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Reviews in the Neurosciences Jul 2019Human aging affects the entire organism, but aging of the brain must undoubtedly be different from that of all other organs, as neurons are highly differentiated... (Review)
Review
Human aging affects the entire organism, but aging of the brain must undoubtedly be different from that of all other organs, as neurons are highly differentiated postmitotic cells, for the majority of which the lifespan in the postnatal period is equal to the lifespan of the entire organism. In this work, we examine the distinctive features of brain aging and neurogenesis during normal aging, pathological aging (Alzheimer's disease), and accelerated aging (Hutchinson-Gilford progeria syndrome and Werner syndrome).
Topics: Aging; Alzheimer Disease; Animals; Brain; Humans; Neurogenesis
PubMed: 30763272
DOI: 10.1515/revneuro-2018-0084 -
Cells Dec 2021Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining,... (Review)
Review
Methylene blue (MB), as the first fully man-made medicine, has a wide range of clinical applications. Apart from its well-known applications in surgical staining, malaria, and methemoglobinemia, the anti-oxidative properties of MB recently brought new attention to this century-old drug. Mitochondrial dysfunction has been observed in systematic aging that affects many different tissues, including the brain and skin. This leads to increaseding oxidative stress and results in downstream phenotypes under age-related conditions. MB can bypass Complex I/III activity in mitochondria and diminish oxidative stress to some degree. This review summarizes the recent studies on the applications of MB in treating age-related conditions, including neurodegeneration, memory loss, skin aging, and a premature aging disease, progeria.
Topics: Aging; Animals; Brain; Humans; Methylene Blue; Models, Biological; Skin Aging
PubMed: 34943887
DOI: 10.3390/cells10123379 -
Ageing Research Reviews Jan 2017Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including... (Review)
Review
Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1-3) and two complementation groups (CSA and CSB), and CS overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been ascribed to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility for molecular interventions in CS, and by extrapolation, possibly in aging.
Topics: Aging; Aging, Premature; Animals; Cockayne Syndrome; Cognition; DNA Repair; Humans; Mitochondria; Models, Biological; Symptom Assessment; Transcriptional Activation
PubMed: 27507608
DOI: 10.1016/j.arr.2016.08.002 -
Ageing Research Reviews Jan 2017Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is... (Review)
Review
Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.
Topics: Aging; Aging, Premature; Cellular Senescence; DNA Repair; Disease Management; Genomic Instability; Humans; Lamin Type A; Mutation; Progeria
PubMed: 27374873
DOI: 10.1016/j.arr.2016.06.007 -
Nature Jan 2021Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that...
Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.
Topics: Adenine; Alleles; Alternative Splicing; Animals; Aorta; Base Pairing; Child; DNA; Disease Models, Animal; Female; Fibroblasts; Gene Editing; Humans; Lamin Type A; Longevity; Male; Mice; Mice, Transgenic; Mutant Proteins; Mutation; Progeria; RNA
PubMed: 33408413
DOI: 10.1038/s41586-020-03086-7 -
Cell Apr 2016Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely...
Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.
Topics: Adipose Tissue, White; Amino Acid Sequence; Animals; Antibodies; Circadian Rhythm; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Fasting; Female; Fetal Growth Retardation; Fibrillin-1; Glucose; Humans; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microfilament Proteins; Molecular Sequence Data; Peptide Fragments; Peptide Hormones; Progeria; Recombinant Proteins; Sequence Alignment
PubMed: 27087445
DOI: 10.1016/j.cell.2016.02.063 -
Cell Reports Nov 2022Mitochondrial dysfunction, a hallmark of aging, has been associated with the onset of aging phenotypes and age-related diseases. Here, we report that impaired...
Mitochondrial dysfunction, a hallmark of aging, has been associated with the onset of aging phenotypes and age-related diseases. Here, we report that impaired mitochondrial function is associated with increased glutamine catabolism in senescent human mesenchymal stem cells (MSCs) and myofibroblasts derived from patients suffering from Hutchinson-Gilford progeria syndrome. Increased glutaminase (GLS1) activity accompanied by loss of urea transporter SLC14A1 induces urea accumulation, mitochondrial dysfunction, and DNA damage. Conversely, blocking GLS1 activity restores mitochondrial function and leads to amelioration of aging hallmarks. Interestingly, GLS1 expression is regulated through the JNK pathway, as demonstrated by chemical and genetic inhibition. In agreement with our in vitro findings, tissues isolated from aged or progeria mice display increased urea accumulation and GLS1 activity, concomitant with declined mitochondrial function. Inhibition of glutaminolysis in progeria mice improves mitochondrial respiratory chain activity, suggesting that targeting glutaminolysis may be a promising strategy for restoring age-associated loss of mitochondrial function.
Topics: Humans; Mice; Animals; Aged; Progeria; Mitochondria; Stem Cells; Mitochondrial Membranes; Aging; Psychomotor Agitation
PubMed: 36450260
DOI: 10.1016/j.celrep.2022.111744 -
Archives of Medical Research Jul 2023In humans, aging is characterized by a gradual decline of physical and psychological functions, with the concomitant onset of chronic-degenerative diseases, which... (Review)
Review
In humans, aging is characterized by a gradual decline of physical and psychological functions, with the concomitant onset of chronic-degenerative diseases, which ultimately lead to death. The study of Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder that recapitulates several features of natural aging, has provided important insights into deciphering the aging process. The genetic origin of HGPS is a de novo point mutation in the LMNA gene that drives the synthesis of progerin, mutant version of lamin A. Progerin is aberrantly anchored to the nuclear envelope disrupting a plethora of molecular processes; nonetheless, how progerin exerts a cascade of deleterious alterations at the cellular and systemic levels is not fully understood. Over the past decade, the use of different cellular and animal models for HGPS has allowed the identification of the molecular mechanisms underlying HGPS, paving the way towards the development of therapeutic treatments against the disease. In this review, we present an updated overview of the biology of HGPS, including its clinical features, description of key cellular processes affected by progerin (nuclear morphology and function, nucleolar activity, mitochondrial function, protein nucleocytoplasmic trafficking and telomere homeostasis), as well as discussion of the therapeutic strategies under development.
Topics: Animals; Humans; Progeria; Aging; Mitochondria
PubMed: 37390702
DOI: 10.1016/j.arcmed.2023.06.002 -
Nucleus (Austin, Tex.) Jan 2018Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually due to cardiovascular complications. HGPS is caused by a de novo point mutation in the LMNA gene encoding the intermediate filament proteins lamins A and C which are structural components of the nuclear lamina. This mutation leads to the production of a truncated toxic form of lamin A, issued from aberrant splicing and called progerin. Progerin accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. HGPS cells and animal preclinical models have provided insights into the molecular and cellular pathways that underlie the disease and have also highlighted possible mechanisms involved in normal aging. This review reports recent medical advances and treatment approaches for patients affected with HGPS.
Topics: Animals; Cell Nucleus; Humans; Mutation; Progeria
PubMed: 29619863
DOI: 10.1080/19491034.2018.1460045