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At least 19 recordsLinked to original sources
PubMed2026

Developmental regulation of progenitor aging shapes long-term intestinal homeostasis in Drosophila.

Aging causes disruption of tissue homeostasis, with stem cell exhaustion as a major hallmark. However, whether aging trajectories are established during development remains unexplored. Here, we demonstrate that genetic modulation of aging-associated pathways in larval adult midgut progenitors (AMPs) determines the trajectory of Drosophila adult intestinal homeostasis. Induction of aging-associated pathways in the AMPs results in aberrant proliferation, skewed differentiation, barrier dysfunction, and genomic instability. Ultimately, AMP islet architecture is destabilized and age-related molecular signatures are altered. In contrast, reversing aging-associated effects results in a decrease in the enteroendocrine population and the barrier is unaffected. Together, our findings demonstrate that aging-associated pathways are tightly regulated during early development and perturbation can hamper adult gut homeostasis, establishing AMPs as key developmental determinants.

Drosophila↗
PubMed2025

Nanobioreactor detection of space-associated hematopoietic stem and progenitor cell aging.

Human hematopoietic stem and progenitor cell (HSPC) fitness declines following exposure to stressors that reduce survival, dormancy, telomere maintenance, and self-renewal, thereby accelerating aging. While previous National Aeronautics and Space Administration (NASA) research revealed immune dysfunction in low-earth orbit (LEO), the impact of spaceflight on human HSPC aging had not been studied. To study HSPC aging, our NASA-supported Integrated Space Stem Cell Orbital Research (ISSCOR) team developed bone marrow niche nanobioreactors with lentiviral bicistronic fluorescent, ubiquitination-based cell-cycle indicator (FUCCI2BL) reporter for real-time HSPC tracking in artificial intelligence (AI)-driven CubeLabs. In month-long International Space Station (ISS) missions (SpX-24, SpX-25, SpX-26, and SpX-27) compared with ground controls, FUCCI2BL reporter, whole-genome and transcriptome sequencing, and cytokine arrays demonstrated cell-cycle, inflammatory cytokine, mitochondrial gene, human repetitive element, and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) deregulation together with clonal hematopoietic mutations. Furthermore, HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses revealed reduced telomere maintenance, adenosine deaminase acting on RNA1 (ADAR1) p150 self-renewal gene expression, and replating capacity indicative of space-associated HSPC aging that may limit long-duration spaceflight.

Humans↗
PubMed2023

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging.

Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation, these MVPCs adapt a unique transcriptome signature and emerge as a venous subpopulation in the angiodiverse microvascular endothelial subclusters. Thus, our findings support a significant role for mTOR in the maintenance of MVPC function and microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.

Mice↗
PubMed1977

Age-related decrease in mouse T cell progenitors.

Mice were given a lethal dose of whole-body gamma-radiation and injected with a 10(5) or 10(6) marrow cells from 10- to 143-week-old syngeneic donors. Nine days later, colony-forming units (CFU) were counted in the spleens of mice given 10(5) cells, and 15 to 21 days after irradiation thymus weights and in some experiments 3H-thymidine uptake or total thymic cellularity were determined in the recipients of 10(6) cells. It was found that in the majority of mouse strains studied there were no significant changes with age in marrow CFU. In contrast, thymic regeneration was significantly impaired when the recipients received marrow cells from donors 100 weeks of age or older. These observations and results obtained in dose-response and time-course studies are best explained by an age-related decrease in marrow T cell progenitors; however, certain findings suggest that in addition the proliferative capacity of these stem cells may at times be moderately impaired.

Aging↗
PubMed1978

[Acrocephalosyndactylia. Apert' syndrome. A review of literature (author's transl)].

Authors revise world bibliography up to 153 cases. As introduction, they study the different anomalies that are presented, making special mention to the frequency of this syndrome, quoting to the statistics of different authors. Familiar antecedents, parents age and the alterations that had been presented in children affected with this process, including considerations not only within race, related by blood and sex, but also those malformations that in an accessorial way were displayed with more frequency have been taken into consideration. Between all the conclusions, it's significative that syndactily appears with more frequency in fatherly antecedents and although this syndrome appears in young parents, it's increases in great proportion as the age of the progenitors advances.

Acrocephalosyndactylia↗
PubMed2022

Destabilizing heterochromatin by APOE mediates senescence.

