Stem Cell Exhaustion
Today we will take a look at one of the reasons we are thought to age: Stem Cell Exhaustion.
What do stem cells do?
Stem cells are essential for maintaining the body’s ability to repair and regenerate tissues. These unique cells can divide and produce specialized cell types, replacing damaged or dying cells and supporting tissue growth.
Stem cells are found in many parts of the body. They are in bone marrow, muscles, organs, and skin. These cells are important for keeping organs healthy and working well throughout life [1].
One important feature of stem cells is their ability to remain in a state of readiness. This “standby mode” is called quiescence. They remain in quiescence until signals tell them to divide and specialize.
This balance between resting and active helps keep stem cell reserves for future use. It also allows for quick responses to repair needs.
Stem cells help prevent organ decline and contribute to long-term health by sustaining tissue balance [1].
Stem cells are broadly divided into two types. There are Embryonic stem cells which can develop into any cell type in the body. These stem cells are much more flexible in terms of what types of cells they can turn into. Through a series of changes they give rise to the many specialized stem cell populations in our body.
There are also adult stem cells that are more specialized and can only regenerate specific tissues. Adult stem cells, such as those in the blood and bone marrow, are crucial for producing blood and immune cells. Mesenchymal stem cells help repair bone, cartilage, and fat tissues. Neural stem cells support brain function and cognitive health [1].
The ability of stem cells to sustain tissue repair declines with age. As we age, stem cells experience stress, accumulate damage, and lose their capacity to regenerate effectively. This process, known as stem cell exhaustion, is now recognized as a hallmark of aging.
It impairs tissue maintenance and increases disease risk, including anemia, osteoporosis, and neurodegenerative conditions.
Understanding why this decline happens and creating treatments to fight it are important goals for the field [2].
Stem cell exhaustion interacts with other aging hallmarks
Stem cell exhaustion is driven by multiple biological processes that gradually impair stem cells’ ability to function effectively. Over time, stem cells face internal and external stresses. These stresses can harm their genetic stability, metabolic function, and ability to repair damage [2].
A close look at these mechanisms helps us understand why stem cells decline as we age. It also highlights opportunities to create therapies to combat this process.
DNA damage and mutations
One of the primary causes of stem cell exhaustion is the build up of DNA damage. Stem cells are exposed to environmental factors such as radiation, toxins, and metabolic byproducts that generate reactive oxygen species. These reactive molecules cause oxidative stress that damages DNA, proteins, and cellular membranes.
Although stem cells possess repair mechanisms to fix DNA damage, these systems become less efficient with age. This then allows errors to accumulate over time leading to genomic instability [3].
DNA mutations build up over time reducing the ability of stem cells to regenerate. It also raises the risk of abnormal cell growth and cancer.
As their ability to maintain genetic stability declines, stem cells may enter a state of senescence. Unlike quiescence, senescence is a state in which they stop dividing altogether. This process serves as a protective mechanism to prevent damaged cells from propagating. However, it also leads to the gradual depletion of functional stem cells [3].
Epigenetic alterations
Stem cell exhaustion is influenced by epigenetic alterations that alter gene expression without modifying the genetic code. Mechanisms of epigenetics, like DNA methylation and histone changes, control which genes are on or off. These systems determine the identity and function of stem cells [4].
With age, these epigenetic patterns become disrupted, leading to the incorrect activation or silencing of genes. For example, DNA methylation can turn off genes that help with DNA repair or control the cell cycle. This can impair stem cells’ ability to keep tissues and organs healthy.
Similarly, changes in histone modifications can alter chromatin structure. These make it more difficult for transcription factors to access DNA and activate necessary genes [4].
These epigenetic alterations lock stem cells into dysfunctional states, reducing their flexibility and repair capacity. Changes in chromatin organization can lead to a loss of cell identity. This may cause stem cells to lose their ability to become specialized cell types. This process accelerates tissue decline and limits the effectiveness of repair mechanisms [4].
DNA damage and epigenetic changes create a feedback loop that reinforces stem cell exhaustion. As cells lose their ability to repair and manage gene expression, they struggle to keep tissue healthy.
Metabolic dysfunction and mitochondrial decline
Metabolic dysfunction is key to stem cell exhaustion. As cells age, they struggle to produce energy efficiently. Mitochondria, often called the cell’s powerhouses, generate adenosine triphosphate (ATP), which fuels cellular activities.
Over time, mitochondrial dysfunction reduces energy output and increases harmful byproducts such as reactive oxygen species. These byproducts cause damage to proteins, lipids, and DNA. This further impairs cellular processes and accelerates stem cell aging [5].
Metabolic pathways, especially AMP-activated protein kinase (AMPK) and sirtuins like SIRT1, play key roles in energy balance. They also help manage stress responses in stem cells.
AMPK acts as a sensor for low energy levels, activating pathways that restore ATP production and repair cellular damage. SIRT1, on the other hand, influences gene expression, promotes healthy mitochondria, and protects cells from damage.
With age, the activity of these pathways declines, leaving stem cells vulnerable to energy depletion and metabolic stress. This means that aging stem cells struggle to balance self-renewal and differentiation. This leads to exhaustion and less ability to regenerate [5-6].
Inflammaging and chronic inflammation
Inflammaging is a term for the chronic low-grade inflammation that accompanies aging. This smoldering background of inflammation speeds up stem cell exhaustion.
Over time, the immune system produces elevated levels of inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). These molecules create inflammation that disrupts normal stem cell signaling and function [7-9].
