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Aging Cell Oct 2023Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (Lmna and Zmpste24 mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.
Topics: Humans; Mice; Animals; Progeria; Aging, Premature; Proteomics; Proteome; Secretome; Lamin Type A
PubMed: 37565451
DOI: 10.1111/acel.13952 -
Aging Feb 2024Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the...
Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the large variation in clinical presentation the diseases pose a diagnostic challenge for clinicians which consequently restricts medical research. To accommodate the challenge, we compiled a list of known progeroid syndromes and calculated the mean prevalence of their associated phenotypes, defining what we term the 'progeria phenome'. The data were used to train a support vector machine that is available at https://www.mitodb.com and able to classify progerias based on phenotypes. Furthermore, this allowed us to investigate the correlation of progeroid syndromes and syndromes with various pathogenesis using hierarchical clustering algorithms and disease networks. We detected that ataxia-telangiectasia like disorder 2, spastic paraplegia 49 and Meier-Gorlin syndrome display strong association to progeroid syndromes, thereby implying that the syndromes are previously unrecognized progerias. In conclusion, our study has provided tools to evaluate the likelihood of a syndrome or patient being progeroid. This is a considerable step forward in our understanding of what constitutes a premature aging disorder and how to diagnose them.
Topics: Humans; Progeria; Aging, Premature; Aging; Phenotype; Growth Disorders; Cockayne Syndrome
PubMed: 38345566
DOI: 10.18632/aging.205537 -
Frontiers in Aging 2024The inexorability of the aging process has sparked the curiosity of human beings since ancient times. However, despite this interest and the extraordinary scientific... (Review)
Review
The inexorability of the aging process has sparked the curiosity of human beings since ancient times. However, despite this interest and the extraordinary scientific advances in the field, the complexity of the process has hampered its comprehension. In this context, The Hallmarks of Aging were defined in 2013 with the aim of establishing an organized, systematic and integrative view of this topic, which would serve as a conceptual framework for aging research. Ten years later and promoted by the progress in the area, an updated version included three new hallmarks while maintaining the original scope. The aim of this review is to determine to what extent The Hallmarks of Aging achieved the purpose that gave rise to them. For this aim, we have reviewed the literature citing any of the two versions of The Hallmarks of Aging and conclude that they have served as a conceptual framework not only for aging research but also for related areas of knowledge. Finally, this review discusses the new candidates to become part of the Hallmarks list, analyzing the evidence that supports whether they should or should not be incorporated.
PubMed: 38292053
DOI: 10.3389/fragi.2024.1334261 -
Dermatologie (Heidelberg, Germany) Sep 2023Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. PSs display a wide range of heterogeneous pathological symptoms that also... (Review)
Review
Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. PSs display a wide range of heterogeneous pathological symptoms that also manifest during natural aging, including vision and hearing loss, atrophy, hair loss, progressive neurodegeneration, and cardiovascular defects. Recent advances in molecular pathology have led to a better understanding of the underlying mechanisms of these diseases. The genetic mutations underlying PSs are functionally linked to genome maintenance and repair, supporting the causative role of DNA damage accumulation in aging. While some of those genes encode proteins with a direct involvement in a DNA repair machinery, such as nucleotide excision repair (NER), others destabilize the genome by compromising the stability of the nuclear envelope, when lamin A is dysfunctional in Hutchinson-Gilford progeria syndrome (HGPS) or regulate the DNA damage response (DDR) such as the ataxia telangiectasia-mutated (ATM) gene. Understanding the molecular pathology of progeroid diseases is crucial in developing potential treatments to manage and prevent the onset of symptoms. This knowledge provides insight into the underlying mechanisms of premature aging and could lead to improved quality of life for individuals affected by progeroid diseases.
Topics: Humans; Skin Aging; Quality of Life; Aging; Cockayne Syndrome; Aging, Premature
PubMed: 37650893
DOI: 10.1007/s00105-023-05212-8 -
Trends in Endocrinology and Metabolism:... Feb 2024Lipodystrophy syndromes are rare diseases characterized by low levels and an abnormal distribution of adipose tissue, caused by diverse genetic or acquired causes. These... (Review)
Review
Lipodystrophy syndromes are rare diseases characterized by low levels and an abnormal distribution of adipose tissue, caused by diverse genetic or acquired causes. These conditions commonly exhibit metabolic complications, including insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, and adipose tissue dysfunction. Moreover, genetic lipodystrophic laminopathies exhibit a premature aging phenotype, emphasizing the importance of restoring adipose tissue distribution and function. In this opinion, we discuss the relevance of adipose tissue reestablishment as a potential approach to alleviate premature aging and age-related complications in genetic lipodystrophy syndromes.