Apolipoprotein E (APOE) is a component of lipoprotein particles that function in the homeostasis of cholesterol and other lipids. Although APOE is genetically associated with human longevity and Alzheimer's disease, its mechanistic role in aging is largely unknown. Here, we used human genetic, stress-induced and physiological cellular aging models to explore APOE-driven processes in stem cell homeostasis and aging. We report that in aged human mesenchymal progenitor cells (MPCs), APOE accumulation is a driver for cellular senescence. By contrast, CRISPR-Cas9-mediated deletion of APOE endows human MPCs with resistance to cellular senescence. Mechanistically, we discovered that APOE functions as a destabilizer for heterochromatin. Specifically, increased APOE leads to the degradation of nuclear lamina proteins and a heterochromatin-associated protein KRAB-associated protein 1 via the autophagy-lysosomal pathway, thereby disrupting heterochromatin and causing senescence. Altogether, our findings uncover a role of APOE as an epigenetic mediator of senescence and provide potential targets to ameliorate aging-related diseases.

Humans↗
PubMed2025

Granulopoietic Dysregulation in a Patient-Tailored Mouse Model of Barth Syndrome.

Barth syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy, skeletal muscle myopathy and fatigue, growth restriction, and neutropenia. Neutropenia increases the risk of life-threatening bacterial infections, a major cause of death in individuals with BTHS. Currently, there is no curative treatment for BTHS or associated neutropenia. The development of therapeutic strategies to correct BTHS-associated neutropenia has been hindered by a limited understanding of the underlying molecular mechanisms involved. BTHS is caused by a mutation in the Tafazzin gene encoding a transacylase required for the maturation of cardiolipin, an inner mitochondrial membrane phospholipid crucial for mitochondrial structure and function. We introduced a BTHS patient's point mutation (TAZD75H) into the mouse Tafazzin enzyme's critical acyltransferase site using CRISPR/Cas9-mediated genome editing, resulting in a patient-tailored point mutant knock-in BTHS model (TazD75H) that expresses a stable mutant TazD75H protein lacking transacylase activity. TazD75H mice were then used to investigate how loss of Tafazzin enzymatic activity impacts hematopoiesis. Male TazD75H mice exhibited impaired granulopoiesis and neutropenia secondary to impaired function of hematopoietic progenitors. Furthermore, they demonstrated age-dependent neutrophil maturation impairment reflecting the variable neutropenia observed in BTHS patients. Additionally, male TazD75H mice exhibit chronic lymphopenia that persists post TazD75H bone marrow transplantation. Mechanistically, the TAZD75H point mutation caused hematopoietic cell mitochondrial dysfunction in patient-derived immortalized TAZD75H lymphoblasts, increasing reactive oxygen species production and mitochondrial membrane depolarization. Likewise, Cyclosporine A treatment rescued these mitochondrial phenotypes in vitro, confirming TAZD75H mitochondrial dysfunction. Overall, our findings demonstrate that mitochondrial dysfunction secondary to TAFAZZIN loss of enzymatic function underlies BTHS-associated neutropenia and lymphopenia.

Animals↗
PubMed2025

Ischemic Injury Drives Nascent Tumor Growth Via Accelerated Hematopoietic Aging.

BACKGROUND: Patients with peripheral artery disease have an increased risk of cancer development. Aging-associated changes in hematopoietic stem and progenitor cells (HSPCs), including inflammation and increased myelopoiesis, are implicated in both cardiovascular disease and cancer, but their contributions to cardiovascular disease-driven tumor progression are unclear. OBJECTIVES: This study sought to study tumor growth after peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes cancer. METHODS: Mammary cancer (E0771) growth was monitored in C57BL/6J mice after hind limb ischemia (HLI) or sham surgery. The tumor immune microenvironment, circulatory immune cells, and HSPC compartment were assessed by flow cytometry. Next-generation single-cell RNA and assay for transposase-accessible chromatin sequencing of bone marrow progenitors was performed to assess the distinct and synergistic transcriptomic and epigenetic changes of cancer and peripheral ischemia. The functional impact on tumor progression and persistence of ischemia-induced epigenetic reprogramming of HSPCs and their myeloid progeny was examined by bone marrow transplantation. RESULTS: Peripheral ischemia increased monocyte and neutrophil output at the expense of lymphocytes, driven by a shift toward CD150hi myeloid-biased hematopoietic stem cells. This was associated with accelerated cancer growth and enrichment of tumors with myeloid cells (monocytes, macrophages, neutrophils) and regulatory T cells. Increased myelopoiesis was also supported by sequencing analyses showing HLI and tumor-induced transcriptional and epigenetic enrichment for inflammatory (NLRP3 inflammasome) and aging-associated neogenin-1, thrombospondin-1) signatures in subsets of monocyte/dendritic progenitors. HLI-accelerated tumor growth and myeloid-skewing was transmissible via bone marrow transplantation, indicating long-term reprogramming of innate immune responses. CONCLUSIONS: Peripheral ischemia enhances inflammaging of hematopoietic stem cells and long-lasting alterations to antitumoral immunity, accelerating breast tumor growth.

bone marrow transplantation↗
PubMed2026

Differences between mitotically old and young endometrial tumors.