Inflammatory cytokines interfere with signaling pathways that regulate stem cell quiescence and activation. For example, TNF-α can harm blood stem cells. It encourages these cells to specialize into a new cell type instead of self-renew. This process reduces the number of stem cells available from the stem cell pool.
IL-6 is a key cytokine that helps myeloid cells grow while reducing lymphoid cells. This causes imbalances in the immune system. Chronic exposure to these signals increases oxidative stress, accelerates DNA damage, and promotes senescence. These things further contribute to stem cell dysfunction [9].
The pro-inflammatory environment also disrupts the stem cell niche, a supportive enclosed pocket required for stem cell maintenance. The niche becomes less effective in aged tissues at shielding stem cells from inflammatory signals, speeding up their decline.
This creates a feedback loop where inflammation promotes stem cell exhaustion and exhausted stem cells fail to repair tissues. This perpetuates damage and dysfunction [8].
Telomere shortening and senescence
Telomeres, the protective caps at the ends of chromosomes, are critical for preserving genetic stability during cell division. Telomere attrition occurs each time a cell divides.
In stem cells, mechanisms like telomerase activity help replenish telomere length, but this capacity diminishes with age. Once telomeres become critically short, cells enter a state of senescence or undergo programmed cell death (apoptosis) [10].
Senescent stem cells lose their ability to divide and contribute to tissue repair. They also secrete inflammatory factors that further damage the surrounding niche. This condition, the senescence-associated secretory phenotype (SASP), amplifies chronic inflammation and accelerates tissue aging.
Telomere erosion not only limits repair potential but also makes stem cells more prone to DNA damage. This worsens the effects of oxidative stress and metabolic problems [11-12].
Telomere attrition acts as a biological clock, signaling when cells have reached the end of their lifespan. This mechanism helps stop damaged cells from dividing, but it also slowly reduces the number of healthy stem cells. This is especially true in tissues that need constant renewal, like the skin, gut, and blood.
Changes in the stem cell niche
The stem cell niche is a specialized environment that helps stem cells work. It is important for keeping a balance between rest, activation, and change [13].
Unfortunately, aging contributes to this niche’s significant decline, contributing to stem cell exhaustion. The bone marrow niche is where blood stem cells are housed. This undergoes structural and functional changes that reduce its ability to support stem cell maintenance [14].
One notable shift is the conversion of supportive stromal cells into inflammatory fat cells. As stromal cells lose their self-renewal potential, they are increasingly replaced by fat cells. These fat cells then start to secrete inflammatory signals.
This transformation alters the composition of the niche, creating a pro-inflammatory environment. This disrupts stem cell signaling and impairs its ability to regenerate. This loss of structural support and growth factors from stromal cells further exacerbates stem cell decline [15-16].
Aged niches also accumulate oxidative stress and DNA damage, weakening the ability of niche cells to provide protective signals. These changes affect stem cells’ ability to stay quiescent. This forces them to activate and multiply more often, which accelerates exhaustion [12].
Stem cell exhaustion in specific tissue types
Stem cell exhaustion affects a number of tissues differently.
Blood stem cells
Blood stem cells produce all blood and immune cells throughout life. As these cells age, their ability to generate new blood cells declines. This leads to reduced immunity and an increased risk of anemia.
Older blood stem cells often produce more myeloid cells than lymphoid cells. This imbalance can weaken the immune response. This reduces the diversity of immune cells, leaving the body vulnerable to infections and inflammatory conditions [17].
Aging blood stem cells gather DNA damage and epigenetic changes. This hurts their ability to renew themselves and specialize properly. These defects increase the risk of developing blood cancers and leukemia.
The bone marrow niche’s decline also exacerbates blood stem cell dysfunction. This is due to its failure to provide the necessary signals to maintain healthy stem cell populations.
Neural stem cells
Neural stem cells reside in the brain and are essential for generating new neurons and supporting cognitive function. Aging significantly reduces neural stem cell activity, contributing to a decline in the production of new nerve cells (neurogenesis).
This is linked to cognitive decline and issues with memory. It also carries an increased risk for neurodegenerative diseases such as Alzheimer’s and Parkinson’s [18].
Factors such as inflammation, oxidative stress, and changes in metabolic signaling influence the decline of neural stem cells. Chronic inflammation in the brain often happens with microglial activation. It creates a harmful environment that affects the function of neural stem cells.
Additionally, mitochondrial dysfunction reduces the energy needed for neurogenesis, further limiting stem cell activity [19].
In Alzheimer’s disease, the loss of neural stem cells contributes to the buildup of amyloid plaques and tau tangles [20-21]. In Parkinson’s disease, the decline in dopamine producing neurons is linked to impaired neural stem cell replacement [22].
Mesenchymal stem cells
Mesenchymal stem cells (MSCs) are multipotent cells found in bone marrow, fat, and other tissues. They play a critical role in maintaining skeletal integrity and promoting wound healing.
Unfortunately with age, MSCs experience a decline in number and function, reducing their ability to repair bone and cartilage. This decline contributes to age-related conditions such as osteoporosis, in which bones become brittle and prone to fractures.
It also leads to slower wound healing, as these cells are less effective in coordinating tissue regeneration [23].
Metabolic dysfunction, oxidative stress, and inflammatory signals within their niche influence MSC decline. MSCs often exhibit reduced growth rates in aging tissues and impaired differentiation capacity. This limits their ability to form new bone or cartilage.
Additionally, changes in the extracellular matrix surrounding MSCs further restrict their ability to migrate and interact with damaged tissues.
