Canthaxanthin Mitigates Cardiovascular Senescence in Vitro and in Vivo.

BACKGROUND: The number of older people in the world is increasing year by year; studies have shown that more than 90% of cardiovascular disease occurs in the older people population, indicating that aging is one of the major risks involved in the development of cardiovascular disease. Therefore, retarding the development of cardiac aging is an important strategy to prevent aging-related cardiovascular diseases. METHODS: In the current study, we examined the anti-cardiovascular aging potential of canthaxanthin in vitro and in vivo experiments. For this, a model of cardiomyocyte senescence induced by D-galactose was established, which was used to investigate the canthaxanthin's effect on cardiac premature aging. RESULTS: We found that canthaxanthin obviously mitigated the cardiomyocyte senescence in vitro. Further mechanistic studies revealed that canthaxanthin seems to alleviate cardiomyocyte senescence by regulating the autophagy process. Furthermore, the effects of canthaxanthin on cardiovascular senescence were further evaluated. We also observed that canthaxanthin mitigated cardiac aging and fibrosis in the aged mice model. CONCLUSIONS: To sum up, the current work showed that canthaxanthin could obviously alleviate cardiac premature aging, indicating that canthaxanthin could be used as a biologically active molecule for the treatment of cardiac aging and fibrosis.

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.

"Brain age" predicts disability accumulation in multiple sclerosis.

OBJECTIVE: Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of "brain age" analysis on disability in MS using a large, real-world dataset. METHODS: Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models. RESULTS: MS was associated with advanced predicted brain age cross-sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability. INTERPRETATION: Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation.

White matter hyperintensity load is associated with premature brain aging.

BACKGROUND: Brain age is an MRI-derived estimate of brain tissue loss that has a similar pattern to aging-related atrophy. White matter hyperintensities (WMHs) are neuroimaging markers of small vessel disease and may represent subtle signs of brain compromise. We tested the hypothesis that WMHs are independently associated with premature brain age in an original aging cohort. METHODS: Brain age was calculated using machine-learning on whole-brain tissue estimates from T1-weighted images using the BrainAgeR analysis pipeline in 166 healthy adult participants. WMHs were manually delineated on FLAIR images. WMH load was defined as the cumulative volume of WMHs. A positive difference between estimated brain age and chronological age (BrainGAP) was used as a measure of premature brain aging. Then, partial Pearson correlations between BrainGAP and volume of WMHs were calculated (accounting for chronological age). RESULTS: Brain and chronological age were strongly correlated (r(163)=0.932, p<0.001). There was significant negative correlation between BrainGAP scores and chronological age (r(163)=-0.244, p<0.001) indicating that younger participants had higher BrainGAP (premature brain aging). Chronological age also showed a positive correlation with WMH load (r(163)=0.506, p<0.001) indicating older participants had increased WMH load. Controlling for chronological age, there was a statistically significant relationship between premature brain aging and WMHs load (r(163)=0.216, p=0.003). Each additional year in brain age beyond chronological age corresponded to an additional 1.1mm3 in WMH load. CONCLUSIONS: WMHs are an independent factor associated with premature brain aging. This finding underscores the impact of white matter disease on global brain integrity and progressive age-like brain atrophy.

Testicular aging, male fertility and beyond.

Normal spermatogenesis and sperm function are crucial for male fertility. The effects of healthy testicular aging and testicular premature aging on spermatogenesis, sperm function, and the spermatogenesis microenvironment cannot be ignored. Compared with younger men, the testis of older men tends to have disturbed spermatogenic processes, sperm abnormalities, sperm dysfunction, and impaired Sertoli and Leydig cells, which ultimately results in male infertility. Various exogenous and endogenous factors also contribute to pathological testicular premature aging, such as adverse environmental stressors and gene mutations. Mechanistically, Y-chromosomal microdeletions, increase in telomere length and oxidative stress, accumulation of DNA damage with decreased repair ability, alterations in epigenetic modifications, miRNA and lncRNA expression abnormalities, have been associated with impaired male fertility due to aging. In recent years, the key molecules and signaling pathways that regulate testicular aging and premature aging have been identified, thereby providing new strategies for diagnosis and treatment. This review provides a comprehensive overview of the underlying mechanisms of aging on spermatogenesis. Furthermore, potential rescue measures for reproductive aging have been discussed. Finally, the inadequacy of testicular aging research and future directions for research have been envisaged to aid in the diagnosis and treatment of testicular aging and premature aging.