Human tumors likely differ in their mitotic ages, reflecting how many divisions elapse between the final tumor progenitor cell and surgical removal. We used a rapidly fluctuating CpG (fCpG) methylation clock to infer relative endometrial adenocarcinomas (EAC) mitotic ages. Experimentally, young tumors initiated from single cells show low-diversity, high-variance fCpG distributions with trimodal peaks near 0%, 50%, and 100%, reflecting inherited progenitor methylation states. fCpG methylation becomes polymorphic with divisions, and older tumors exhibit higher diversity, lower variance, and unimodal distributions centered around 50%. Mitotic ages varied across EAC samples. Synchronous hyperplasia and invasive regions generally shared similar ages, and primary-metastatic EAC pairs showed both synchronous and stepwise progression. The Cancer Genome Atlas (TCGA) EACs also showed variable mitotic ages: younger tumors were enriched for proliferation pathways, whereas older tumors showed more immune infiltration, immune-pathway activation, and evidence of T-cell exhaustion. These results show that human tumors can be ranked by mitotic age and suggest that the growth of older cancers is restrained by immune surveillance. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Humans↗
PubMed1978

Significance of 14q translocations in non-Hodgkin lymphomas.

Chromosome studies were performed on malignant cells obtained from 22 patients with non-Hodgkin lymphomas. A marker chromosome resulting from a translocation that affected the long arm of No. 14 (14q+) was the single most frequent abnormality and was noted in 14 of these patients. The frequency of the 14q+ marker chromosome varied with the type of lymphoma as defined by Rappaport. When the Lukes and Collins classification was used, the 14q+ marker was consistently associated with lymphomas having a clone of large noncleaved cells, small cleaved cells, and small noncleaved cells, but was absent in lymphomas composed of a clone of large cleaved cells and small lymphocytes. The findings suggest that, in certain groups of lymphoid malignancies, cells with a 14q translocation have a proliferative advantage compared with cells having other chromosome rearrangements, and that these malignant cells could be derived from a common progenitor.

Adult↗
PubMed1976

Impaired thymic regeneration in lethally irradiated mice given bone marrow from aged donors.

Mice were given a lethal dose of whole-body gamma radiation and injected with 10(5) or 10(6) marrow cells from 10- to 143-week-old syngeneic donors. Nine days later, colony-forming units (CFU) were counted in the spleens of mice given 10(5) cells, and 21 days after irradiation, spleen and thymus weights were determined in the recipients of 10(6) cells. It was found that there were no significant changes with age in marrow CFU or in the ability of marrow cells to repopulate host spleens. In contrast, thymic regeneration was significantly impaired when the recipients received marrow cells from donors 117 weeks of age or older. These observations suggest that with aging there is a decrease in marrow T-cell progenitors and/or a decline in their proliferative capacity.

Aging↗
PubMed1979

The presence of Thy-1 on the surface of rat lymphoid stem cells and colony-forming units.

By labeling Thy-1-positive cells of rats with xenoanti-Thy-1 or mouse alloanti-Thy-1 antibody and separating them from Thy-1-negative cells on a fluorescence-activated cell sorter, it was shown that early lymphopoietic stem cells all carry Thy-1-antigen. This was so for both young, adult bone marrow and near-term fetal liver cells. Two kinds of assay were used: long-term radiation chimeras employing B and T cell alloantigens to mark cells of donor origin, and in vivo colony-forming units in the spleens of irradiated recipients (bone marrow only). Thy-1-negative cells gave essentially no B or T progeny, even 6 to 12 months after reconstitution of the chimeras. The kinetics of appearance of Thy-1-positive cells in rat marrow, which peaked at 6-8 weeks of age, were also studied. In rats, Thy-1 is on the surface of pluripotent stem cells and on early progenitors of both B and T lymphocytes.

Aging↗
PubMed1979

Reduced number of peripheral blood granulocytic progenitor cells in patients with Down's syndrome.

The number of granulocytic progenitor cells (colony forming units in culture: CFUc) in the blood of patients with Down's syndrome was found to be reduced by 73.2% when compared to a group of age and sex matched controls. However, the blood CFUc of the Down's syndrome patients and the controls showed similar sensitivity to hydroxyurea which suggests that the low number of progenitor cells in Down's syndrome is not compensated by a marked increase in their cellular proliferation. The colony size distributions were similar for both the patients and the controls and, in addition, repeated assays at various intervals revealed no marked fluctuation in the number of blood CFUc in either group. The significance of the reduced number of circulating CFUc in Down's syndrome in relation to the known susceptibility of such patients to leukaemia is discussed.

Adolescent↗
PubMed1979

[On the nature and significance of nodular renal blastoma (author's transl)].

