Defining the progeria phenome.

Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. Due to the large variation in clinical presentation the diseases pose a diagnostic challenge for clinicians which consequently restricts medical research. To accommodate the challenge, we compiled a list of known progeroid syndromes and calculated the mean prevalence of their associated phenotypes, defining what we term the 'progeria phenome'. The data were used to train a support vector machine that is available at https://www.mitodb.com and able to classify progerias based on phenotypes. Furthermore, this allowed us to investigate the correlation of progeroid syndromes and syndromes with various pathogenesis using hierarchical clustering algorithms and disease networks. We detected that ataxia-telangiectasia like disorder 2, spastic paraplegia 49 and Meier-Gorlin syndrome display strong association to progeroid syndromes, thereby implying that the syndromes are previously unrecognized progerias. In conclusion, our study has provided tools to evaluate the likelihood of a syndrome or patient being progeroid. This is a considerable step forward in our understanding of what constitutes a premature aging disorder and how to diagnose them.

H2A.Z is involved in premature aging and DSB repair initiation in muscle fibers.

Histone variants are key epigenetic players, but their functional and physiological roles remain poorly understood. Here, we show that depletion of the histone variant H2A.Z in mouse skeletal muscle causes oxidative stress, oxidation of proteins, accumulation of DNA damages, and both neuromuscular junction and mitochondria lesions that consequently lead to premature muscle aging and reduced life span. Investigation of the molecular mechanisms involved shows that H2A.Z is required to initiate DNA double strand break repair by recruiting Ku80 at DNA lesions. This is achieved via specific interactions of Ku80 vWA domain with H2A.Z. Taken as a whole, our data reveal that H2A.Z containing nucleosomes act as a molecular platform to bring together the proteins required to initiate and process DNA double strand break repair.

Lipodystrophy as a target to delay premature aging.

Lipodystrophy syndromes are rare diseases characterized by low levels and an abnormal distribution of adipose tissue, caused by diverse genetic or acquired causes. These conditions commonly exhibit metabolic complications, including insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, and adipose tissue dysfunction. Moreover, genetic lipodystrophic laminopathies exhibit a premature aging phenotype, emphasizing the importance of restoring adipose tissue distribution and function. In this opinion, we discuss the relevance of adipose tissue reestablishment as a potential approach to alleviate premature aging and age-related complications in genetic lipodystrophy syndromes.

DNA repair-deficient premature aging models display accelerated epigenetic age.

Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.

Excessive apoptosis of Rip1-deficient T cells leads to premature aging.

In mammals, the most remarkable T cell variations with aging are the shrinking of the naïve T cell pool and the enlargement of the memory T cell pool, which are partially caused by thymic involution. However, the mechanism underlying the relationship between T-cell changes and aging remains unclear. In this study, we find that T-cell-specific Rip1 KO mice show similar age-related T cell changes and exhibit signs of accelerated aging-like phenotypes, including inflammation, multiple age-related diseases, and a shorter lifespan. Mechanistically, Rip1-deficient T cells undergo excessive apoptosis and promote chronic inflammation. Consistent with this, blocking apoptosis by co-deletion of Fadd in Rip1-deficient T cells significantly rescues lymphopenia, the imbalance between naïve and memory T cells, and aging-like phenotypes, and prolongs life span in T-cell-specific Rip1 KO mice. These results suggest that the reduction and hyperactivation of T cells can have a significant impact on organismal health and lifespan, underscoring the importance of maintaining T cell homeostasis for healthy aging and prevention or treatment of age-related diseases.

Tissue-specific expression of senescence biomarkers in spontaneously hypertensive rats: evidence of premature aging in hypertension.

Background: Cellular senescence is an age-related physiological process that contributes to tissue dysfunction and accelerated onset of chronic metabolic diseases including hypertension. Indeed, elevation of blood pressure in hypertension coincides with premature vascular aging and dysfunction. In addition, onsets of metabolic disturbance and osteopenia in patients with hypertension have also been reported. It is possible that hypertension enhances premature aging and causes progressive loss of function in multiple organs. However, the landscape of cellular senescence in critical tissues affected by hypertension remains elusive. Materials and Methods: Heart, liver, bone, hypothalamus, and kidney were collected from spontaneously hypertensive rats (SHR) and age- and sex-matched normotensive Wistar rats (WT) at 6, 12, 24 and 36 weeks of age (n = 10 animals/group). Changes in mRNA levels of senescence biomarkers namely cyclin-dependent kinase (CDK) inhibitors (CDKIs), i.e., Cdkn2a (encoding p16Ink4a) and Cdkn1a (encoding p21cip1) as well as senescence-associated secretory phenotypes (SASPs), i.e., Timp1, Mmp12, Il6 and Cxcl1, were determined. Additionally, bone collagen alignment and hydroxy apatite crystal dimensions were determined by synchrotron radiation small- and wide-angle X-ray scattering (SAXS/WAXS) techniques. Results: Real-time PCR revealed that transcript levels of genes encoding CDKIs and SASPs in the heart and liver were upregulated in SHR from 6 to 36 weeks of age. Expression of Timp1 and Cxcl1 was increased in bone tissues isolated from 36-week-old SHR. In contrast, we found that expression levels of Timp1 and Il6 mRNA were decreased in hypothalamus and kidney of SHR in all age groups. Simultaneous SAXS/WAXS analysis also revealed misalignment of bone collagen fibers in SHR as compared to WT. Conclusion: Premature aging was identified in an organ directly affected by high blood pressure (i.e., heart) and those with known functional defects in SHR (i.e., liver and bone). Cellular senescence was not evident in organs with autoregulation of blood pressure (i.e., brain and kidney). Our study suggested that cellular senescence is induced by persistently elevated blood pressure and in part, leading to organ dysfunction. Therefore, interventions that can both lower blood pressure and prevent cellular senescence should provide therapeutic benefits for treatment of cardiovascular and metabolic consequences.