Cardiometabolic risk factors associated with brain age and accelerate brain ageing.

The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.

Calcification in Werner syndrome associated with lymphatic vessels aging.

In addition to the symptoms of aging, the main symptoms in Werner syndrome (WS), a hereditary premature aging disease, include calcification of subcutaneous tissue with solid pain and refractory skin ulcers. However, the mechanism of calcification in WS remains unclear. In this study, the histological analysis of the skin around the ulcer with calcification revealed an accumulation of calcium phosphate in the lymphatic vessels. Moreover, the morphological comparison with the lymphatic vessels in PAD patients with chronic skin ulcers demonstrated the ongoing lymphatic remodeling in WS patients because of the narrow luminal cross-sectional area (LA) of the lymphatic vessels but the increment of lymphatic microvessels density (MLVD). Additionally, fluorescence immunohistochemical analysis presented the cytoplasmic distribution and the accumulation of WRN proteins in endothelial cells on remodeling lymphatic vessels. In summary, these results point out a relationship between calcification in lymphatic vessels and the remodeling of lymphatic vessels and suggest the significance of the accumulation of WRN mutant proteins as an age-related change in WS patients. Thus, cytoplasmic accumulation of WRN protein can be an indicator of the decreasing drainage function of the lymphatic vessels and the increased risk of skin ulcers and calcification in the lymphatic vessels.

Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models.

Ageing is a complex process, induced by multifaceted interaction of genetic, epigenetic, and environmental factors. It is manifested by a decline in the physiological functions of organisms and associated to the development of age-related chronic diseases and cancer development. It is considered that ageing follows a strictly-regulated program, in which some signaling pathways critically contribute to the establishment and maintenance of the aged state. Chronic inflammation is a major mechanism that promotes the biological ageing process and comorbidity, with the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) as a crucial mediator of inflammatory responses. This, together with the finding that the activation or inhibition of NF-κB can induce or reverse respectively the main features of aged organisms, has brought it under consideration as a key transcription factor that acts as a driver of ageing. In this review, we focused on the data obtained entirely through the generation of knockout and transgenic mouse models of either protein involved in the NF-κB signaling pathway that have provided relevant information about the intricate processes or molecular mechanisms that control ageing. We have reviewed the relationship of NF-κB and premature ageing; the development of cancer associated with ageing and the implication of NF-κB activation in the development of age-related diseases, some of which greatly increase the risk of developing cancer.

Antiaging Effects of Vicatia thibetica de Boiss Root Extract on Caenorhabditis elegans and Doxorubicin-Induced Premature Aging in Adult Mice.

The roots of Vicatia thibetica de Boiss are a kind of Chinese herb with homology of medicine and food. This is the first report showing the property of the extract of Vicatia thibetica de Boiss roots (HLB01) to extend the lifespan as well as promote the healthy parameters in Caenorhabditis elegans (C. elegans). For doxorubicin- (Doxo-) induced premature aging in adult mice, HLB01 counteracted the senescence-associated biomarkers, including P21 and γH2AX. Interestingly, HLB01 promoted the expression of collagen in C. elegans and mammalian cell systemically, which might be one of the essential factors to exert the antiaging effects. In addition, HLB01 was also found as a scavenger of free radicals, thereby performing the antioxidant ability. Lifespan extension by HLB01 was also dependent on DAF-16 and HSF-1 via oxidative stress resistance and heat stress resistance. Taken together, overall data suggested that HLB01 could extend the lifespan and healthspan of C. elegans and resist Doxo-induced senescence in mice via promoting the expression of collagen, antioxidant potential, and stress resistance.

Association of Epilepsy Surgery With Changes in Imaging-Defined Brain Age.

