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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 -
ELife Jan 2021Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality.... (Review)
Review
Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.
Topics: Aging; Animals; DNA Damage; Humans; Inflammation; Proteostasis
PubMed: 33512317
DOI: 10.7554/eLife.62852 -
Cureus Aug 2022Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging condition that involves genetic mutations, resulting in debilitating phenotypic features. The present... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging condition that involves genetic mutations, resulting in debilitating phenotypic features. The present state of knowledge on the molecular pathways that contribute to the pathophysiology of HGPS and the techniques being tested and to combat progerin toxicity have been discussed here. Nuclear morphological abnormalities, dysregulated gene expression, DNA repair deficiencies, telomere shortening, and genomic instability are all caused by progerin accumulation, all of which impair cellular proliferative capability. In addition, HGPS cells and preclinical animal models have revealed new information about the disease's molecular and cellular pathways and putative mechanisms involved in normal aging. This article has discussed the understanding of the molecular pathways by which progerin expression leads to HGPS and how the advanced therapy options for HGPS patients can help us understand and treat the condition.
PubMed: 36196312
DOI: 10.7759/cureus.28629 -
Annual Review of Biomedical Engineering Jun 2023The process of aging manifests from a highly interconnected network of biological cascades resulting in the degradation and breakdown of every living organism over time.... (Review)
Review
The process of aging manifests from a highly interconnected network of biological cascades resulting in the degradation and breakdown of every living organism over time. This natural development increases risk for numerous diseases and can be debilitating. Academic and industrial investigators have long sought to impede, or potentially reverse, aging in the hopes of alleviating clinical burden, restoring functionality, and promoting longevity. Despite widespread investigation, identifying impactful therapeutics has been hindered by narrow experimental validation and the lack of rigorous study design. In this review, we explore the current understanding of the biological mechanisms of aging and how this understanding both informs and limits interpreting data from experimental models based on these mechanisms. We also discuss select therapeutic strategies that have yielded promising data in these model systems with potential clinical translation. Lastly, we propose a unifying approach needed to rigorously vet current and future therapeutics and guide evaluation toward efficacious therapies.
Topics: Humans; Aging; Longevity; Models, Biological; Models, Theoretical; Rejuvenation
PubMed: 37289554
DOI: 10.1146/annurev-bioeng-120122-123054 -
Nature Reviews. Genetics Feb 2020The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an... (Review)
Review
The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified many loci that influence key human ageing traits, including lifespan. Multi-trait loci have been linked with several age-related diseases, suggesting shared ageing influences. Mutations that drive accelerated ageing in prototypical progeria syndromes in humans point to an important role for genome maintenance and stability. Together, these different strands of genetic research are highlighting pathways for the discovery of anti-ageing interventions that may be applicable in humans.
Topics: Aging; Animals; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Longevity; Mutation; Phenotype; Reproduction
PubMed: 31690828
DOI: 10.1038/s41576-019-0183-6 -
Cell Reports Dec 2022Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation...
Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune- and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here, we have performed a mitochondria-targeted CRISPR knockout screen for regulators of the IFN-I response. Strikingly, our screen reveals dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, mitochondrial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the FF-ATP synthase. Disrupting these cristae organizers consistently induces mtDNA release and the STING-dependent IFN-I response. Furthermore, knocking out MTX2, a subunit of the SAM complex whose null mutations cause progeria in humans, induces a robust STING-dependent IFN-I response in mouse liver. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.
Topics: Humans; Animals; Mice; DNA, Mitochondrial
PubMed: 36476853
DOI: 10.1016/j.celrep.2022.111774 -
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 -
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