A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.

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Altered Nuclear Functions in Progeroid Syndromes: a Paradigm for Aging Research

The Scientific World JOURNAL ◽

10.1100/tsw.2009.159 ◽

2009 ◽

Vol 9 ◽

pp. 1449-1462 ◽

Cited By ~ 3

Author(s):

Baomin Li ◽

Sonali Jog ◽

Jose Candelario ◽

Sita Reddy ◽

Lucio Comai

Keyword(s):

Werner Syndrome ◽

Accelerated Aging ◽

Natural Aging ◽

Aging Research ◽

Cellular Processes ◽

Functional Connections ◽

Age Related ◽

Progeroid Syndromes ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), and highlight functional connections to cellular processes that may contribute to normal aging.

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Neurogenesis and brain aging

Reviews in the Neurosciences ◽

10.1515/revneuro-2018-0084 ◽

2019 ◽

Vol 30 (6) ◽

pp. 573-580 ◽

Cited By ~ 7

Author(s):

Nickolay K. Isaev ◽

Elena V. Stelmashook ◽

Elisaveta E. Genrikhs

Keyword(s):

Brain Aging ◽

Werner Syndrome ◽

Accelerated Aging ◽

Normal Aging ◽

Postnatal Period ◽

Human Aging ◽

Distinctive Features ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

The Brain

AbstractHuman 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).

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Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells

The Journals of Gerontology Series A ◽

10.1093/gerona/glz280 ◽

2020 ◽

Vol 75 (6) ◽

pp. 1073-1078 ◽

Cited By ~ 3

Author(s):

Célia A Aveleira ◽

Marisa Ferreira-Marques ◽

Luísa Cortes ◽

Jorge Valero ◽

Dina Pereira ◽

...

Keyword(s):

Neuropeptide Y ◽

Caloric Restriction ◽

Cellular Senescence ◽

Dermal Fibroblasts ◽

Cellular Aging ◽

Premature Aging ◽

Whole Body ◽

Lamin A ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Abstract Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

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Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

Nature Communications ◽

10.1038/s41467-019-13018-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 20

Author(s):

Julio Aguado ◽

Agustin Sola-Carvajal ◽

Valeria Cancila ◽

Gwladys Revêchon ◽

Peh Fern Ong ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Cellular Senescence ◽

Genetic Disorder ◽

Premature Aging ◽

Telomere Dysfunction ◽

Damage Response ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

AbstractHutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.

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Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools

Scientific Reports ◽

10.1038/s41598-021-92631-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna Kychygina ◽

Marina Dall’Osto ◽

Joshua A. M. Allen ◽

Jean-Charles Cadoret ◽

Vincent Piras ◽

...

Keyword(s):

Genetic Disorder ◽

Nuclear Lamina ◽

Replication Timing ◽

Premature Aging ◽

Functional Connection ◽

3D Genome ◽

Genome Wide ◽

Associated Proteins ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

AbstractChromatin organization within the nuclear volume is essential to regulate many aspects of its function and to safeguard its integrity. A key player in this spatial scattering of chromosomes is the nuclear envelope (NE). The NE tethers large chromatin domains through interaction with the nuclear lamina and other associated proteins. This organization is perturbed in cells from Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging features. Here, we show that HGPS-related lamina defects trigger an altered 3D telomere organization with increased contact sites between telomeres and the nuclear lamina, and an altered telomeric chromatin state. The genome-wide replication timing signature of these cells is perturbed, with a shift to earlier replication for regions that normally replicate late. As a consequence, we detected a higher density of replication forks traveling simultaneously on DNA fibers, which relies on limiting cellular dNTP pools to support processive DNA synthesis. Remarkably, increasing dNTP levels in HGPS cells rescued fragile telomeres, and improved the replicative capacity of the cells. Our work highlights a functional connection between NE dysfunction and telomere homeostasis in the context of premature aging.

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Arterial stiffness and cardiac dysfunction in Hutchinson–Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase

Life Science Alliance ◽

10.26508/lsa.202000997 ◽

2021 ◽

Vol 4 (5) ◽

pp. e202000997

Author(s):

Ryan von Kleeck ◽

Emilia Roberts ◽

Paola Castagnino ◽

Kyle Bruun ◽

Sonja A Brankovic ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Carotid Arteries ◽

Lysyl Oxidase ◽

Premature Aging ◽

Wild Type ◽

Arterial Stiffening ◽

Genome Wide ◽

Mechanistic Analysis ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson–Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminAG609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.

