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Molecular Medicine (Cambridge, Mass.) Jul 2023The telomerase RNA component (TERC) gene plays an important role in telomerase-dependent extension and maintenance of the telomeres. In the event of TERC... (Review)
Review
The telomerase RNA component (TERC) gene plays an important role in telomerase-dependent extension and maintenance of the telomeres. In the event of TERC haploinsufficiency, telomere length is often affected; this, in turn, can result in the development of progeria-related diseases such as aplastic anemia (AA) and congenital keratosis. Cell reprogramming can reverse the differentiation process and can, therefore, transform cells into pluripotent stem cells with stronger differentiation and self-renewal abilities; further, cell reprograming can also extend the telomere length of these cells, which may be crucial in the diagnosis and treatment of telomere depletion diseases such as AA. In this study, we summarized the effects of TERC haploid cell reprogramming on telomere length and the correlation between this alteration and the pathogenesis of AA; by investigating the role of cell reprogramming in AA, we aimed to identify novel diagnostic indicators and therapeutic strategies for patients with AA.
Topics: Humans; Telomerase; Anemia, Aplastic; Cellular Reprogramming; Haploidy
PubMed: 37424004
DOI: 10.1186/s10020-023-00691-w -
Nucleus (Austin, Tex.) Dec 2023As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders.... (Review)
Review
As human longevity increases, understanding the molecular mechanisms that drive aging becomes ever more critical to promote health and prevent age-related disorders. Premature aging disorders or progeroid syndromes can provide critical insights into aspects of physiological aging. A major cause of progeroid syndromes which result from mutations in the genes and is disruption of the final posttranslational processing step in the production of the nuclear scaffold protein lamin A. encodes the lamin A precursor, prelamin A and encodes the prelamin A processing enzyme, the zinc metalloprotease ZMPSTE24. Progeroid syndromes resulting from mutations in these genes include the clinically related disorders Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia-type B, and restrictive dermopathy. These diseases have features that overlap with one another and with some aspects of physiological aging, including bone defects resembling osteoporosis and atherosclerosis (the latter primarily in HGPS). The progeroid syndromes have ignited keen interest in the relationship between defective prelamin A processing and its accumulation in normal physiological aging. In this review, we examine the hypothesis that diminished processing of prelamin A by ZMPSTE24 is a driver of physiological aging. We review features a new mouse () that produces solely unprocessed prelamin A and provides an ideal model for examining the effects of its accumulation during aging. We also discuss existing data on the accumulation of prelamin A or its variants in human physiological aging, which call out for further validation and more rigorous experimental approaches to determine if prelamin A contributes to normal aging.
Topics: Humans; Animals; Mice; Lamin Type A; Metalloendopeptidases; Health Promotion; Progeria; Aging; Membrane Proteins
PubMed: 37885131
DOI: 10.1080/19491034.2023.2270345 -
Cells Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.
Topics: Child; Humans; Lamin Type A; Progeria; Quality of Life; Medicine; Aging; Rare Diseases
PubMed: 37759521
DOI: 10.3390/cells12182299 -
Communications Biology Sep 2023Cytosolic citrate is imported from the mitochondria by SLC25A1, and from the extracellular milieu by SLC13A5. In the cytosol, citrate is used by ACLY to generate...
Cytosolic citrate is imported from the mitochondria by SLC25A1, and from the extracellular milieu by SLC13A5. In the cytosol, citrate is used by ACLY to generate acetyl-CoA, which can then be exported to the endoplasmic reticulum (ER) by SLC33A1. Here, we report the generation of mice with systemic overexpression (sTg) of SLC25A1 or SLC13A5. Both animals displayed increased cytosolic levels of citrate and acetyl-CoA; however, SLC13A5 sTg mice developed a progeria-like phenotype with premature death, while SLC25A1 sTg mice did not. Analysis of the metabolic profile revealed widespread differences. Furthermore, SLC13A5 sTg mice displayed increased engagement of the ER acetylation machinery through SLC33A1, while SLC25A1 sTg mice did not. In conclusion, our findings point to different biological responses to SLC13A5- or SLC25A1-mediated import of citrate and suggest that the directionality of the citrate/acetyl-CoA pathway can transduce different signals.