Researchers are exploring therapies that restore MSC activity. This includes targeting inflammation, metabolic pathways, and extracellular signaling to rejuvenate MSCs [24].
Muscle stem cells (satellite cells)
Muscle stem cells, or satellite cells, are essential for muscle repair and regeneration. These cells are found in skeletal muscle. They activate when there is injury or stress and divide to create new muscle fibers.
With age, satellite cells become less responsive to activation signals, leading to diminished muscle regeneration. This decline greatly contributes to sarcopenia, a condition where people lose muscle mass and strength. This loss raises the risk of frailty and physical disability [25].
Aging satellite cells become fewer in number and have impaired self-renewal capacity. They also experience disruptions in signaling pathways, including decreased activation of growth factors and increased inflammatory signals that interfere with regeneration.
Mitochondrial dysfunction and oxidative stress further compromise their ability to maintain energy balance. This makes it harder for these cells to respond effectively to tissue damage [25].
New treatments, like gene editing and stem cell factors, aim to help satellite cells work better. They also aim to promote muscle repair in older adults [26].
Therapeutic approaches
To tackle the problem of stem cell exhaustion researchers are exploring a number of approaches.
Lifestyle Interventions
Lifestyle changes, such as exercise and dietary strategies, have shown promise in improving stem cell function and delaying exhaustion.
Regular physical activity has been demonstrated to enhance stem cell growth, particularly in muscle and bone tissues. Exercise stimulates blood flow, increases oxygen delivery, and activates signaling pathways that promote cell growth and repair. This supports muscle regeneration and lowers the risk of muscle wastage [27-29].
Caloric restriction and intermittent fasting have also been studied for their effects on stem cell health. These dietary interventions reduce inflammation, lower oxidative stress, and activate metabolic pathways that improve cellular repair.
Caloric restriction stimulates AMPK and SIRT1 activity, enhancing mitochondrial function and promoting DNA repair mechanisms. Fasting can boost the production of stem cells in the gut and immune system. This helps with tissue maintenance and strengthens immune resilience [30].
Drugs for stem cell exhaustion
Drug based approaches offer promising strategies to combat stem cell exhaustion by targeting cellular damage, inflammation, and metabolic dysfunction. Senolytics, a class of drugs designed to eliminate senescent cells, have gained attention for their ability to rejuvenate tissues.
Senescent cells accumulate with age and release inflammatory molecules that damage surrounding tissues and impair stem cell function. By selectively clearing these cells, senolytics reduce inflammation and promote tissue regeneration, creating a more supportive environment for stem cell activity [31-32].
Another approach focuses on boosting mitochondrial function using NAD+ precursors. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme essential for energy production and DNA repair. Levels of NAD+ decline with age, contributing to mitochondrial dysfunction and metabolic stress.
Taking NAD+ precursors like nicotinamide riboside or nicotinamide mononucleotide has helped restore mitochondrial health. It has also improved stem cell function in preclinical studies [33-35].
Drugs like metformin and resveratrol also show potential for improving metabolic health and enhancing stem cell longevity. Metformin, commonly used to treat diabetes, activates AMPK, a key regulator of energy balance, and reduces oxidative stress.
Resveratrol, a compound found in grapes, activates SIRT1, which supports mitochondrial function and reduces inflammation. Both compounds have demonstrated anti-aging effects, making them promising candidates for preserving stem cell health [36-37].
Gene editing and epigenetic changes
Gene editing technologies have opened new possibilities for repairing genetic damage and restoring the function of aged stem cells. CRISPR-Cas9, a gene-editing tool, allows scientists to modify DNA sequences, correcting mutations that impair cell function [38].
This technology can potentially address inherited diseases and age-related genetic damage, restoring stem cells’ ability to regenerate tissues.
Epigenetic changes, which regulate gene expression, are also being explored to reverse stem cell aging [4]. Histone modification and DNA methylation adjustments can reset gene expression patterns. This could be used to promote a more youthful state in aged cells [39].
Reprogramming aged cells into induced pluripotent stem cells (iPSCs) is another possible solution. This approach restores their ability to change into various cell types. iPSCs could be a renewable source of healthy stem cells that can be used for transplantation and tissue repair [40].
Researchers are also investigating partial reprogramming, which rejuvenates aged cells without completely erasing their identities. This may allow for targeted restoration of function in specific tissues [41-42].
Stem cell-based therapies
Stem cell-based therapies remain a cornerstone of regenerative medicine, offering direct tissue repair and restoration solutions.
Blood stem cell transplantation has been widely used to treat blood disorders, including leukemia and anemia. This therapy replaces damaged blood-forming cells with healthy ones. This helps restore normal blood cell production and immune function. [43].
MSC transplantation is another promising approach for repairing bone, cartilage, and connective tissues. MSCs secrete growth factors and anti-inflammatory molecules that promote tissue regeneration and modulate immune responses. Clinical trials continue to explore their effectiveness in treating osteoarthritis, heart disease, and autoimmune disorders [44-45].
Induced pluripotent stem cells (iPSCs) represent an innovative advancement in stem cell therapies. These cells are reprogrammed from adult cells to regain pluripotency, allowing them to change into any cell type. iPSCs provide a tailored and potentially limitless source of stem cells.
While stem cell transplantation holds significant potential, challenges like immune rejection, production at scale, and safety concerns remain [46].
Advances in gene editing and materials are being integrated into these therapies to enhance their effectiveness and reliability. Together, these approaches provide a varied strategy for addressing stem cell exhaustion [47].