Ghrelin delays premature aging in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition that arises from a single nucleotide alteration in the LMNA gene, leading to the production of a defective lamin A protein known as progerin. The accumulation of progerin accelerates the onset of a dramatic premature aging phenotype in children with HGPS, characterized by low body weight, lipodystrophy, metabolic dysfunction, skin, and musculoskeletal age-related dysfunctions. In most cases, these children die of age-related cardiovascular dysfunction by their early teenage years. The absence of effective treatments for HGPS underscores the critical need to explore novel safe therapeutic strategies. In this study, we show that treatment with the hormone ghrelin increases autophagy, decreases progerin levels, and alleviates other cellular hallmarks of premature aging in human HGPS fibroblasts. Additionally, using a HGPS mouse model (LmnaG609G/G609G mice), we demonstrate that ghrelin administration effectively rescues molecular and histopathological progeroid features, prevents progressive weight loss in later stages, reverses the lipodystrophic phenotype, and extends lifespan of these short-lived mice. Therefore, our findings uncover the potential of modulating ghrelin signaling offers new treatment targets and translational approaches that may improve outcomes and enhance the quality of life for patients with HGPS and other age-related pathologies.

Decreased hepatic thyroid hormone signaling in systemic and liver-specific but not brain-specific accelerated aging due to DNA repair deficiency in mice.

Background: Thyroid hormone signaling is essential for development, metabolism, and response to stress but declines during aging, the cause of which is unknown. DNA damage accumulating with time is a main cause of aging, driving many age-related diseases. Previous studies in normal and premature aging mice, due to defective DNA repair, indicated reduced hepatic thyroid hormone signaling accompanied by decreased type 1 deiodinase (DIO1) and increased DIO3 activities. We investigated whether aging-related changes in deiodinase activity are driven by systemic signals or represent cell- or organ-autonomous changes. Methods: We quantified liver and plasma thyroid hormone concentrations, deiodinase activities and expression of T3-responsive genes in mice with a global, liver-specific and for comparison brain-specific inactivation of Xpg, one of the endonucleases critically involved in multiple DNA repair pathways. Results: Both in global and liver-specific Xpg knockout mice, hepatic DIO1 activity was decreased. Interestingly, hepatic DIO3 activity was increased in global, but not in liver-specific Xpg mutants. Selective Xpg deficiency and premature aging in the brain did not affect liver or systemic thyroid signaling. Concomitant with DIO1 inhibition, Xpg -/- and Alb-Xpg mice displayed reduced thyroid hormone-related gene expression changes, correlating with markers of liver damage and cellular senescence. Conclusions: Our findings suggest that DIO1 activity during aging is predominantly modified in a tissue-autonomous manner driven by organ/cell-intrinsic accumulating DNA damage. The increase in hepatic DIO3 activity during aging largely depends on systemic signals, possibly reflecting the presence of circulating cells rather than activity in hepatocytes.

[Progeroid syndromes : Aging, skin aging, and mechanisms of progeroid syndromes]. / Progeroide Syndrome : Alterung, Hautalterung und Mechanismen progeroider Erkrankungen.

Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. PSs display a wide range of heterogeneous pathological symptoms that also manifest during natural aging, including vision and hearing loss, atrophy, hair loss, progressive neurodegeneration, and cardiovascular defects. Recent advances in molecular pathology have led to a better understanding of the underlying mechanisms of these diseases. The genetic mutations underlying PSs are functionally linked to genome maintenance and repair, supporting the causative role of DNA damage accumulation in aging. While some of those genes encode proteins with a direct involvement in a DNA repair machinery, such as nucleotide excision repair (NER), others destabilize the genome by compromising the stability of the nuclear envelope, when lamin A is dysfunctional in Hutchinson-Gilford progeria syndrome (HGPS) or regulate the DNA damage response (DDR) such as the ataxia telangiectasia-mutated (ATM) gene. Understanding the molecular pathology of progeroid diseases is crucial in developing potential treatments to manage and prevent the onset of symptoms. This knowledge provides insight into the underlying mechanisms of premature aging and could lead to improved quality of life for individuals affected by progeroid diseases.