Topics: Animals; Mice; Acetyl Coenzyme A; Acetylation; Citrates; Citric Acid; Phenotype
PubMed: 37689798
DOI: 10.1038/s42003-023-05311-1 -
International Journal of Molecular... Oct 2023Cardiovascular diseases are the leading cause of death globally. Within cardiovascular aging, arterial aging holds significant importance, as it involves structural and... (Review)
Review
Cardiovascular diseases are the leading cause of death globally. Within cardiovascular aging, arterial aging holds significant importance, as it involves structural and functional alterations in arteries that contribute substantially to the overall decline in cardiovascular health during the aging process. As arteries age, their ability to respond to stress and injury diminishes, while their luminal diameter increases. Moreover, they experience intimal and medial thickening, endothelial dysfunction, loss of vascular smooth muscle cells, cellular senescence, extracellular matrix remodeling, and deposition of collagen and calcium. This aging process also leads to overall arterial stiffening and cellular remodeling. The process of genomic instability plays a vital role in accelerating vascular aging. Progeria syndromes, rare genetic disorders causing premature aging, exemplify the impact of genomic instability. Throughout life, our DNA faces constant challenges from environmental radiation, chemicals, and endogenous metabolic products, leading to DNA damage and genome instability as we age. The accumulation of unrepaired damages over time manifests as an aging phenotype. To study vascular aging, various models are available, ranging from in vivo mouse studies to cell culture options, and there are also microfluidic in vitro model systems known as vessels-on-a-chip. Together, these models offer valuable insights into the aging process of blood vessels.
Topics: Mice; Animals; Aging; Cellular Senescence; Arteries; Aging, Premature; Genomic Instability
PubMed: 37895059
DOI: 10.3390/ijms242015379 -
Nature Aging Nov 2023The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks...
The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks unequivocal experimental support. Here, using lineage tracing and single-cell transcriptomics, we identify a population of CD133 bone marrow-derived endothelial-like cells (ELCs) as potential endothelial progenitor cells, which contribute to tubular structures in vitro and neovascularization in vivo. We demonstrate that supplementation with wild-type and young ELCs respectively restores neovascularization and extends lifespan in progeric and naturally aged mice. Mechanistically, we identify an upregulation of farnesyl diphosphate synthase (FDPS) in aged CD133 ELCs-a key enzyme in isoprenoid biosynthesis. Overexpression of FDPS compromises the neovascularization capacity of CD133 ELCs, whereas FDPS inhibition by pamidronate enhances neovascularization, improves health measures and extends lifespan in aged mice. These findings highlight stem cell-based strategies for the treatment of progeria and age-related pathologies.
Topics: Mice; Animals; Endothelial Progenitor Cells; Longevity; Neovascularization, Pathologic; Stem Cells
PubMed: 37946040
DOI: 10.1038/s43587-023-00512-z -
Proceedings of the National Academy of... Nov 2023Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of...
Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of cardiovascular complications. Although vascular pathologies have been reported, whether HGPS patients exhibit cardiac dysfunction and its underlying mechanism is unclear, rendering limited options for treating HGPS-related cardiomyopathy. In this study, we reported a cardiac atrophy phenotype in the mice (hereafter, HGPS mice). Using a GFP-based reporter system, we demonstrated that the efficiency of nonhomologous end joining (NHEJ) declined by 50% in HGPS cardiomyocytes in vivo, due to the attenuated interaction between γH2AX and Progerin, the causative factor of HGPS. As a result, genomic instability in cardiomyocytes led to an increase of CHK2 protein level, promoting the LKB1-AMPKα interaction and AMPKα phosphorylation, which further led to the activation of FOXO3A-mediated transcription of atrophy-related genes. Moreover, inhibiting AMPK enlarged cardiomyocyte sizes both in vitro and in vivo. Most importantly, our proof-of-concept study indicated that isoproterenol treatment significantly reduced AMPKα and FOXO3A phosphorylation in the heart, attenuated the atrophy phenotype, and extended the mean lifespan of HGPS mice by ~21%, implying that targeting cardiac atrophy may be an approach to HGPS treatment.