Stem cell-conditioned media (secretome therapy)
Stem cell-conditioned media, often called secretome therapy, uses the self-renewing properties of stem cells without direct transplantation.
This approach relies on the active molecules secreted by stem cells, including growth factors, cytokines, and extracellular vesicles. This promotes healing and reduces inflammation. These secreted components influence surrounding cells, enhancing tissue repair and modulating immune responses [48-49].
One main benefit of conditioned media is that it has a lower risk of immune rejection. It also has a lower risk of tumor growth compared to live-cell therapies. This makes it a more accessible and scalable option for therapeutic use.
Conditioned media has shown promise in heart tissue repair [50], protecting the brain, and wound healing [48]. It has been demonstrated to improve blood vessel formation and reduce tissue damage following heart attacks. In neurological studies, it has shown the ability to protect neurons. It may also help recovery from stroke and neurodegenerative diseases [51].
For wound healing, growth factors and cytokines in the media help cells move, produce collagen, and remodel tissue. This makes it a useful tool for skin regeneration [48].
Triggering a stress response as a treatment
Stress erythropoiesis provides a useful model for understanding how stem cells respond to injury and disease. It describes how the body quickly makes more red blood cells when faced with anemia or stress.
This process relies on activating progenitor cells primed to produce red blood cells. It highlights the potential for targeted therapies that stimulate specific stem cell populations [52].
Enhancing this process has been explored as a therapeutic strategy for addressing anemia and blood disorders. Treatments that can trigger this stress response can help make more red blood cells. These include hormones and growth factors from stem cells. They can also improve recovery after blood loss or bone marrow failure.
Researchers want to use this stress mechanism to create therapies. These therapies will help improve the ability of blood stem cells to regenerate. They also aim to tackle the decline in blood cell production that comes with age [52].
Challenges in therapeutic development
Despite advances in stem cell research, translating therapies into clinical practice remains challenging. One big challenge is the variation in how stem cells behave.
These differences come from the donor sources, culture conditions, and genetic backgrounds. This makes it more difficult to standardize treatments and ensure consistent outcomes [53].
Standardizing therapy development is essential to address these issues. Researchers are working to create protocols for isolating, expanding, and modifying stem cells to maintain their therapeutic potential.
Fortunately, advances in quality control and manufacturing methods are happening. These changes are helping to make sure that therapies are safer and more effective for clinical use [53].
Complexity of pathways and regulation
Stem cell function is governed by intricate signaling networks coordinating quiescence, activation, and differentiation. These pathways keep stem cells inactive when they are not needed. However, they can quickly become active when repair or regeneration is needed [54].
Key regulatory pathways include Wnt, Notch, and TGF-β signaling, which guide stem cell fate decisions. There is a lot of Crosstalk between these pathways which adds complexity. This makes it challenging to design therapies that target a single mechanism without unintended consequences.
For example, stimulating one pathway to promote regeneration may suppress another, reducing stem cell survival. Research continues to explore methods to fine-tune these pathways. This will help control stem cell activity better without triggering exhaustion or dysfunction [55-56].
Ethical and safety concerns
Ethical considerations are central to developing stem cell therapies. Using embryonic stem cells raises questions about the ethics of getting cells from embryos. This has led researchers to focus more on induced pluripotent stem cells (iPSCs) as an alternative
However, iPSCs carry safety risks, including the potential for tumor formation due to their rapid growth [57].
Gene editing technologies, such as CRISPR, also present ethical challenges. They provide powerful tools to fix genetic defects. However, there are concerns about unexpected side effects and changes that can be passed down. This raises questions about the long-term safety and ethics of altering the human genome [58].
To address these concerns, regulatory frameworks emphasize rigorous preclinical testing, transparency in research, and public dialogue to build trust. Ensuring that therapies adhere to ethical guidelines while advancing scientific innovation remains a delicate balance.
Regulatory hurdles
The development and approval of stem cell therapies face significant regulatory challenges. These treatments require extensive preclinical testing before progressing to clinical trials.
Regulatory agencies like the FDA need lots of data on dosing, manufacturing consistency, and long-term effects. This can delay approvals and raise costs significantly [59-60].
Standardization is another obstacle, as variations in cell culture conditions, donor sources, and processing techniques can affect therapeutic outcomes. Establishing uniform protocols and quality control measures is essential for ensuring consistency and production at scale.
Clinical trials for stem cell therapies often face additional scrutiny. This is because of potential risks like immune rejection, tumor formation, and unusual responses [59]. As a result, researchers must demonstrate therapeutic effectiveness and long-term safety in diverse patient populations [60].
Collaboration between scientists, regulatory bodies, and companies is critical to overcoming these hurdles and bringing stem cell therapies to broader clinical use.
Future directions and emerging strategies
Advances in gene editing technologies, particularly CRISPR, are reshaping the future of stem cell research and therapies.
CRISPR enables precise edits to DNA. It may help fix genetic mutations that build up with age or cause inherited conditions. This approach can restore normal function in exhausted stem cells by repairing damaged genes or removing harmful mutations [61].
The ability to customize gene-editing treatments for each patient is personalized medicine. This means that therapies are tailored to fit a person’s specific genetic profile.
Despite its promise, gene editing faces challenges, including concerns about off-target effects that may alter healthy DNA sequences. Researchers continue to develop techniques to improve precision and reduce risks.
Current efforts focus on combining CRISPR with other technologies. This includes epigenetic therapies to fine-tune gene expression. This may help cells rejuvenate without permanently changing the genome [62].