Topics: Humans; Aging, Premature; Lipodystrophy; Insulin Resistance; Diabetes Mellitus; Non-alcoholic Fatty Liver Disease
PubMed: 37968143
DOI: 10.1016/j.tem.2023.10.006 -
Aging Cell Jan 2024Originally identified as an outcome of continuous culture of primary cells, cellular senescence has moved beyond the culture dish and is now a bona fide driver of aging... (Review)
Review
Originally identified as an outcome of continuous culture of primary cells, cellular senescence has moved beyond the culture dish and is now a bona fide driver of aging and disease in animal models, and growing links to human disease. This cellular stress response consists of a stable proliferative arrest coupled to multiple phenotypic changes. Perhaps the most important of these is the senescence-associated secretory phenotype, or senescence-associated secretory phenotype -a complex and variable collection of secreted molecules release by senescent cells with a number of potent biological activities. Senescent cells appear in multiple age-associated conditions in humans and mice, and interventions that eliminate these cells can prevent or even reverse multiple diseases in mouse models. Here, we review salient aspects of senescent cells in the context of human disease and homeostasis. Senescent cells increase in abundance during several diseases that associated with premature aging. Conversely, senescent cells have a key role in beneficial processes such as development and wound healing, and thus can help maintain tissue homeostasis. Finally, we speculate on mechanisms by which deleterious aspects of senescent cells might be targeted while retaining homeostatic aspects in order to improve age-related outcomes.
Topics: Humans; Animals; Mice; Aging; Cellular Senescence; Disease Models, Animal; Senescence-Associated Secretory Phenotype; Homeostasis
PubMed: 37731189
DOI: 10.1111/acel.13988 -
Aging Cell Jun 2024Age-induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases the risk for bone fractures. Despite...
Age-induced decline in osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) potentiates osteoporosis and increases the risk for bone fractures. Despite epidemiology studies reporting concurrent development of vascular and bone diseases in the elderly, the underlying mechanisms for the vascular-bone cross-talk in aging are largely unknown. In this study, we show that accelerated endothelial aging deteriorates bone tissue through paracrine repression of Wnt-driven-axis in BMSCs. Here, we utilize physiologically aged mice in conjunction with our transgenic endothelial progeria mouse model (Hutchinson-Gilford progeria syndrome; HGPS) that displays hallmarks of an aged bone marrow vascular niche. We find bone defects associated with diminished BMSC osteogenic differentiation that implicate the existence of angiocrine factors with long-term inhibitory effects. microRNA-transcriptomics of HGPS patient plasma combined with aged-vascular niche analyses in progeria mice reveal abundant secretion of Wnt-repressive microRNA-31-5p. Moreover, we show that inhibition of microRNA-31-5p as well as selective Wnt-activator CHIR99021 boosts the osteogenic potential of BMSCs through de-repression and activation of the Wnt-signaling, respectively. Our results demonstrate that the vascular niche significantly contributes to osteogenesis defects in aging and pave the ground for microRNA-based therapies of bone loss in elderly.
Topics: Mesenchymal Stem Cells; Animals; Osteogenesis; Mice; Humans; Wnt Signaling Pathway; Paracrine Communication; MicroRNAs; Aging; Mice, Transgenic; Cell Differentiation; Stem Cell Niche
PubMed: 38578073
DOI: 10.1111/acel.14139 -
Scientific Reports Oct 2023Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current...
Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. Progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated Aβ42 to Aβ40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening.
Topics: Humans; Lamin Type A; Alzheimer Disease; Progeria; Aging; Cell Nucleus
PubMed: 37884611
DOI: 10.1038/s41598-023-45826-5 -
Nature Cell Biology May 2024DNA-protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes...
DNA-protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes cause progeria, including Ruijs-Aalfs syndrome (RJALS) and AMeD syndrome (AMeDS) in humans. Although the elimination of DPC during replication has been well established, how cells overcome DPC lesions in transcription remains elusive. Here we show that endogenous aldehyde-induced DPC roadblocks are efficiently resolved by transcription-coupled repair (TCR). We develop a high-throughput sequencing technique to measure the genome-wide distribution of DPCs (DPC-seq). Using proteomics and DPC-seq, we demonstrate that the conventional TCR complex as well as VCP/p97 and the proteasome are required for the removal of formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcription obstacles. Finally, a mouse model lacking both aldehyde clearance and TCR confirms endogenous DPC accumulation in actively transcribed regions. Collectively, our data provide evidence that transcription-coupled DPC repair (TC-DPCR) as well as aldehyde clearance are crucial for protecting against metabolic genotoxin, thus explaining the molecular pathogenesis of AMeDS and other disorders associated with defects in TCR, such as Cockayne syndrome.
Topics: Animals; DNA Repair; Transcription, Genetic; Humans; Aldehydes; Proteasome Endopeptidase Complex; Mice; DNA; DNA Damage; Mice, Knockout; Valosin Containing Protein; RNA Polymerase II; Mice, Inbred C57BL; Formaldehyde; Excision Repair
PubMed: 38600234
DOI: 10.1038/s41556-024-01401-2 -
Aging Cell Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo...
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic "progerin" protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the Lmna knock-in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild-type and KI osteoclasts from marrow-derived precursors was inhibited by KI osteoblast-conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild-type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross-talk contribute to abnormal bone formation in HGPS mice.
Topics: Mice; Animals; Progeria; Aging, Premature; Mutation; Lamin Type A; Cell Differentiation; Bone Diseases, Developmental
PubMed: 37365004
DOI: 10.1111/acel.13903