Bloom syndrome patients and mice display accelerated epigenetic aging.

Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.

The secretome atlas of two mouse models of progeria.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (LmnaG609G/G609G and Zmpste24-/- mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging.

Oxidative stress associated with spatial memory impairment and social olfactory deterioration in female mice reveals premature aging aroused by perinatal protein malnutrition.

Early-life adversity, like perinatal protein malnutrition, increases the vulnerability to develop long-term alterations in brain structures and function. This study aimed to determine whether perinatal protein malnutrition predisposes to premature aging in a murine model and to assess the cellular and molecular mechanisms involved. To this end, mouse dams were fed either with a normal (NP, casein 20%) or a low-protein diet (LP, casein 8%) during gestation and lactation. Female offspring were evaluated at 2, 7 and 12 months of age. Positron emission tomography analysis showed alterations in the hippocampal CA3 region and the accessory olfactory bulb of LP mice during aging. Protein malnutrition impaired spatial memory, coinciding with higher levels of reactive oxygen species in the hippocampus and sirt7 upregulation. Protein malnutrition also led to higher senescence-associated ß-galactosidase activity and p21 expression. LP-12-month-old mice showed a higher number of newborn neurons that did not complete the maturation process. The social-odor discrimination in LP mice was impaired along life. In the olfactory bulb of LP mice, the senescence marker p21 was upregulated, coinciding with a downregulation of Sirt2 and Sirt7. Also, LP-12-month-old mice showed a downregulation of catalase and glutathione peroxidase, and LP-2-month-old mice showed a higher number of newborn neurons in the subventricular zone, which then returned to normal values. Our results show that perinatal protein malnutrition causes long-term impairment in cognitive and olfactory skills through an accelerated senescence phenotype accompanied by an increase in oxidative stress and altered sirtuin expression in the hippocampus and olfactory bulb.

Nuclear proteostasis imbalance in laminopathy-associated premature aging diseases.

Laminopathies are a group of rare genetic disorders with heterogeneous clinical phenotypes such as premature aging, cardiomyopathy, lipodystrophy, muscular dystrophy, microcephaly, epilepsy, and so on. The cellular phenomena associated with laminopathy invariably show disruption of nucleoskeleton of lamina due to deregulated expression, localization, function, and interaction of mutant lamin proteins. Impaired spatial and temporal tethering of lamin proteins to the lamina or nucleoplasmic aggregation of lamins are the primary molecular events that can trigger nuclear proteotoxicity by modulating differential protein-protein interactions, sequestering quality control proteins, and initiating a cascade of abnormal post-translational modifications. Clearly, laminopathic cells exhibit moderate to high nuclear proteotoxicity, raising the question of whether an imbalance in nuclear proteostasis is involved in laminopathic diseases, particularly in diseases of early aging such as HGPS and laminopathy-associated premature aging. Here, we review nuclear proteostasis and its deregulation in the context of lamin proteins and laminopathies.

Premature aging and reduced cancer incidence associated with near-complete body-wide Myc inactivation.

MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc+/- mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. "MycKO" mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.

Gut-specific telomerase expression counteracts systemic aging in telomerase-deficient zebrafish.

Telomere shortening is a hallmark of aging and is counteracted by telomerase. As in humans, the zebrafish gut is one of the organs with the fastest rate of telomere decline, triggering early tissue dysfunction during normal zebrafish aging and in prematurely aged telomerase mutants. However, whether telomere-dependent aging of an individual organ, the gut, causes systemic aging is unknown. Here we show that tissue-specific telomerase expression in the gut can prevent telomere shortening and rescues premature aging of tert-/-. Induction of telomerase rescues gut senescence and low cell proliferation, while restoring tissue integrity, inflammation and age-dependent microbiota dysbiosis. Averting gut aging causes systemic beneficial impacts, rescuing aging of distant organs such as reproductive and hematopoietic systems. Conclusively, we show that gut-specific telomerase expression extends the lifespan of tert-/- by 40%, while ameliorating natural aging. Our work demonstrates that gut-specific rescue of telomerase expression leading to telomere elongation is sufficient to systemically counteract aging in zebrafish.

Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns.