Biomaterials and tissue engineering offer innovative tools to enhance stem cell-based therapies. Biologically compatible scaffolds made from synthetic or natural materials provide structural support, helping stem cells integrate into damaged tissues and improving their survival. These scaffolds mimic the extracellular matrix, promoting cell attachment, growth, and differentiation.
Controlled-release systems in these materials provide growth factors and cytokines. This helps to stimulate repair and reduce inflammation [63].
Tissue engineering strategies are being tested for bone, cartilage, and skin repair applications, with promising results. Researchers can create functional tissues that restore structural integrity and biological function by combining stem cells with these materials. These approaches benefit treating injuries and degenerative diseases where traditional therapies may fall short [47].
Artificial extracellular vesicles represent a cutting-edge approach to delivering therapeutic molecules without using live cells. These vesicles mimic the natural ability of extracellular vesicles to transfer proteins, RNA, and other active compounds between cells. By engineering vesicles to carry specific therapeutic cargo, researchers can precisely target damaged tissues and signaling pathways [64].
Artificial vesicles can be customized for different conditions, such as reducing inflammation, promoting regeneration, or modulating immune responses. Because they do not contain living cells, they present fewer safety risks, including immune rejection and tumor formation. As research advances, artificial vesicles may provide scalable and cost-effective solutions for regenerative medicine [64].
Combining drugs, gene editing, and biomaterials is emerging as a powerful strategy to address stem cell exhaustion. These therapies target multiple mechanisms simultaneously, offering synergistic effects that enhance regenerative potential.
For example, using NAD+ precursors can improve mitochondrial function. Combining this with CRISPR gene editing could help repair DNA damage [65].
Integrating these new materials with drug treatments also allows for sustained delivery of therapeutic agents. This combination approach leverages the strengths of each therapy, creating flexible solutions tailored to specific conditions [63].
Inflammaging, the chronic low-grade inflammation associated with aging, is a key factor contributing to stem cell exhaustion. Future research aims to deepen our understanding of the molecular mechanisms driving inflammaging and identify biomarkers that predict risk of inflammation-related decline [66].
Therapies targeting inflammaging focus on reducing pro-inflammatory cytokines, clearing senescent cells, and modulating immune responses. Preclinical studies have shown promise in anti-inflammatory drugs, senolytics, and dietary interventions such as fasting and caloric restriction.
By addressing inflammation at its source, researchers hope to preserve stem cell function and delay age-related diseases [67].
Emerging strategies also involve identifying genetic and epigenetic regulators of inflammaging, providing new targets for drug development. Advances in this field may lead to earlier interventions and more personalized therapies, improving health outcomes as people age.
Stem cell exhaustion is a key part of aging. However, new science and technology offer ways to tackle this issue. By using new therapies and studying aging further, researchers are building a path to healthy longer lives.
Literature
[1] Bueno, V. Stem Cell Exhaustion. Cellular and Molecular Aspects of Ageing 2024, 77–86.
[2] Chaudhary, J.K.; Rath, P.C. Stem Cells and Aging. Models, Molecules and Mechanisms in Biogerontology: Cellular Processes, Metabolism and Diseases 2020, 213–234.
[3] Vitale, I.; Manic, G.; De Maria, R.; Kroemer, G.; Galluzzi, L. DNA Damage in Stem Cells. Mol Cell 2017, 66, 306–319.
[4] Ren, R.; Ocampo, A.; Liu, G.H.; Izpisua Belmonte, J.C. Regulation of Stem Cell Aging by Metabolism and Epigenetics. Cell Metab 2017, 26, 460–474.
[5] Mansilla, E.; Díaz Aquino, V.; Zambn, D.; Marin, G.H.; Mártire, K.; Roque, G.; Ichim, T.; Riordan, N.H.; Patel, A.; Sturla, F.; et al. Could Metabolic Syndrome, Lipodystrophy, and Aging Be Mesenchymal Stem Cell Exhaustion Syndromes? Stem Cells Int 2011, doi:10.4061/2011/943216.
[6] Rajagopalan, K.S.; Kazeminia, S.; Glasstetter, L.M.; Farahani, R.A.; Zhu, X.Y.; Tang, H.; Jordan, K.L.; Chade, A.R.; Lerman, A.; Lerman, L.O.; et al. Metabolic Syndrome Induces Epigenetic Alterations in Mitochondria-Related Genes in Swine Mesenchymal Stem Cells. Cells 2023, 12, 1274.
[7] López-Otín, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. Hallmarks of Aging: An Expanding Universe. Cell 2023, 186, 243–278.
[8] Bogeska, R.; Mikecin, A.M.; Kaschutnig, P.; Fawaz, M.; Büchler-Schäff, M.; Le, D.; Ganuza, M.; Vollmer, A.; Paffenholz, S. V.; Asada, N.; et al. Inflammatory Exposure Drives Long-Lived Impairment of Hematopoietic Stem Cell Self-Renewal Activity and Accelerated Aging. Cell Stem Cell 2022, 29, 1273-1284.e8.
[9] Clapes, T.; Lefkopoulos, S.; Trompouki, E. Stress and Non-Stress Roles of Inflammatory Signals during HSC Emergence and Maintenance. Front Immunol 2016, 7.
[10] Fathi, E.; Charoudeh, H.N.; Sanaat, Z.; Farahzadi, R. Telomere Shortening as a Hallmark of Stem Cell Senescence. Stem Cell Investig 2019, 6, 7.
[11] Allen, N.D.; Baird, D.M. Telomere Length Maintenance in Stem Cell Populations. Biochim Biophys Acta Mol Basis Dis 2009, 1792, 324–328.
