Intestinal Stem Cell Aging: Origins and Interventions

Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized in mammalian models. This review presents a model for age-related regenerative decline in the fly intestine and discusses recent findings that start to establish molecular mechanisms of age-related decline of mammalian ISC function.

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New insights into skin stem cell aging and cancer

Biochemical Society Transactions ◽

10.1042/bst20140045 ◽

2014 ◽

Vol 42 (3) ◽

pp. 663-669 ◽

Cited By ~ 7

Author(s):

M. Carmen Ortells ◽

William M. Keyes

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Cell Aging ◽

Adult Tissue ◽

Self Renewal ◽

Tissue Specific ◽

Regulatory Processes ◽

Age Related ◽

Stem Cell Aging ◽

Growth Properties

Adult tissue homoeostasis requires continual replacement of cells that are lost due to normal turnover, injury and disease. However, aging is associated with an overall decline in tissue function and homoeostasis, suggesting that the normal regulatory processes that govern self-renewal and regeneration may become impaired with age. Tissue-specific SCs (stem cells) lie at the apex of organismal conservation and regeneration, ultimately being responsible for continued tissue maintenance. In many tissues, there are changes in SC numbers, or alteration of their growth properties during aging, often involving imbalances in tumour-suppressor- and oncogene-mediated pathways. Uncovering the molecular mechanisms leading to changes in SC function during aging will provide an essential tool to address tissue-specific age-related pathologies. In the present review, we summarize the age-related alterations found in different tissue SC populations, highlighting recently identified changes in aged HFSCs (hair-follicle SCs) in the skin.

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Causes and Mechanisms of Hematopoietic Stem Cell Aging

International Journal of Molecular Sciences ◽

10.3390/ijms20061272 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1272 ◽

Cited By ~ 10

Author(s):

Jungwoon Lee ◽

Suk Yoon ◽

Inpyo Choi ◽

Haiyoung Jung

Keyword(s):

Immune System ◽

Molecular Mechanisms ◽

The Elderly ◽

Cell Aging ◽

Extrinsic Factors ◽

Hematopoietic Stem ◽

Age Related ◽

Stem Cell Aging ◽

Related Stress

Many elderly people suffer from hematological diseases known to be highly age-dependent. Hematopoietic stem cells (HSCs) maintain the immune system by producing all blood cells throughout the lifetime of an organism. Recent reports have suggested that HSCs are susceptible to age-related stress and gradually lose their self-renewal and regeneration capacity with aging. HSC aging is driven by cell-intrinsic and -extrinsic factors that result in the disruption of the immune system. Thus, the study of HSC aging is important to our understanding of age-related immune diseases and can also provide potential strategies to improve quality of life in the elderly. In this review, we delineate our understanding of the phenotypes, causes, and molecular mechanisms involved in HSC aging.

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Manifestations and mechanisms of stem cell aging

The Journal of Cell Biology ◽

10.1083/jcb.201010131 ◽

2011 ◽

Vol 193 (2) ◽

pp. 257-266 ◽

Cited By ~ 204

Author(s):

Ling Liu ◽

Thomas A. Rando

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Adult Stem Cells ◽

Cell Aging ◽

Functional Changes ◽

Cell Based Therapy ◽

Age Related ◽

Stem Cell Aging ◽

Genetic Interventions ◽

Cell Functionality

Adult stem cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem cell functionality but not a depletion of stem cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, and proteome, some of which arise cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem cells. Such findings have profound implications for the stem cell–based therapy of age-related diseases.

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Aging of hematopoietic stem cells

Blood ◽

10.1182/blood-2017-06-746412 ◽

2018 ◽

Vol 131 (5) ◽

pp. 479-487 ◽

Cited By ~ 83

Author(s):

Gerald de Haan ◽

Seka Simone Lazare

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Blood Cells ◽

Aging Process ◽

Molecular Mechanisms ◽

Cell Aging ◽

Self Renewal ◽

Hematopoietic Stem ◽

Stem Cell Aging

Abstract Hematopoietic stem cells (HSCs) ensure a balanced production of all blood cells throughout life. As they age, HSCs gradually lose their self-renewal and regenerative potential, whereas the occurrence of cellular derailment strongly increases. Here we review our current understanding of the molecular mechanisms that contribute to HSC aging. We argue that most of the causes that underlie HSC aging result from cell-intrinsic pathways, and reflect on which aspects of the aging process may be reversible. Because many hematological pathologies are strongly age-associated, strategies to intervene in aspects of the stem cell aging process may have significant clinical relevance.

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Mitochondrial Dysfunction in Stem Cell Aging

The Indonesian Biomedical Journal ◽

10.18585/inabj.v7i1.18 ◽

2015 ◽

Vol 7 (1) ◽

pp. 15

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mitochondrial Dysfunction ◽

Stress Responses ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Tissue Homeostasis ◽

Cell Aging ◽

Aging Research ◽

Age Related

BACKGROUND: Regardless of the precise underlying molecular mechanisms, the fundamental defining manifestation of aging is an overall decline in the functional capacity of various organs to maintain baseline tissue homeostasis and to respond adequately to physiological needs under stress. There is an increasingly urgent need for a more complete understanding of the molecular pathways and biological processes underlying aging and age-related disorders.CONTENT: Mitochondria constitute the most prominent source of adenosine triphosphate (ATP) and are implicated in multiple anabolic and catabolic circuitries. In addition, mitochondria coordinate cell-wide stress responses and control non-apoptotic cell death routines. The involvement of mitochondria in both vital and lethal processes is crucial for both embryonic and postembryonic development, as well as for the maintenance of adult tissue homeostasis. Age-associated telomere damage, diminution of telomere ‘capping’ function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, ‘stemness’ and metabolism provides a framework for how diverse factors contribute to aging and age-related disorders.SUMMARY: Cellular senescence defined as an irreversible proliferation arrest promotes age-related decline in mammalian tissue homeostasis. The aging of tissue-specific stem cell and progenitor cell compartments is believed to be central to the decline of tissue and organ integrity and function in the elderly. Taken into consideration that the overwhelming majority of intracellular reactive oxygen species (ROS) are of mitochondrial origin, it is reasonable to posit that the elevated ROS production might be caused by alteration in mitochondrial function during senescence. It is likely that mitochondria and stem cells will remain at the forefront of aging research also for the next decade.KEYWORDS: aging, stem cell, mitochondrial biogenesis, mitophagy, senescence, telomeres