Topics: Humans; Mice; Animals; Progeria; Aging, Premature; Heart; DNA Damage; Genomic Instability; AMP-Activated Protein Kinases; Lamin Type A
PubMed: 37967221
DOI: 10.1073/pnas.2309200120 -
Aging Cell Dec 2023The NAD -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role...
The NAD -dependent deacylase family of sirtuin enzymes have been implicated in biological ageing, late-life health and overall lifespan, though of these members, a role for sirtuin-2 (SIRT2) is less clear. Transgenic overexpression of SIRT2 in the BubR1 hypomorph model of progeria can rescue many aspects of health and increase overall lifespan, due to a specific interaction between SIRT2 and BubR1 that improves the stability of this protein. It is less clear whether SIRT2 is relevant to biological ageing outside of a model where BubR1 is under-expressed. Here, we sought to test whether SIRT2 over-expression would impact the overall health and lifespan of mice on a nonprogeroid, wild-type background. While we previously found that SIRT2 transgenic overexpression prolonged female fertility, here, we did not observe any additional impact on health or lifespan, which was measured in both male and female mice on standard chow diets, and in males challenged with a high-fat diet. At the biochemical level, NMR studies revealed an increase in total levels of a number of metabolites in the brain of SIRT2-Tg animals, pointing to a potential impact in cell composition; however, this did not translate into functional differences. Overall, we conclude that strategies to enhance SIRT2 protein levels may not lead to increased longevity.
Topics: Animals; Female; Male; Mice; Aging; Animals, Genetically Modified; Brain; Longevity; Sirtuin 2
PubMed: 38009412
DOI: 10.1111/acel.14027 -
Frontiers in Cell and Developmental... 2023Despite being among the most intensively studied oncogenes, its role in normal development has not been determined as mice do not survival beyond mid-gestation. ±... (Review)
Review
Despite being among the most intensively studied oncogenes, its role in normal development has not been determined as mice do not survival beyond mid-gestation. ± mice live longer than their wild-type counterparts and are slower to accumulate many age-related phenotypes. However, haplo-insufficiency likely conceals other important phenotypes as many high-affinity Myc targets genes continue to be regulated normally. By delaying inactivation until after birth it has recently been possible to study the consequences of its near-complete total body loss and thus to infer its normal function. Against expectation, these KO" mice lived significantly longer than control wild-type mice but manifested a marked premature aging phenotype. This seemingly paradoxical behavior was potentially explained by a >3-fold lower lifetime incidence of cancer, normally the most common cause of death in mice and often Myc-driven. loss accelerated the accumulation of numerous "Aging Hallmarks", including the loss of mitochondrial and ribosomal structural and functional integrity, the generation of reactive oxygen species, the acquisition of genotoxic damage, the detrimental rewiring of metabolism and the onset of senescence. In both mice and humans, normal aging in many tissues was accompaniued by the downregulation of Myc and the loss of Myc target gene regulation. Unlike most mouse models of premature aging, which are based on monogenic disorders of DNA damage recognition and repair, the KO mouse model directly impacts most Aging Hallmarks and may therefore more faithfully replicate the normal aging process of both mice and humans. It further establishes that the strong association between aging and cancer can be genetically separated and is maintained by a single gene.
PubMed: 37621775
DOI: 10.3389/fcell.2023.1244321 -
Liver International : Official Journal... Aug 2023Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5-10% of chronic hepatitis B patients worldwide are... (Review)
Review
Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5-10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15-25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct-acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow-up, we propose that HIV-HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta.
Topics: Humans; Antiviral Agents; Hepatitis Delta Virus; HIV Infections; Hepatitis C, Chronic; Hepatitis B, Chronic; Hepatitis B virus; Hepatitis D; Hepatitis B; Coinfection
PubMed: 35748639
DOI: 10.1111/liv.15345