OBJECTIVE: To determine whether surgery in patients with mesial temporal lobe epilepsy (mTLE) is associated with reduced brain-predicted age as a neural marker overall brain health, we compared brain-predicted and chronologic age difference (brain age gap estimation [BrainAGE]) in patients before and after surgery with healthy controls. METHODS: We acquired 3D T1-weighted MRI scans for 48 patients with mTLE before and after temporal lobe surgery to estimate brain age using a gaussian processes regression model. We examined BrainAGE before and after surgery controlling for brain volume change, comparing patients to 37 age- and sex-matched controls. RESULTS: Preoperatively, patients showed an increased BrainAGE of more than 7 years compared to controls. However, surgery was associated with a mean BrainAGE reduction of 5 years irrespective of whether or not surgery resulted in complete seizure freedom. We observed a lateralization effect as patients with left mTLE had BrainAGE values that more closely resembled control group values following surgery. CONCLUSIONS: Our findings suggest that while morphologic brain alterations linked to accelerated aging have been observed in mTLE, surgery may be associated with changes that reverse such alterations in some patients. This work highlights the advantages of resective surgery on overall brain health in patients with refractory focal epilepsy.

Obesity as a Risk Factor for Accelerated Brain Ageing in First-Episode Psychosis-A Longitudinal Study.

BACKGROUND: Obesity is highly prevalent in schizophrenia, with implications for psychiatric prognosis, possibly through links between obesity and brain structure. In this longitudinal study in first episode of psychosis (FEP), we used machine learning and structural magnetic resonance imaging (MRI) to study the impact of psychotic illness and obesity on brain ageing/neuroprogression shortly after illness onset. METHODS: We acquired 2 prospective MRI scans on average 1.61 years apart in 183 FEP and 155 control individuals. We used a machine learning model trained on an independent sample of 504 controls to estimate the individual brain ages of study participants and calculated BrainAGE by subtracting chronological from the estimated brain age. RESULTS: Individuals with FEP had a higher initial BrainAGE than controls (3.39 ± 6.36 vs 1.72 ± 5.56 years; ß = 1.68, t(336) = 2.59, P = .01), but similar annual rates of brain ageing over time (1.28 ± 2.40 vs 1.07±1.74 estimated years/actual year; t(333) = 0.93, P = .18). Across both cohorts, greater baseline body mass index (BMI) predicted faster brain ageing (ß = 0.08, t(333) = 2.59, P = .01). For each additional BMI point, the brain aged by an additional month per year. Worsening of functioning over time (Global Assessment of Functioning; ß = -0.04, t(164) = -2.48, P = .01) and increases especially in negative symptoms on the Positive and Negative Syndrome Scale (ß = 0.11, t(175) = 3.11, P = .002) were associated with faster brain ageing in FEP. CONCLUSIONS: Brain alterations in psychosis are manifest already during the first episode and over time get worse in those with worsening clinical outcomes or higher baseline BMI. As baseline BMI predicted faster brain ageing, obesity may represent a modifiable risk factor in FEP that is linked with psychiatric outcomes via effects on brain structure.

The stage-specifically accelerated brain aging in never-treated first-episode patients with depression.

Depression associated with structural brain abnormalities is hypothesized to be related with accelerated brain aging. However, there is far from a unified conclusion because of clinical variations such as medication status, cumulative illness burden. To explore whether brain age is accelerated in never-treated first-episode patients with depression and its association with clinical characteristics, we constructed a prediction model where gray matter volumes measured by voxel-based morphometry derived from T1-weighted MRI scans were treated as features. The prediction model was first validated using healthy controls (HCs) in two Chinese Han datasets (Dataset 1, N = 130 for HCs and N = 195 for patients with depression; Dataset 2, N = 270 for HCs) separately or jointly, then the trained prediction model using HCs (N = 400) was applied to never-treated first-episode patients with depression (N = 195). The brain-predicted age difference (brain-PAD) scores defined as the difference between predicted brain age and chronological age, were calculated for all participants and compared between patients with age-, gender-, educational level-matched HCs in Dataset 1. Overall, patients presented higher brain-PAD scores suggesting patients with depression having an "older" brain than expected. More specially, this difference occurred at illness onset (illness duration <3 months) and following 2 years then disappeared as the illness further advanced (>2 years) in patients. This phenomenon was verified by another data-driven method and significant correlation between brain-PAD scores and illness duration in patients. Our results reveal that accelerated brain aging occurs at illness onset and suggest it is a stage-dependent phenomenon in depression.

