckervordersandforth, R. et al. Role of mitochondrial metabolism in the control of early lineage progression and aging phenotypes in adult hippocampal neurogenesis. Neuron 93, 560–573.e6 (2017). source

In the paper

“Reduced levels of IGF1 in the bone marrow environment (probably because of reduced production by old niche cells) also promote HSC ageing133, although low IGF1 levels lead to increased longevity at the organismal level. Reduced production of IGF1 by stromal fibroblasts can also impair skin stem cells during ageing134.”

What the sources say

• Not checked yetcites [133] Young, K. et al. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell 28, 1473–1482.e7 (2021). source
• Not checked yetcites [134] Maity, P. et al. Persistent JunB activation in fibroblasts disrupts stem cell niche interactions enforcing skin aging. Cell Rep. 36, 109634 (2021). source

In the paper

“While many studies have focused on the role of local niche factors in regulating stem cell function, tissue crosstalk and communication at the system level are also important (FIG. 3). Here we discuss how stem cells in one tissue are influenced by long-range interactions from other tissues and systems altogether”

In the paper

“Alterations in the diet, particularly dietary restriction, have long been used to delay the ageing process206,207.”

What the sources say

• Not checked yetcites [206] McCay, C. M., Cromwell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon ultimate body size. J. Nutr. 10, 63–79 (1935). source
• Not checked yetcites [207] McDonald, R. B. & Ramsey, J. J. Honoring Clive McCay and 75 years of calorie restriction research. J. Nutr. 140, 1205–1210 (2010). source

In the paper

“While dietary restriction and related regimens extend lifespan and healthspan, a key question is whether they have a ‘rejuvenating’ effect and reverse ageing features in already old individuals.”

What the sources say

• Not checked yetcites [206] McCay, C. M., Cromwell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon ultimate body size. J. Nutr. 10, 63–79 (1935). source
• Not checked yetcites [207] McDonald, R. B. & Ramsey, J. J. Honoring Clive McCay and 75 years of calorie restriction research. J. Nutr. 140, 1205–1210 (2010). source

In the paper

“Collectively, these studies indicate that dietary restriction and even complete fasting have a beneficial effect on stem cell pools.”

In the paper

“Thus, dietary restriction has a beneficial effect on stem cell function, but may not affect all stem cell niches (or all cells in the niche) in the same manner.”

In the paper

“However, old HSCs seem to be resistant to the effect of exercise201, although the HSC niche and lymphoid progenitors can respond positively to exercise81.”

What the sources say

• Not checked yetcites [81] Shen, B. et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature 591, 438–444 (2021). source

In the paper

“For example, cyclical expression of OSKM in all tissues of middle-aged mice improves migration of a subtype of newly born hippocampal cells, and this is associated with improved cognitive function229.”

What the sources say

• Not checked yetcites [229] Rodriguez-Matellan, A., Alcazar, N., Hernandez, F., Serrano, M. & Avila, J. In vivo reprogramming ameliorates aging features in dentate gyrus cells and improves memory in mice. Stem Cell Rep. 15, 1056–1066 (2020). source