-
Methods (San Diego, Calif.) Jun 2021What if the next generation of successful treatments was hidden in the current pharmacopoeia? Identifying new indications for existing drugs, also called the drug... (Review)
Review
What if the next generation of successful treatments was hidden in the current pharmacopoeia? Identifying new indications for existing drugs, also called the drug repurposing or drug rediscovery process, is a highly efficient and low-cost strategy. First reported almost a century ago, drug repurposing has emerged as a valuable therapeutic option for diseases that do not have specific treatments and rare diseases, in particular. This review focuses on Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder that induces accelerated and precocious aging, for which drug repurposing has led to the discovery of several potential treatments over the past decade.
Topics: Humans; Lamin Type A; Pharmaceutical Preparations; Progeria
PubMed: 32278808
DOI: 10.1016/j.ymeth.2020.04.005 -
Nihon Ronen Igakkai Zasshi. Japanese... 2021
Topics: Humans; Progeria
PubMed: 34483167
DOI: 10.3143/geriatrics.58.409 -
Frontiers in Bioscience (Scholar... Jun 2011Hutchinson-Gilford Progeria Syndrome (HGPS), a rare human disease characterized by premature aging, is mainly caused by the abnormal accumulation of progerin, a mutant... (Review)
Review
Hutchinson-Gilford Progeria Syndrome (HGPS), a rare human disease characterized by premature aging, is mainly caused by the abnormal accumulation of progerin, a mutant form of the mammalian nuclear envelope component lamin A. HGPS patients exhibit vascular alterations and die at an average age of 13 years, predominantly from myocardial infarction or stroke. Animal models of HGPS have been a valuable tool in the study of the pathological processes implicated in the origin of this disease and its associated cardiovascular alterations. Some of the molecular mechanisms of HGPS might be relevant to the process of normal aging, since progerin is detected in cells from normal elderly humans. Conversely, processes linked to normal aging, such as the increase in oxidative stress, might be relevant to the pathogenic mechanisms of HGPS. In this review, we discuss recent advances in the understanding of the molecular mechanisms underlying the cardiovascular alterations associated with HGPS, the potential role of oxidative stress, and therapeutic approaches for the treatment of this devastating disease.
Topics: Aging; Alternative Splicing; Animals; Cardiovascular Diseases; Cholesterol; Diphosphonates; Genetic Therapy; Humans; Lamin Type A; Membrane Proteins; Metalloendopeptidases; Mice; Mice, Knockout; Nuclear Proteins; Oligonucleotides; Oxidative Stress; Progeria; Protein Precursors; Terpenes
PubMed: 21622271
DOI: 10.2741/226 -
Molekuliarnaia Biologiia 2022Well-known theories of aging suggest that a certain metabolic defect negatively affects vital activity of the cell, be it oxidative stress, the accumulation of lesions...
Well-known theories of aging suggest that a certain metabolic defect negatively affects vital activity of the cell, be it oxidative stress, the accumulation of lesions in DNA, the exhaustion of telomeres, or distorted epigenetic processes. The theory of aging considered in the review postulates that an accumulation of progerin on the inner side of the nuclear envelope underlies the above defects. Progerin is a defective precursor of the lamin A nuclear matrix protein in which the C-terminal cysteine, which is removed normally, is retained and modified with a hydrophobic oligoisoprene chain. Progerin molecules attach with their hydrophobic processes to the inner membrane of the nuclear envelope, pushing away the adjacent fibrils of the nuclear matrix and the chromatin periphery. This changes the morphology and shape of the nucleus and alters the properties of the nuclear envelope and pore complexes embedded in it. As progerin accumulates in the nucleus, structural distortions increase in the nucleus, further distorting the nuclear-cytoplasmic transport of macromolecules and leading to the above defects in cell metabolism. This leads to increasing cell death and aging of the body over time. This mechanism of aging has been identified in patients with Hutchinson-Gilford progeria syndrome (HGPS). Mass progerin production in HGPS is caused by the point mutation c.1824C→T in exon 11 of the LMNA gene, which codes for lamins A and C. The mutation stimulates non-standard splicing of the primary transcript during the formation of the lamin A precursor mRNA, thus causing progerin production. Children with progeria who have received the mutation from one of their parents age rapidly and die before 15 years of age. Approaches to progeria treatment are aimed at preventing the formation of progerin or destroying the progerin that has already accumulated. In the latter case, a promising strategy is to use rapamycin or its analogs and other substances and techniques that activate autophagy to purify the cell from progerin. Although in much smaller amounts, progerin is found in progeria-free people and may therefore play a role in natural aging. A maximum age that a person can reach is possible to estimate by taking account of the role that progerin plays in telomere shortening. Encouraging preliminary results achieved in purifying cells from progerin provide a means to develop an optimal procedure for periodic purification of the human body from progerin in order to reduce the rate of aging.