[12] Zhang, J.; Ju, Z. Telomere, DNA Damage, and Oxidative Stress in Stem Cell Aging. Birth Defects Res C Embryo Today 2010, 90, 297–307.
[13] Mannino, G.; Russo, C.; Maugeri, G.; Musumeci, G.; Vicario, N.; Tibullo, D.; Giuffrida, R.; Parenti, R.; Lo Furno, D. Adult Stem Cell Niches for Tissue Homeostasis. J Cell Physiol 2022, 237, 239–257.
[14] Cain, T.L.; Derecka, M.; McKinney-Freeman, S. The Role of the Haematopoietic Stem Cell Niche in Development and Ageing. Nature Reviews Molecular Cell Biology 2024 26:1 2024, 26, 32–50.
[15] Farkhondeh, T.; Llorens, S.; Pourbagher-Shahri, A.M.; Ashrafizadeh, M.; Talebi, M.; Shakibaei, M.; Samarghandian, S. An Overview of the Role of Adipokines in Cardiometabolic Diseases. Molecules 2020, 25.
[16] Li, Y.; Jin, D.; Xie, W.; Wen, L.; Chen, W.; Xu, J.; Ding, J.; Ren, D. PPAR-γ and Wnt Regulate the Differentiation of MSCs into Adipocytes and Osteoblasts Respectively. Curr Stem Cell Res Ther 2017, 13, 185–192..
[17] de Haan, G.; Lazare, S.S. Aging of Hematopoietic Stem Cells. Blood 2018, 131, 479–487.
[18] Nicaise, A.M.; Willis, C.M.; Crocker, S.J.; Pluchino, S. Stem Cells of the Aging Brain. Front Aging Neurosci 2020, 12, 563285.
[19] Silva-Vargas, V.; Crouch, E.E.; Doetsch, F. Adult Neural Stem Cells and Their Niche: A Dynamic Duo during Homeostasis, Regeneration, and Aging. Curr Opin Neurobiol 2013, 23, 935–942.
[20] Coronel, R.; Palmer, C.; Bernabeu-Zornoza, A.; Monteagudo, M.; Rosca, A.; Zambrano, A.; Liste, I. Physiological Effects of Amyloid Precursor Protein and Its Derivatives on Neural Stem Cell Biology and Signaling Pathways Involved. Neural Regen Res 2019, 14, 1661–1671.
[21] Bernabeu-Zornoza, A.; Coronel, R.; Palmer, C.; Monteagudo, M.; Zambrano, A.; Liste, I. Physiological and Pathological Effects of Amyloid-β Species in Neural Stem Cell Biology. Neural Regen Res 2019, 14, 2035–2042.
[22] Liu, G.H.; Qu, J.; Suzuki, K.; Nivet, E.; Li, M.; Montserrat, N.; Yi, F.; Xu, X.; Ruiz, S.; Zhang, W.; et al. Progressive Degeneration of Human Neural Stem Cells Caused by Pathogenic LRRK2. Nature 2012 491:7425 2012, 491, 603–607.
[23] Fehrer, C.; Lepperdinger, G. Mesenchymal Stem Cell Aging. Exp Gerontol 2005.
[24] Singer, N.G.; Caplan, A.I. Mesenchymal Stem Cells: Mechanisms of Inflammation. Annual Review of Pathology: Mechanisms of Disease 2011, 6, 457–478.
[25] Jiang, H.; Liu, B.; Lin, J.; Xue, T.; Han, Y.; Lu, C.; Zhou, S.; Gu, Y.; Xu, F.; Shen, Y.; et al. MuSCs and IPCs: Roles in Skeletal Muscle Homeostasis, Aging and Injury. Cellular and Molecular Life Sciences 2024 81:1 2024, 81, 1–18.
[26] Yingao, X.; Jianda, K.; Yun, C.; Zhilin, L.; Peng, X. Biological Mechanism of Satellite Cell Aging in Skeletal Muscles and Potential Coping Strategies. Chinese Journal of Tissue Engineering Research 2024, 28, 4094.
[27] Guo, Q.; Luo, Q.; Song, G. Control of Muscle Satellite Cell Function by Specific Exercise-Induced Cytokines and Their Applications in Muscle Maintenance. J Cachexia Sarcopenia Muscle 2024, 15, 466–476.
[28] Rayagiri, S.S.; Ranaldi, D.; Raven, A.; Mohamad Azhar, N.I.F.; Lefebvre, O.; Zammit, P.S.; Borycki, A.G. Basal Lamina Remodeling at the Skeletal Muscle Stem Cell Niche Mediates Stem Cell Self-Renewal. Nat Commun 2018, 9.
[29] Chen, J.; Zhou, R.; Feng, Y.; Cheng, L. Molecular Mechanisms of Exercise Contributing to Tissue Regeneration. Signal Transduct Target Ther 2022, 7.
[30] Puca, F.; Fedele, M.; Rasio, D.; Battista, S. Role of Diet in Stem and Cancer Stem Cells. International Journal of Molecular Sciences 2022, Vol. 23, Page 8108 2022, 23, 8108.
[31] Rose, S.C.; Larsen, M.; Xie, Y.; Sharfstein, S.T. Salivary Gland Bioengineering. Bioengineering 2024, Vol. 11, Page 28 2023, 11, 28.
[32] Grezella, C.; Fernandez-Rebollo, E.; Franzen, J.; Ventura Ferreira, M.S.; Beier, F.; Wagner, W. Effects of Senolytic Drugs on Human Mesenchymal Stromal Cells. Stem Cell Res Ther 2018, 9, 1–6.
