Explore the vast range of titles available.

Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.In this Timeline article, Shay and Wright provide a historical account of progress in our understanding of telomeres (the ends of linear chromosomes) and telomerase (the primary enzyme that maintains and extends telomere lengths). Their perspective covers seminal moments from the early discoveries through to our latest understanding of the roles of telomeres and telomerase in ageing, diverse human diseases and gene regulation.

Key Points The world's most common diseases are chronic ageing-associated illnesses. Premature ageing diseases and ageing-associated diseases (AADs) share the common hallmarks of increased genomic instability, altered metabolic signalling and reduced regenerative potency. Premature ageing diseases are powerful models to study the cellular and molecular causes and mechanisms of physiological ageing and AADs. Decreased efficiency of DNA repair, shortening of telomeres and loss of heterochromatin underlie the loss of genomic integrity in (premature) ageing and AADs. Increased metabolic signalling contributes to increased levels of oxidative stress, which compromise the integrity of the cellular genome and proteome in ageing. Chronic stress permanently alters cellular fate by inducing senescence and reducing the regenerative capacity of stem cells, which ultimately drives physiological decline in ageing. Segmental progeroid syndromes provide exciting new opportunities to understand and therapeutically correct the loss of cellular homeostasis in ageing and disease. The majority of common diseases are associated with ageing. Diseases that cause premature ageing serve as natural model systems for studying the mechanisms of ageing and disease, as they share similar cellular and molecular hallmarks, including genomic instability, metabolic defects and loss of regenerative capacity. Ageing is the predominant risk factor for many common diseases. Human premature ageing diseases are powerful model systems to identify and characterize cellular mechanisms that underpin physiological ageing. Their study also leads to a better understanding of the causes, drivers and potential therapeutic strategies of common diseases associated with ageing, including neurological disorders, diabetes, cardiovascular diseases and cancer. Using the rare premature ageing disorder Hutchinson–Gilford progeria syndrome as a paradigm, we discuss here the shared mechanisms between premature ageing and ageing-associated diseases, including defects in genetic, epigenetic and metabolic pathways; mitochondrial and protein homeostasis; cell cycle; and stem cell-regenerative capacity.

Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging. HGPS is a premature aging disease caused by mutations in the nuclear protein lamin A. Here, the authors show that cells from patients with HGPS have expanded nucleoli and increased protein synthesis, and report that nucleoli also expand as aging progresses in cells derived from healthy individuals.

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Here we show, through direct live-cell imaging of young, middle-aged, and old-aged primary human dermal fibroblasts, that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome mis-segregation in elderly mitotic cells correlates with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives G2/M gene expression. FoxM1 induction in elderly and Hutchison–Gilford progeria syndrome fibroblasts prevents aneuploidy and, importantly, ameliorates cellular aging phenotypes. Moreover, we show that senescent fibroblasts isolated from elderly donors’ cultures are often aneuploid, and that aneuploidy is a key trigger into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes. Evidence for mitotic decline in aged cells and for aneuploidy-driven progression into full senescence is limited. Here, the authors find that in aged cells, mitotic gene repression leads to increased chromosome mis-segregation and aneuploidy that triggers permanent cell cycle arrest and full senescence.

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease. Vascular senescence is closely associated with individual ageing, while its causative role remains unclear. Here Barinda et al. generate endothelial cell-specific progeroind mice, and reveal that endothelial cell senescence directly induces metabolic disorders through senescence-messaging secretomes.

Hutchinson‐Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disorder characterized by accelerated aging. The accumulation of an abnormal and toxic protein called progerin within HGPS nuclei disrupts cellular processes, including gene expression and DNA repair. Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defense, is one of the hallmarks of HGPS. To identify novel molecular mechanisms underlying HGPS pathogenesis, we performed miRNA expression profiling in HGPS compared to healthy control fibroblasts. We identified 10 differentially expressed (DE) miRNAs between HGPS and control cells. We focused on miR‐140‐5p and miR‐140‐3p, 2 miRNAs upregulated in HGPS fibroblasts. miR‐140‐5p is known to directly target the transcript of NRF2, a master regulator of the antioxidant response. Using in vitro mimic and antimiR transfections, we demonstrated that miR‐140‐5p overexpression in HGPS fibroblasts results in the downregulation of the NRF2/KEAP1/HO‐1 antioxidant pathway, leading to increased oxidative stress. Furthermore, our results indicate that miR‐140‐5p overexpression induces mitochondrial dysfunction, characterized by a reduced oxidative phosphorylation capacity and affects other hallmarks of aging. By targeting regulation of oxidative stress and mitochondrial function through NRF2, miR‐140‐5p may play a pivotal role in the pathophysiology of HGPS and open new therapeutic avenues. This study identifies a novel molecular mechanism involving miR‐140‐5p that contributes to the pathogenesis of HGPS. By decreasing NRF2 expression, miR‐140‐5p overexpression results in downregulation of the NRF2/KEAP1/HO‐1 antioxidant pathway in HGPS fibroblasts, leading to increased oxidative stress and mitochondrial dysfunction, two hallmarks of aging. (Figure created in BioRender. Magdinier, F. (2025) https://BioRender.com/zixfr1g).