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Stem Cell Quiescence versus Senescence: The Key for Healthy Aging

The Indonesian Biomedical Journal ◽

10.18585/inabj.v13i4.1655 ◽

2021 ◽

Vol 13 (4) ◽

pp. 337-49

Author(s):

Anna Meiliana ◽

Nurrani Mustika Dewi ◽

Andi Wijaya

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Healthy Aging ◽

Molecular Mechanisms ◽

Adult Stem Cell ◽

Cell Aging ◽

Tissue Specific ◽

Age Related ◽

Cell Decline ◽

Tissue Specific Stem Cells

BACKGROUND: Aging tissues lose their homeostatic and regenerative capacities, which has been linked to the degeneration of the stem cells such as the tissue-specific stem cells, the stem cell niches, and systemic cues that regulate stem cell activity.CONTENT: The maintenance of tissue homeostatic and regeneration dependent on its tissue-specific stem cells, that —long-lived cells with the ability to self-renew and differentiate into mature cells. Understanding the molecular mechanisms that governs stem cell survival, self-renewal, quiescence, proliferation, and commitment to specific differentiated cell lineages is critical for identifying the drivers and effectors of age-associated stem cell failure. Such understanding will be critical for the development of therapeutic approaches that can decrease, and possibly reverse and repair the age-related degenerative process in aging tissues.SUMMARY: The exact mechanisms and reasons of aging process were not fully elucidated until now. Stem cells is one of the keys for maintaining tissues heath and understanding how stem cell decline with age will give us opportunities to find strategy in increasing somatic stem cells regenerative capacity and delay the aging process.KEYWORDS: adult stem cell, aging, epigenetic, metabolism, quiescence, senescence

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The Mechanism of Stem Cell Aging

Stem Cell Reviews and Reports ◽

10.1007/s12015-021-10317-5 ◽

2022 ◽

Author(s):

Liangyu Mi ◽

Junping Hu ◽

Na Li ◽

Jinfang Gao ◽

Rongxiu Huo ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Tissue Repair ◽

Molecular Mechanisms ◽

Cell Aging ◽

Therapeutic Application ◽

Differentiation Potential ◽

Stem Cell Aging ◽

New Directions ◽

Aging Mechanisms

AbstractStem cells have self-renewal ability and multi-directional differentiation potential. They have tissue repair capabilities and are essential for maintaining the tissue homeostasis. The depletion of stem cells is closely related to the occurrence of body aging and aging-related diseases. Therefore, revealing the molecular mechanisms of stem cell aging will set new directions for the therapeutic application of stem cells, the study of aging mechanisms, and the prevention and treatment of aging-related diseases. This review comprehensively describes the molecular mechanisms related to stem cell aging and provides the basis for further investigations aimed at developing new anti-stem cell aging strategies and promoting the clinical application of stem cells.

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Circadian Regulation of Mitochondrial Uncoupling and Lifespan

Innovation in Aging ◽

10.1093/geroni/igaa057.2648 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 740-741

Author(s):

Matthew Ulgherait

Keyword(s):

Stem Cells ◽

Circadian Rhythm ◽

Uncoupling Protein ◽

Intestinal Stem Cells ◽

Intestinal Stem Cell ◽

Cellular Respiration ◽

Circadian Regulation ◽

Lifespan Extension ◽

Diet Restriction ◽

Mitochondrial Uncoupling

Abstract Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways, but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, up-regulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents over-proliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target.

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Antioxidant Effects of Caffeic Acid Lead to Protection of Drosophila Intestinal Stem Cell Aging

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.735483 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiao Sheng ◽

Yuedan Zhu ◽

Juanyu Zhou ◽

La Yan ◽

Gang Du ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Caffeic Acid ◽

Stress Responses ◽

Adult Stem Cells ◽

Cell Function ◽

Cell Aging ◽

Positive Effects ◽

Age Related ◽

Tissue Aging

The dysfunction or exhaustion of adult stem cells during aging is closely linked to tissue aging and age-related diseases. Circumventing this aging-related exhaustion of adult stem cells could significantly alleviate the functional decline of organs. Therefore, identifying small molecular compounds that could prevent the age-related decline of stem cell function is a primary goal in anti-aging research. Caffeic acid (CA), a phenolic compound synthesized in plants, offers substantial health benefits for multiple age-related diseases and aging. However, the effects of CA on adult stem cells remain largely unknown. Using the Drosophila midgut as a model, this study showed that oral administration with CA significantly delayed age-associated Drosophila gut dysplasia caused by the dysregulation of intestinal stem cells (ISCs) upon aging. Moreover, administering CA retarded the decline of intestinal functions in aged Drosophila and prevented hyperproliferation of age-associated ISC by suppressing oxidative stress-associated JNK signaling. On the other hand, CA supplementation significantly ameliorated the gut hyperplasia defect and reduced environmentally induced mortality, revealing the positive effects of CA on tolerance to stress responses. Taken together, our findings report a crucial role of CA in delaying age-related changes in ISCs of Drosophila.

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