[33] Zhang, J.; Shang, J.; Ding, H.; Li, W.; Li, Z.; Yuan, Z.; Zheng, H.; Lou, Y.F.; Wei, Z.; Zhou, H.; et al. Nicotinamide Riboside Promotes the Proliferation of Endogenous Neural Stem Cells to Repair Spinal Cord Injury. Stem Cell Rev Rep 2024, 20, 1854–1868.
[34] Wang, H.; Sun, Y.; Pi, C.; Yu, X.; Gao, X.; Zhang, C.; Sun, H.; Zhang, H.; Shi, Y.; He, X. Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells. Int J Mol Sci 2022, 23, 14739.
[35] Igarashi, M.; Miura, M.; Williams, E.; Jaksch, F.; Kadowaki, T.; Yamauchi, T.; Guarente, L. NAD+ Supplementation Rejuvenates Aged Gut Adult Stem Cells. Aging Cell 2019, 18, e12935.
[36] Liu, X.; Li, Z.; Liu, L.; Zhang, P.; Wang, Y.; Ding, G. Metformin-Mediated Effects on Mesenchymal Stem Cells and Mechanisms: Proliferation, Differentiation and Aging. Front Pharmacol 2024, 15, 1465697.
[37] Jiang, L.L.; Liu, L. Effect of Metformin on Stem Cells: Molecular Mechanism and Clinical Prospect. World J Stem Cells 2020, 12, 1455.
[38] Pulecio, J.; Verma, N.; Mejía-Ramírez, E.; Huangfu, D.; Raya, A. CRISPR/Cas9-Based Engineering of the Epigenome. Cell Stem Cell 2017, 21, 431–447.
[39] Sun, Y.; Zhang, H.; Qiu, T.; Liao, L.; Su, X. Epigenetic Regulation of Mesenchymal Stem Cell Aging through Histone Modifications. Genes Dis 2023, 10, 2443–2456.
[40] Esteves, F.; Brito, D.; Rajado, A.T.; Silva, N.; Apolónio, J.; Roberto, V.P.; Araújo, I.; Nóbrega, C.; Castelo-Branco, P.; Bragança, J.; et al. Reprogramming IPSCs to Study Age-Related Diseases: Models, Therapeutics, and Clinical Trials. Mech Ageing Dev 2023, 214, 111854.
[41] Wang, C.; Rabadan Ros, R.; Martinez-Redondo, P.; Ma, Z.; Shi, L.; Xue, Y.; Guillen-Guillen, I.; Huang, L.; Hishida, T.; Liao, H.K.; et al. In Vivo Partial Reprogramming of Myofibers Promotes Muscle Regeneration by Remodeling the Stem Cell Niche. Nature Communications 2021 12:1 2021, 12, 1–15.
[42] Sahu, S.K.; Reddy, P.; Lu, J.; Shao, Y.; Wang, C.; Tsuji, M.; Delicado, E.N.; Esteban, C.R.; Belmonte, J.C.I. Targeted Partial Reprogramming of Age-Associated Cell States Improves Markers of Health in Mouse Models of Aging. Sci Transl Med 2024, 16.
[43] Swartzrock, L.; Dib, C.; Denis, M.; Willner, H.; Ho, K.; Haslett, E.; Han, J.; Pan, W.; Byrne-Steele, M.; Brown, B.; et al. In Utero Hematopoietic Stem Cell Transplantation for Fanconi Anemia. Blood Adv 2024, 8, 4554–4558.
[44] Kumar, R.; Mishra, N.; Tran, T.; Kumar, M.; Vijayaraghavalu, S.; Gurusamy, N. Emerging Strategies in Mesenchymal Stem Cell-Based Cardiovascular Therapeutics. Cells 2024, Vol. 13, Page 855 2024, 13, 855.
[45] Ma, W.Q.; Zhuo, A.P.; Xiao, Y.L.; Gao, M.; Yang, Y.T.; Tang, L.C.; Wu, Y.H.; Tian, D.; Fu, X.F. Human Bone Marrow Derived-Mesenchymal Stem Cells Treatment for Autoimmune Premature Ovarian Insufficiency. Stem Cell Rev Rep 2024, 20, 538–553.
[46] Lindsay, J.O.; Hind, D.; Swaby, L.; Berntsson, H.; Bradburn, M.; Bannur C, U.; Byrne, J.; Clarke, C.; Desoysa, L.; Dickins, B.; et al. Safety and Efficacy of Autologous Haematopoietic Stem-Cell Transplantation with Low-Dose Cyclophosphamide Mobilisation and Reduced Intensity Conditioning versus Standard of Care in Refractory Crohn’s Disease (ASTIClite): An Open-Label, Multicentre, Randomised Controlled Trial. Lancet Gastroenterol Hepatol 2024, 9, 333–345.
[47] Rose, S. A 3D Co-Culture Model of Senescent Cell Burden and Salivary Gland Fibrosis. Electronic Theses & Dissertations (2024 – present) 2024.
[48] Riazifar, M.; Pone, E.J.; Lotval, J.; Zhao, W. Stem Cell Extracellular Vesicles: Extended Messages of Regeneration. Annu Rev Pharmacol Toxicol 2017, 57, 125–154, doi:10.1146/ANNUREV-PHARMTOX-061616-030146/CITE/REFWORKS.