Pyrophosphate deficiency may explain the excessive vascular calcification found in children with Hutchinson–Gilford progeria syndrome (HGPS) and in a mouse model of this disease. The present study found that hydrolysis products of ATP resulted in a <9% yield of pyrophosphate in wild-type blood and aortas, showing that eNTPD activity (ATP → phosphate) was greater than eNPP activity (ATP → pyrophosphate). Moreover, pyrophosphate synthesis from ATP was reduced and pyrophosphate hydrolysis (via TNAP; pyrophosphate → phosphate) was increased in both aortas and blood obtained from mice with HGPS. The reduced production of pyrophosphate, together with the reduction in plasma ATP, resulted in marked reduction of plasma pyrophosphate. The combination of TNAP inhibitor levamisole and eNTPD inhibitor ARL67156 increased the synthesis and reduced the degradation of pyrophosphate in aortas and blood ex vivo, suggesting that these combined inhibitors could represent a therapeutic approach for this devastating progeroid syndrome. Treatment with ATP prevented vascular calcification in HGPS mice but did not extend longevity. By contrast, combined treatment with ATP, levamisole, and ARL67156 prevented vascular calcification and extended longevity by 12% in HGPS mice. These findings suggest a therapeutic approach for children with HGPS.

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by a mutation in the LMNA gene that provokes the synthesis of progerin, a mutant version of the nuclear protein lamin A that accelerates aging and precipitates death. The most clinically relevant feature of HGPS is the development of cardiac anomalies and severe vascular alterations, including massive loss of vascular smooth muscle cells, increased fibrosis, and generalized atherosclerosis. However, it is unclear if progerin expression in endothelial cells (ECs) causes the cardiovascular manifestations of HGPS. To tackle this question, we generated atherosclerosis‐free mice (LmnaLCS/LCSCdh5‐CreERT2) and atheroprone mice (Apoe−/−LmnaLCS/LCSCdh5‐CreERT2) with EC‐specific progerin expression. Like progerin‐free controls, LmnaLCS/LCSCdh5‐CreERT2 mice did not develop heart fibrosis or cardiac electrical and functional alterations, and had normal vascular structure, body weight, and lifespan. Similarly, atheroprone Apoe−/−LmnaLCS/LCSCdh5‐CreERT2 mice showed no alteration in body weight or lifespan versus Apoe−/−LmnaLCS/LCS controls and did not develop vascular alterations or aggravated atherosclerosis. Our results indicate that progerin expression in ECs is not sufficient to cause the cardiovascular phenotype and premature death associated with progeria. Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant protein that is expressed in multiple cell types and accelerates aging, induces cardiovascular disease, and precipitates death. This study shows that mice with progerin expression restricted to endothelial cells do not develop heart fibrosis, cardiac electrical or functional alterations, or aggravated atherosclerosis, and have normal vascular structure, body weight, and lifespan.

Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A‐type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF‐1 and SRSF‐5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of Lmna G609G/G609G mice locally reduces SRSF‐1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS. Synopsis Progerin is a toxic protein that accumulates in the nuclei of Progeria patients' cells, sequestered in abnormal PML‐NBs. The proteasome inhibitor MG132 is shown to degrade progerin by activating autophagy and transcriptional inhibition through SRSF‐1 and SRSF‐5 splicing regulation. Ubiquitinylated progerin is sequestered into abnormal ProMyelocytic Leukemia Nuclear Bodies (PML‐NBs). Progerin reduction is based on MG132 dual action: autophagy activation and splicing regulation. MG132 in vitro treatment rescues most of the biological hallmarks of progeria. MG132 local treatment efficiently reduces progerin levels in vivo , in the Lmna G609G/G609G mouse model. The powerful and dual activities of MG132 make it a promising drug towards a future and safe therapeutic development for Progeria and related Prelamin‐A processing defective diseases. Graphical Abstract Progerin is a toxic protein that accumulates in the nuclei of Progeria patients' cells, sequestered in abnormal PML‐NBs. The proteasome inhibitor MG132 is shown to degrade progerin by activating autophagy and transcriptional inhibition through SRSF‐1 and SRSF‐5 splicing regulation.

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature aging and primarily caused by the accumulation of progerin, a mutant form of lamin A. Although the effects of progerin on multiple tissues have been previously studied, its impact on brain development is not completely understood. We established cortical organoids derived from HGPS patient‐induced pluripotent stem cells (iPSCs) from patients with HGPS to investigate the role of progerin in the brain. HGPS cortical organoids showed hallmarks of HGPS pathology, including elevated progerin expression and irregular nuclear morphology during early developmental stages. Additionally, we observed abnormal morphology and increased cellular senescence specifically in the rosette regions of HGPS organoids. This senescence appeared to interfere with normal neuronal differentiation, resulting in a significant reduction in mature neuron development and synapse formation in HGPS cortical organoids. Transcriptome profiling of HGPS cortical organoids revealed the downregulation of key genes related to neural development and synapse formation, with these changes persisting over time, potentially contributing to impaired neuronal differentiation and maturation. These findings suggest the role of progerin in early neural development and establish cortical organoids as a model for studying HGPS‐related brain development. HGPS patient‐derived cortical organoids exhibit progerin accumulation, nuclear abnormalities, and increased senescence in rosette structures, leading to impaired neuronal differentiation and altered gene expression.