In Cell Stem Cell, a trio of reviewers has proposed five hallmarks that are specific to the aging of stem cells.
Functional rather than molecular
This review begins with a note that its classifications focus on the physical features and overall behavior rather than what is going on biochemically. This is because the hallmarks of aging are largely universal across cells; things such as genomic instability, epigenetic alterations, mitochondrial dysfunction, and loss of proteostasis affect every cell in the body, not just stem cells. Additionally, these molecular markers vary greatly across cells; while these will surely have to be dealt with in future work targeting individual populations, these reviewers are endeavoring to deliver a broad understanding rather than a detailed analysis.
Therefore, this work focuses on what stem cells do in their roles and how they survive and proliferate. They propose five key hallmarks whose changes are fundamental to stem cell aging: quiescence, self-renewal propensity, cell fates, resilience, and heterogeneity.
Quiescence
The majority of stem cells are not actively dividing [1]. Instead, they remain quiescent, sitting idly by and waiting for some event to prompt their action. Some stem cell populations are exceptions; for example, the skin consistently renews itself [2].
Quiescence can be impaired in both directions. If the quiescence is too deep, the cells are slow to wake up; this has been found to impair muscle regeneration, as the stem cells responsible for replenishing muscle tissue (MuSCs) produce too few functional progeny [3], a problem that also happens in the brain [4] and the bone marrow [5]. On the other hand, shallow quiescence leads to a failure of stem cell populations to self-renew, thus leading to stem cell exhaustion [6].
Self-renewal
Changes to self-renewal are their own hallmark according to this framework. Like quiescence, this has problems in both directions. With age, some cells, such as hemapoietic stem cells (HSCs), replicate into more stem cells that fail to properly differentiate into somatic cells, leading to a buildup of useless cells [7].
On the other hand, cells that fail to properly replicate themselves and only differentiate into somatic cells will gradually become depleted. This occurs in multiple tissues, including the brain [4], and this is linked to the senescence-related tumor suppressor p16 [8].
The reviewers note here that the relationships between stem and somatic cells have not been fully explored and may vary greatly by tissue; some differentiated cells may, for example, revert back to a stem-like state, and this ability may be impaired by aging.
Altered cell fate
This paper highlights three ways in which differentiation can go wrong with aging. First, multipotent stem cells can produce too many of one cell type and not enough of another. This has been well-documented to occur in HSCs, with a variety of age-related disorders, such as thrombosis, being the result [9].
The second problem is when stem cells start dividing into cells that they should not have become. This occurs in muscle tissue; differentiated cells that were supposed to have become functional muscle cells become fibrotic instead [10]. This also occurs in HSCs, which are known to turn into fat tissue rather than functional bone marrow with age [11].
The third problem, of course, is cancer. The reviewers note that mutations that lead to other stem cell problems also lead to cancer.
Resilience
Resilience is the ability of cells to compensate for stresses, and this ability declines with aging. For example, the intestinal stem cells of older mice are much more likely to die by apoptosis when exposed to low doses of radiation [12]. This loss of resilience also leads to death in ordinary situations such as division, a phenomenon known as mitotic catastrophe [13].
Sometimes, undesirable cells gain resilience instead of losing it, compounding the self-renewal problems. Endlessly self-renewing HSCs, for example, have been found to have better mitochondrial energy generation than their functional counterparts [14].
Heterogeneity
The distinctiveness between individual stem cells changes with age. Due to the accumulation of mutations, this heterogeneity increases during adulthood, and the reviewers note that this may increase the heterogeneity of all the other hallmarks; some stem cells may be less or more resilient and willing to self-renew than others [15].
However, with truly advanced age, only a few clones survive, and heterogeneity dramatically decreases. The literature does not yet have a complete explanation for why this occurs. The reviewers suggest that this is due to certain mutations being able to outcompete others, particularly in an aged environment [16]. The extent to which mutations drive aging is also not yet fully understood.