Pharmacological inhibition of asparaginyl endopeptidase by δ-secretase inhibitor 11 mitigates Alzheimer's disease-related pathologies in a senescence-accelerated mouse model.

BACKGROUND: Currently, there is no cure for Alzheimer's disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown. METHODS: The senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid ß (Aß) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses. RESULTS: The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC50) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aß1-40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain. CONCLUSIONS: Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.

Aging faster: worry and rumination in late life are associated with greater brain age.

Older adults with anxiety have lower gray matter brain volume-a component of accelerated aging. We have previously validated a machine learning model to predict brain age, an estimate of an individual's age based on voxel-wise gray matter images. We investigated associations between brain age and anxiety, depression, stress, and emotion regulation. We recruited 78 participants (≥50 years) along a wide range of worry severity. We collected imaging data and computed voxel-wise gray matter images, which were input into an existing machine learning model to estimate brain age. We conducted a multivariable linear regression between brain age and age, sex, race, education, worry, anxiety, depression, rumination, neuroticism, stress, reappraisal, and suppression. We found that greater brain age was significantly associated with greater age, male sex, greater worry, greater rumination, and lower suppression. Male sex, worry, and rumination are associated with accelerated aging in late life and expressive suppression may have a protective effect. These results provide evidence for the transdiagnostic model of negative repetitive thoughts, which are associated with cognitive decline, amyloid, and tau.

Prenatal Hypoxia Induces Premature Aging Accompanied by Impaired Function of the Glutamatergic System in Rat Hippocampus.

Prenatal hypoxia is among leading causes of progressive brain pathologies in postnatal life. This study aimed to analyze the characteristics of the hippocampal glutamatergic system and behavior of rats in early (2 weeks), adult (3 months) and advanced (18 months) postnatal ontogenesis after exposure to prenatal severe hypoxia (PSH, 180 Torr, 5% O2, 3 h) during the critical period in the formation of the hippocampus (days 14-16 of gestation). We have shown an age-dependent progressive decrease in the hippocampal glutamate levels, a decrease of the neuronal cell number in the CA1 hippocampal region, as well as impairment of spatial long-term memory in the Morris water navigation task. The gradual decrease of glutamate was accompanied by decreased expression of the genes that mediate glutamate metabolism and recycling in the hippocampus. That deficiency apparently correlated with an increase of the metabotropic glutamate receptor type 1 (mGluR1) and synaptophysin expression. Generation of the lipid peroxidation products in the hippocampus of adult rats subjected to prenatal severe hypoxia (PSH rats) was not increased compared to the control animals when tested in a model of glutamate excitotoxicity induced by severe hypoxia. This demonstrates that excessive glutamate sensitivity in PSH rats does not compensate for glutamate deficiency. Our results show a significant contribution of the glutamate system dysfunction to age-associated decrease of this mediator, cognitive decline, and early neuronal loss in PSH rats.

Xeroderma Pigmentosum: A Model for Human Premature Aging.

Aging results from intrinsic changes (chronologic) and damage from external exposures (extrinsic) on the human body. The skin is ideal to visually differentiate their unique features. Inherited diseases of DNA repair, such as xeroderma pigmentosum (XP), provide an excellent model for human aging due to the accelerated accumulation of DNA damage. Poikiloderma, atypical lentigines, and skin cancers, the primary cutaneous features of XP, occur in the general population but at a much older age. Patients with XP also exhibit ocular changes secondary to premature photoaging, including ocular surface tumors and pterygium. Internal manifestations of premature aging, including peripheral neuropathy, progressive sensorineural hearing loss, and neurodegeneration, are reported in 25% of patients with XP. Internal malignancies, such as lung cancer, CNS tumors, and leukemia and/or lymphoma, occur at a younger age in patients with XP, as do thyroid nodules. Premature ovarian failure is overrepresented among females with XP, occurring 20 years earlier than in the general population. Taken together, these clinical findings highlight the importance of DNA repair in maintaining genomic integrity. XP is a unique model of human premature aging, which is revealing new insights into aging mechanisms.