The genetic disorder, ataxia-telangiectasia (A-T), is caused by loss of the homeostatic protein kinase, ATM, and combines genome instability, tissue degeneration, cancer predisposition, and premature aging. Primary fibroblasts from A-T patients exhibit premature senescence when grown at ambient oxygen concentration (21%). Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A-T skin fibroblasts. However, they still undergo senescence earlier than control cells grown under the same conditions and exhibit high genome instability. Comparative RNA-seq analysis of A-T and control fibroblasts cultured at 3% oxygen followed by cluster analysis of differentially expressed genes and functional enrichment analysis, revealed distinct transcriptional dynamics in A-T fibroblasts senescing in physiological oxygen concentration. While some transcriptional patterns were similar to those observed during replicative senescence of control cells, others were unique to the senescing A-T cells. We observed in them a robust activation of interferon-stimulated genes, with undetected expression the interferon genes themselves. This finding suggests an activation of a non-canonical cGAS-STING-mediated pathway, which presumably responds to cytosolic DNA emanating from extranuclear micronuclei detected in these cells. Senescing A-T fibroblasts also exhibited a marked, intriguely complex alteration in the expression of genes associated with extracellular matrix (ECM) remodeling. Notably, many of the induced ECM genes encode senescence-associated secretory phenotype (SASP) factors known for their paracrine pro-fibrotic effects. Our data provide a molecular dimension to the segmental premature aging observed in A-T patients and its associated symptoms, which develop as the patients advance in age.

Association of DNA methylation signatures with premature ageing and cardiovascular death in patients with end-stage kidney disease: a pilot epigenome-wide association study.

Patients with end-stage kidney disease (ESKD) display features of premature aging. There is strong evidence that changes in DNA methylation (DNAm) contribute to age-related pathologies; however, little is known about their association with premature aging and cardiovascular mortality in patients with ESKD. We assayed genome-wide DNAm in a pilot case-control study of 60 hemodialysis patients with (n=30, cases) and without (n=30, controls) a fatal cardiovascular event. DNAm was profiled on the Illumina EPIC BeadChip. Four established DNAm clocks (i.e., Horvath-, Hannum-, Pheno-, and GrimAge) were used to estimate epigenetic age (DNAmAge). Epigenetic age acceleration (EAA) was derived as the residuals of regressing DNAmAge on chronological age (chroAge), and its association with cardiovascular death was examined using multivariable conditional logistic regression. An epigenome-wide association study (EWAS) was performed to identify differentially methylated CpGs associated with cardiovascular death. All clocks performed well at predicting chroAge (correlation between DNAmAges and chroAge of r=0.76-0.89), with GrimAge showing the largest deviation from chroAge (a mean of +21.3 years). There was no significant association of EAAs with cardiovascular death. In the EWAS, a CpG (cg22305782) in the FBXL19 gene had the strongest association with cardiovascular death with significantly lower DNAm in cases vs. controls (PFDR=2.0x10-6). FBXL19 is involved in cell apoptosis, inflammation, and adipogenesis. Overall, we observed more accelerated aging in patients with ESKD, although there was no significant association of EAAs with cardiovascular death. EWAS suggests a potential novel DNAm biomarker for premature cardiovascular mortality in ESKD.

The Consideration of Pseudoxanthoma Elasticum as a Progeria Syndrome.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene. Patients with PXE show molecular and clinical characteristics of known premature aging syndromes, such as Hutchinson-Gilford progeria syndrome (HGPS). Nevertheless, PXE has only barely been discussed against the background of premature aging, although a detailed characterization of aging processes in PXE could contribute to a better understanding of its pathogenesis. Thus, this study was performed to evaluate whether relevant factors which are known to play a role in accelerated aging processes in HGPS pathogenesis are also dysregulated in PXE. METHODS: Primary human dermal fibroblasts from healthy donors (n = 3) and PXE patients (n = 3) and were cultivated under different culture conditions as our previous studies point towards effects of nutrient depletion on PXE phenotype. Gene expression of lamin A, lamin C, nucleolin, farnesyltransferase and zinc metallopeptidase STE24 were determined by quantitative real-time polymerase chain reaction. Additionally, protein levels of lamin A, C and nucleolin were evaluated by immunofluorescence and the telomere length was analyzed. RESULTS: We could show a significant decrease of lamin A and C gene expression in PXE fibroblasts under nutrient depletion compared to controls. The gene expression of progerin and farnesyltransferase showed a significant increase in PXE fibroblasts when cultivated in 10% fetal calf serum (FCS) compared to controls. Immunofluorescence microscopy of lamin A/C and nucleolin and mRNA expression of zinc metallopeptidase STE24 and nucleolin showed no significant changes in any case. The determination of the relative telomere length showed significantly longer telomeres for PXE fibroblasts compared to controls when cultivated in 10% FCS. CONCLUSIONS: These data indicate that PXE fibroblasts possibly undergo a kind of senescence which is independent of telomere damage and not triggered by defects of the nuclear envelope or nucleoli deformation.