Like the Hallmarks of Aging, these five broad hallmarks of stem cell aging are meant to serve as a guideline for understanding both aging and rejuvenation. The effectiveness of interventions that may reverse some aspects of stem cell aging, including basic interventions, such as dietary restriction and exercise, along with more advanced approaches, such as introducing factors that affect intercellular communication or replacing stem cells in their niche, can be judged by their impacts on these hallmarks.
Literature
[1] Marescal, O., & Cheeseman, I. M. (2020). Cellular mechanisms and regulation of quiescence. Developmental cell, 55(3), 259-271.
[2] Giangreco, A., Qin, M., Pintar, J. E., & Watt, F. M. (2008). Epidermal stem cells are retained in vivo throughout skin aging. Aging cell, 7(2), 250-259.
[3] Benjamin, D. I., Brett, J. O., Both, P., Benjamin, J. S., Ishak, H. L., Kang, J., … & Rando, T. A. (2023). Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging. Cell metabolism, 35(3), 472-486.
[4] Bast, L., Calzolari, F., Strasser, M. K., Hasenauer, J., Theis, F. J., Ninkovic, J., & Marr, C. (2018). Increasing neural stem cell division asymmetry and quiescence are predicted to contribute to the age-related decline in neurogenesis. Cell reports, 25(12), 3231-3240.
[5] Hammond, C. A., Wu, S. W., Wang, F., MacAldaz, M. E., & Eaves, C. J. (2023). Aging alters the cell cycle control and mitogenic signaling responses of human hematopoietic stem cells. Blood, 141(16), 1990-2002.
[6] Chakkalakal, J. V., Jones, K. M., Basson, M. A., & Brack, A. S. (2012). The aged niche disrupts muscle stem cell quiescence. Nature, 490(7420), 355-360.
[7] Sun, D., Luo, M., Jeong, M., Rodriguez, B., Xia, Z., Hannah, R., … & Goodell, M. A. (2014). Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell stem cell, 14(5), 673-688.
[8] Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., … & Morrison, S. J. (2006). Increasing p16 INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature, 443(7110), 448-452.
[9] Poscablo, D. M., Worthington, A. K., Smith-Berdan, S., Rommel, M. G., Manso, B. A., Adili, R., … & Forsberg, E. C. (2024). An age-progressive platelet differentiation path from hematopoietic stem cells causes exacerbated thrombosis. Cell, 187(12), 3090-3107.
[10] Brack, A. S., Conboy, M. J., Roy, S., Lee, M., Kuo, C. J., Keller, C., & Rando, T. A. (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science, 317(5839), 807-810.
[11] Moerman, E. J., Teng, K., Lipschitz, D. A., & Lecka‐Czernik, B. (2004). Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR‐γ2 transcription factor and TGF‐β/BMP signaling pathways. Aging cell, 3(6), 379-389.
[12] Martin, K., Potten, C. S., Roberts, S. A., & Kirkwood, T. B. L. (1998). Altered stem cell regeneration in irradiated intestinal crypts of senescent mice. Journal of cell science, 111(16), 2297-2303.
[13] Castedo, M., Perfettini, J. L., Roumier, T., Andreau, K., Medema, R., & Kroemer, G. (2004). Cell death by mitotic catastrophe: a molecular definition. Oncogene, 23(16), 2825-2837.
[14] Watanuki, S., Kobayashi, H., Sugiura, Y., Yamamoto, M., Karigane, D., Shiroshita, K., … & Takubo, K. (2024). SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production. Cell Stem Cell, 31(8), 1145-1161.
[15] Yang, D., & de Haan, G. (2021). Inflammation and aging of hematopoietic stem cells in their niche. Cells, 10(8), 1849.
[16] Mitchell, E., Spencer Chapman, M., Williams, N., Dawson, K. J., Mende, N., Calderbank, E. F., … & Campbell, P. J. (2022). Clonal dynamics of haematopoiesis across the human lifespan. Nature, 606(7913), 343-350.
View the article at lifespan.io