In nephrectomy specimens from a series of 24 Wilms' tumors three different types of neoplastic lesion were found in the uninvolved kidney parenchyma: nodular renal blastema, Wilms' tumorlet and metanephric hamartomas. The histologic features of the first two abnormalities are presented. They show the following characteristics: Being found in patients of younger age they occur mostly bilateral. In older children they are associated to Wilms' tumor. They are related, as this is the case with Wilms' tumors, to certain congenital malformation syndromes. Nodular blastema has been also observed in association with Wilms' tumor in siblings. These findings suggest a genetic relationship between nodular renal blastema-nephroblastomatosis complex and Wilms' tumor. Furthermore, such lesions may represent potential progenitor stages of most nephroblastomas. The clinical implications hereof are discussed.

Age Factors↗
PubMed1978

Genetic analyses of differences in incidence of mammary tumors and reticulum cell neoplasms with the use of recombinant inbred lines of mice.

The influence of genes, in addition to genes in the H-2 complex, that effect the genesis of mammary tumors was studied. The recombinant inbred (RI) CXB lines were chosen for this investigation, because they are well suited for the study of the genetics of a trait for which the genotype affects probability of phenotype expression and which therefore is measured as incidence. Females of seven RI lines (CXBD, CXBE, CXBG, CXBH, CXBI, CXBJ, and CXBK) and their progenitor strains C57BL/6By (B6) and BALB/cBy (BALB/c) were given ip injections of MuMTV at 3 months of age and were force bred. They were observed for mammary tumors. The B6 strain was least susceptible, and mammary tumors appeared late in life. The BALB/c strain was most susceptible, and the tumors appeared early in life. The course of tumor development in the RI lines fell between these extremes. The RI strain distribution pattern of mammary tumor incidence indicated that at least one and probably several loci in addition to those at H-2 determined the difference between the BALB/c and B6 strains. Effects of the other gene(s) appeared to be even more important than those of H-2. The locations of those loci were not made clear by this study. The spontaneous incidence of reticulum cell neoplasms was also recorded. The most frequently formed neoplasm of the reticular system was a Hodgkin's-like lesion. The data suggested an influence of the H-2 complex.

Animals↗
PubMed1979

The ontogeny of B lymphocytes. V. Lipopolysaccharide-induced changes of IgD expression on murine B lymphocytes.

Murine splenocytes contain two minor subpopulations of B cells, one inducible by lipopolysaccharide to convert within 2 h from IgD- to IgD+ and the other to change from IgD+ TO IgD-. These two subpopulations can be separated by density centrifugation. Their relative proportions show a marked age dependency: IgD- leads to IgD+ cells are more frequent in suckling mice, while IgD+ leads to IgD- inducible cells become predominant in mice older than 3 weeks. The age dependency observed in the relative proportions between the two cell types suggest that they are ontogenetically related as progenitor-successor. This hypothesis is corroborated by phenotype analysis of the two subsets, revealing IgD- leads to IgD+ cells as IgM+, Ia+, complement receptor- (CR-) and IgD+ leads to IgD- cells as IgM+, Ia+, CR+. Our data show that IgD and CR are expressed concomitantly during B cell differentiation. On further differentiation, induced by lipopolysaccharide, both markers are lost from the cell surface at different rates: IgD decreases significantly in a very short period (less than 2.5 h) while induction of a decline in CR requires longer culture periods (greater than 8 h). Th: loss of IgD may thus herald an early differentiation event toward antibody-producing cells.

Aging↗
PubMed1979

Autoradiographic study on some proliferative properties of human buccal mucosa.

This study was designed to investigate the proliferative activity of the buccal mucosa in healthy adult persons with regard to individual age. Punch biopsy specimens were taken from the buccal mucosa of 19 individuals (10 females, 9 males) ranging in age from 24 to 80 years, and were then examined autoradiographically, applying nuclear 3H-thymidine labelling in vitro under oxygen pressure of 2.2 atm. The mean total labelling index in the progenitor compartment amounted to 26.0 +/- 2.6% including 6.2 +/- 2.0% labelled basal nuclei and 19.8 +/- 2.6% labelled suprabasal nuclei. Related to 1,000 mu surface length, the mean number of basal cells runs up to 270.7 +/- 38.6 and the total nuclear labelling index to 70.9 +/- 10.4. This high rate of S phase nuclei, exceeding that of the epidermis several times, depends on the ample progenitor compartment as well as on the basal epithelium length which, as compared to the epithelium surface length, was shown to be extended by a mean proportion of 1.75. None of the autoradiographic results obtained in the present study revealed an age dependency of the buccal mucosa proliferative activity. The magnitude of the proliferative pool constitutes the matrix of the high renewal rate of the healthy buccal mucosa and provides a steady state of superficial cell loss and basal cell regeneration, that was proved, at least in the normal mucosa, to continue until senile age.

Adult↗