Topics: Adolescent; Aging; Child; Humans; Mutation; Progeria; Telomere
PubMed: 35403615
DOI: 10.31857/S0026898422020124 -
British Journal of Clinical Pharmacology Nov 2016The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes, such as cell growth, survival,... (Review)
Review
The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes, such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, this signalling pathway has come to the attention of the scientific community owing to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends lifespan in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome [Hutchinson-Gilford Progeria syndrome (HGPS)] that recapitulates most of the traits of physiological ageing. The promising perspectives raised by these results warrant a better understanding of mTOR signalling and the potential applications of mTOR inhibitors to counteract ageing-associated diseases and increase longevity. This review is focused on these issues.
Topics: Aging; Animals; Humans; Models, Biological; Progeria; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases
PubMed: 26952863
DOI: 10.1111/bcp.12928 -
Aging Cell Jun 2023Partial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c-Myc induces rejuvenation and reduces aged-cell phenotypes. In this study, we found...
Partial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c-Myc induces rejuvenation and reduces aged-cell phenotypes. In this study, we found that transcriptional activation of the endogenous Oct4 gene by using the CRISPR/dCas9 activator system can efficiently ameliorate hallmarks of aging in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). We observed that the dCas9-Oct4 activator induced epigenetic remodeling, as evidenced by increased H3K9me3 and decreased H4K20me3 levels, without tumorization. Moreover, the progerin accumulation in HGPS aorta was significantly suppressed by the dCas9 activator-mediated Oct4 induction. Importantly, CRISPR/dCas9-activated Oct4 expression rescued the HGPS-associated vascular pathological features and lifespan shortening in the mouse model. These results suggest that partial rejuvenation via CRISPR/dCas9-mediated Oct4 activation can be used as a novel strategy in treating geriatric diseases.
Topics: Mice; Animals; Progeria; Transcriptional Activation; Clustered Regularly Interspaced Short Palindromic Repeats; Aging; Cellular Reprogramming; Disease Models, Animal; Lamin Type A
PubMed: 36964992
DOI: 10.1111/acel.13825 -
Cell Stem Cell Sep 2019Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic...
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
Topics: Adrenergic Agonists; Aging; Aging, Premature; Animals; Bone Marrow; Cell Differentiation; Cell Encapsulation; Cell Proliferation; Disease Models, Animal; Hematopoietic Stem Cells; Humans; Interleukin-6; Megakaryocytes; Mice; Myeloid Cells; Nitric Oxide Synthase Type I; Progeria; Receptors, Adrenergic, beta-2; Signal Transduction; Stem Cell Niche
PubMed: 31303548
DOI: 10.1016/j.stem.2019.06.007 -
JAMA Apr 2018
Topics: Humans; Precision Medicine; Progeria
PubMed: 29710145
DOI: 10.1001/jama.2018.2199 -
Microcirculation (New York, N.Y. : 1994) Apr 2010Endothelial cells are stimulated by shear stress throughout the vasculature and respond with changes in gene expression and by morphological reorganization. Mechanical... (Review)
Review
Endothelial cells are stimulated by shear stress throughout the vasculature and respond with changes in gene expression and by morphological reorganization. Mechanical sensors of the cell are varied and include cell surface sensors that activate intracellular chemical signaling pathways. Here, possible mechanical sensors of the cell including reorganization of the cytoskeleton and the nucleus are discussed in relation to shear flow. A mutation in the nuclear structural protein lamin A, related to Hutchinson-Gilford progeria syndrome, is reviewed specifically as the mutation results in altered nuclear structure and stiffer nuclei; animal models also suggest significantly altered vascular structure. Nuclear and cellular deformation of endothelial cells in response to shear stress provides partial understanding of possible mechanical regulation in the microcirculation. Increasing sophistication of fluid flow simulations inside the vessel is also an emerging area relevant to the microcirculation as visualization in situ is difficult. This integrated approach to study--including medicine, molecular and cell biology, biophysics and engineering--provides a unique understanding of multi-scale interactions in the microcirculation.
Topics: Animals; Biomechanical Phenomena; Cardiovascular Diseases; Cell Nucleus; Hemodynamics; Hemorheology; Humans; Lamin Type A; Mechanotransduction, Cellular; Microcirculation; Models, Cardiovascular; Mutation; Progeria; Signal Transduction
PubMed: 20374482
DOI: 10.1111/j.1549-8719.2009.00016.x -
Aging Jun 2021
Topics: Extracellular Vesicles; Gastrointestinal Microbiome; Gene Editing; Humans; Molecular Targeted Therapy; Point Mutation; Progeria
PubMed: 34176790
DOI: 10.18632/aging.203254