[49] Jafarzadeh, A.; PourMohammad, A.; Goodarzi, A. A Systematic Review of the Efficacy, Safety and Satisfaction of Regenerative Medicine Treatments, Including Platelet-Rich Plasma, Stromal Vascular Fraction and Stem Cell-Conditioned Medium for Hypertrophic Scars and Keloids. Int Wound J 2024, 21, e14557, doi:10.1111/IWJ.14557.
[50] Li, J.; Sun, S.; Zhu, D.; Mei, X.; Lyu, Y.; Huang, K.; Li, Y.; Liu, S.; Wang, Z.; Hu, S.; et al. Inhalable Stem Cell Exosomes Promote Heart Repair after Myocardial Infarction. Circulation 2024, 150, 710–723.
[51] Subbarayan, R.; Murugan Girija, D.; Raja, S.T.K.; Krishnamoorthy, A.; Srinivasan, D.; Shrestha, R.; Srivastava, N.; Ranga Rao, S. Conditioned Medium-Enriched Umbilical Cord Mesenchymal Stem Cells: A Potential Therapeutic Strategy for Spinal Cord Injury, Unveiling Transcriptomic and Secretomic Insights. Mol Biol Rep 2024, 51, 1–14.
[52] Țichil, I.; Mitre, I.; Zdrenghea, M.T.; Bojan, A.S.; Tomuleasa, C.I.; Cenariu, D. A Review of Key Regulators of Steady-State and Ineffective Erythropoiesis. Journal of Clinical Medicine 2024, Vol. 13, Page 2585 2024, 13, 2585.
[53] Maličev, E.; Jazbec, K. An Overview of Mesenchymal Stem Cell Heterogeneity and Concentration. Pharmaceuticals 2024, Vol. 17, Page 350 2024, 17, 350, doi:10.3390/PH17030350.
[54] Cain, T.L.; Derecka, M.; McKinney-Freeman, S. The Role of the Haematopoietic Stem Cell Niche in Development and Ageing. Nature Reviews Molecular Cell Biology 2024 26:1 2024, 26, 32–50.
[55] Gumede, D.B.; Abrahamse, H.; Houreld, N.N. Targeting Wnt/β-Catenin Signaling and Its Interplay with TGF-β and Notch Signaling Pathways for the Treatment of Chronic Wounds. Cell Communication and Signaling 2024 22:1 2024, 22, 1–17.
[56] Aval, S.F.; Lotfi, H.; Sheervalilou, R.; Zarghami, N. Tuning of Major Signaling Networks (TGF-β, Wnt, Notch and Hedgehog) by MiRNAs in Human Stem Cells Commitment to Different Lineages: Possible Clinical Application. Biomedicine & Pharmacotherapy 2017, 91, 849–860.
[57] King, N.M.P.; Perrin, J. Ethical Issues in Stem Cell Research and Therapy. Stem Cell Res Ther 2014, 5, 1–6.
[59] Malhotra, P.; Saraswat, S.K.; Khatri, N.; Verma, R.; Datt, R.; Pandey, S. Stem Cell-Based Products and the Regulatory Hurdle Race. Stem Cells: an Alternative Therapy for COVID-19 and Cytokine Storm 2024, 371–38,.
[60] Knoepfler, P.S. From Bench to FDA to Bedside: US Regulatory Trends for New Stem Cell Therapies. Adv Drug Deliv Rev 2015, 82–83, 192–196.
[61] Yoon, D.E.; Lee, H.; Kim, K. Recent Research Trends in Stem Cells Using CRISPR/Cas-Based Genome Editing Methods. Int J Stem Cells 2023, 17, 1–14.
[62] Abusalah, M.A.H.; Priyanka; Abd Rahman, E.N.S.E.; Choudhary, O.P. Evolving Trends in Stem Cell Therapy: An Emerging and Promising Approach against Various Diseases. International Journal of Surgery 2024.
[63] Ramesh, P. Biomimetic Scaffolds Targeting Remediation of Fibrosis and Regeneration of the Salivary Gland. 2022.
[64] Zmievskaya, E.A.; Mukhametshin, S.A.; Ganeeva, I.A.; Gilyazova, E.M.; Siraeva, E.T.; Kutyreva, M.P.; Khannanov, A.A.; Yuan, Y.; Bulatov, E.R. Artificial Extracellular Vesicles Generated from T Cells Using Different Induction Techniques. Biomedicines 2024, 12, 919.
[65] Salazar-Noratto, G.E.; Luo, G.; Denoeud, C.; Padrona, M.; Moya, A.; Bensidhoum, M.; Bizios, R.; Potier, E.; Logeart-Avramoglou, D.; Petite, H. Understanding and Leveraging Cell Metabolism to Enhance Mesenchymal Stem Cell Transplantation Survival in Tissue Engineering and Regenerative Medicine Applications. Stem Cells 2020, 38, 22–33.
[66] Tatullo, M.; Rengo, S.; Sammartino, G.; Simeone, M.; Valletta, A.; Gasparro, R. Inflammaging, Epigenetic Damage, Mitochondrial Dysfunctions, and Macrophage Alterations Are the Main Missing Pieces in the Complex Mosaic of Stem Cell Physiology. Discov Med 2024, 36, 1772.
[67] Andonian, B.J.; Hippensteel, J.A.; Abuabara, K.; Boyle, E.M.; Colbert, J.F.; Devinney, M.J.; Faye, A.S.; Kochar, B.; Lee, J.; Litke, R.; et al. Inflammation and Aging-Related Disease: A Transdisciplinary Inflammaging Framework. GeroScience 2024 2024, 1–28.
Related Organizations
Related Community Members