Senescence in RASopathies, a possible novel contributor to a complex pathophenoype.

Senescence is a biological process that induces a permanent cell cycle arrest and a specific gene expression program in response to various stressors. Following studies over the last few decades, the concept of senescence has evolved from an antiproliferative mechanism in cancer (oncogene-induced senescence) to a critical component of physiological processes associated with embryonic development, tissue regeneration, ageing and its associated diseases. In somatic cells, oncogenic mutations in RAS-MAPK pathway genes are associated with oncogene-induced senescence and cancer, while germline mutations in the same pathway are linked to a group of monogenic developmental disorders generally termed RASopathies. Here, we consider that in these disorders, senescence induction may result in opposing outcomes, a tumour protective effect and a possible contributor to a premature ageing phenotype identified in Costello syndrome, which belongs to the RASopathy group. In this review, we will highlight the role of senescence in organismal homeostasis and we will describe the current knowledge about senescence in RASopathies. Additionally, we provide a perspective on examples of experimentally characterised RASopathy mutations that, alone or in combination with various stressors, may also trigger an age-dependent chronic senescence, possibly contributing to the age-dependent worsening of RASopathy pathophenotype and the reduction of lifespan.

Skin Abnormalities in Disorders with DNA Repair Defects, Premature Aging, and Mitochondrial Dysfunction.

Defects in DNA repair pathways and alterations of mitochondrial energy metabolism have been reported in multiple skin disorders. More than 10% of patients with primary mitochondrial dysfunction exhibit dermatological features including rashes and hair and pigmentation abnormalities. Accumulation of oxidative DNA damage and dysfunctional mitochondria affect cellular homeostasis leading to increased apoptosis. Emerging evidence demonstrates that genetic disorders of premature aging that alter DNA repair pathways and cause mitochondrial dysfunction, such as Rothmund-Thomson syndrome, Werner syndrome, and Cockayne syndrome, also exhibit skin disease. This article summarizes recent advances in the research pertaining to these syndromes and molecular mechanisms underlying their skin pathologies.

An additional case of Néstor-Guillermo progeria syndrome diagnosed in early childhood.

Néstor-Guillermo progeria syndrome (NGPS; OMIM 614008) is characterized by early onset and slow progression of symptoms including poor growth, lipoatrophy, pseudosenile facial appearance, and normal cognitive development. In contrast to other progeria syndromes, NGPS is associated with a longer lifespan and higher risk for developing severe skeletal abnormalities. It is an autosomal recessive condition caused by biallelic pathogenic variants in BANF1. There are two previously reported patients with NGPS, both Spanish with molecular diagnoses made in adulthood and having the same homozygous pathogenic variant c.34G > A; p.Ala12Thr. Presented here is a 2 year, 8 month old girl with short stature, poor weight gain, sparse hair, and dysmorphic facial features reminiscent of premature aging. Whole exome sequencing identified the same c.34G > A homozygous pathogenic variant in BANF1 as reported in the previous patients. This is the first reported case of a child and is supporting evidence for this recurrent loss of function variant.

Measurements of Hydrogen Peroxide and Oxidative DNA Damage in a Cell Model of Premature Aging.

Reactive oxygen species (ROS) represent a number of highly reactive oxygen-derived by-products generated by the normal mitochondrial respiration and other cellular metabolic reactions. ROS can oxidize macromolecules including lipids, proteins, and nucleic acids. Under physiological condition, the cellular levels of ROS are controlled by several antioxidant enzymes. However, an imbalance between ROS production and detoxification results in oxidative stress, which leads to the accumulation of macromolecular damage and progressive decline in normal physiological functions.Oxidative deterioration of DNA can result in lesion that are mutagenic and contribute to aging and age-related diseases. Therefore, methods for the detection of ROS and oxidative deterioration of macromolecules such as DNA in cells provide important tool in aging research. Here, we described protocols for the detection of cytoplasmic and mitochondria pools of hydrogen peroxide, and the DNA modification 8-oxoguanine, a biomarker of oxidative damage, that are applicable to cell-based studies on aging and other related areas.