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Metabolomic profiling revels systemic signatures of premature aging induced by Hutchinson-Gilford Progeria Syndrome

10.1101/554220 ◽

2019 ◽

Author(s):

Gustavo Monnerat ◽

Geisa Paulino Caprini Evaristo ◽

Joseph Albert Medeiros Evaristo ◽

Caleb Guedes Miranda dos Santos ◽

Gabriel Carneiro ◽

...

Keyword(s):

Energy Use ◽

Genetic Disorder ◽

Accelerated Aging ◽

Cardiovascular Complications ◽

Premature Aging ◽

Targeted Metabolomics ◽

Area Under Roc Curve ◽

Progeria Syndrome ◽

Metabolic Biomarkers ◽

Hutchinson Gilford Progeria Syndrome

AbstractHutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder. HGPS children present a high incidence of cardiovascular complications along with altered metabolic processes and accelerated aging process. No metabolic biomarker is known and the mechanisms underlying premature aging are not fully understood. The present study analysed plasma from six HGPS patients of both sexes (7.7±1.4 years old; mean±SD) and eight controls (8.6±2.3 years old) by LC-MS/MS in high-resolution non-targeted metabolomics (Q-Exactive Plus). Several endogenous metabolites with statistical difference were found. Multivariate statistics analysis showed a clear separation between groups. Potential novel metabolic biomarkers are identified using the multivariate area under ROC curve (AUROC) based analysis, showing an AUC value higher than 0.80 using only two metabolites, and reaching 1.00 when increasing the number of metabolites in the AUROC model. Targeted metabolomics was used to validate some of the metabolites identified by the non-targeted method. Taken together, changed metabolic pathways in that panel involve sphingolipid, amino acid, and oxidation of fatty acids among others. In conclusion our data show significant alterations in cellular energy use and availability, in signal transduction, and in lipid metabolites, creating new insights on metabolic alterations associated with premature aging.

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Accelerated aging and aging process in the brain

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0051 ◽

2018 ◽

Vol 29 (3) ◽

pp. 233-240 ◽

Cited By ~ 13

Author(s):

Nickolay K. Isaev ◽

Elisaveta E. Genrikhs ◽

Maria V. Oborina ◽

Elena V. Stelmashook

Keyword(s):

Down Syndrome ◽

Brain Aging ◽

Werner Syndrome ◽

Accelerated Aging ◽

Whole Body ◽

Chronic Oxidative Stress ◽

Neuronal Mechanisms ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

The Brain

AbstractOne of the approaches to the research of the problem of aging is the study of genetic pathologies leading to accelerated aging, such as the Hutchinson-Gilford progeria syndrome, Werner syndrome, and Down syndrome. Probably, this approach can be used in an attempt to understand the neuronal mechanisms underlying normal and pathological brain aging. The analysis of the current state of scientific knowledge about these pathologies shows that in the Hutchinson-Gilford progeria and Werner syndrome, the rate of brain aging is significantly lower than the rate of whole body aging, whereas in Down syndrome, the brain ages faster than other organs due to amyloid-beta accumulation and chronic oxidative stress in the brain tissue. The main point of a previously proposed hypothesis is that the aging of higher animals and humans is associated with an increased level of reactive oxygen species in mitochondria with age, which activates apoptosis, thus reducing the number of functioning cells.

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Impact of Progerin Expression on Adipogenesis in Hutchinson—Gilford Progeria Skin-Derived Precursor Cells

Cells ◽

10.3390/cells10071598 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1598

Author(s):

Farah Najdi ◽

Peter Krüger ◽

Karima Djabali

Keyword(s):

Cellular Senescence ◽

Adipogenic Differentiation ◽

Subcutaneous Fat ◽

Premature Aging ◽

Normal Fibroblast ◽

Potential Treatment ◽

Differentiation Potential ◽

Prelamin A ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a segmental premature aging disease caused by a mutation in LMNA. The mutation generates a truncated and farnesylated form of prelamin A, called progerin. Affected individuals develop several features of normal aging, including lipodystrophy caused by the loss of general subcutaneous fat. To determine whether premature cellular senescence is responsible for the altered adipogenesis in patients with HGPS, we evaluated the differentiation of HGPS skin-derived precursor stem cells (SKPs) into adipocytes. The SKPs were isolated from primary human HGPS and normal fibroblast cultures, with senescence of 5 and 30%. We observed that the presence of high numbers of senescent cells reduced SKPs’ adipogenic differentiation potential. Treatment with baricitinib, a JAK–STAT inhibitor, ameliorated the ability of HGPS SKPs to differentiate into adipocytes. Our findings suggest that the development of lipodystrophy in patients with HGPS may be associated with an increased rate of cellular senescence and chronic inflammation.

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