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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. The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs). 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). Tissue‐specific brain age prediction using machine learning revealed older‐appearing brains and accelerated ageing in people with higher cardiometabolic risk.

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.

Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)–kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.

Abstract 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; β = 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 (β = 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; β = −0.04, t(164) = −2.48, P = .01) and increases especially in negative symptoms on the Positive and Negative Syndrome Scale (β = 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.

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.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna G609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS. Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Schizophrenia is associated with increased physical morbidity and early mortality, suggesting that the aging process may be accelerated in schizophrenia. However, the biological underpinnings of these alterations in aging in schizophrenia are unclear. We conducted a detailed search of peer-reviewed empirical studies to evaluate evidence for accelerated biological aging in schizophrenia based on systemic, age-related biomarkers. We included studies that investigated differences between persons with schizophrenia and healthy comparison subjects in levels of biomarkers known to be associated with aging and examined the relationship of these biomarkers to age in the 2 groups. Forty-two articles that met our selection criteria were reviewed. Nearly 75% reported abnormal biomarker levels among individuals with schizophrenia, including indices of inflammation, cytotoxicity, oxidative stress, metabolic health, gene expression, and receptor/synaptic function, with medium to large effect sizes reported in many studies. Twenty-nine percent of the studies observed differential age-related decline in schizophrenia. Markers of receptor/synaptic function and gene expression were most frequently differentially related to age in schizophrenia. Schizophrenia patients with greater disease severity and longer illness duration exhibited higher levels of inflammatory and oxidative stress biomarkers and shorter telomere length. Most studies show biomarker abnormalities in schizophrenia, and there is some suggestion for accelerated aging. Although definitive interpretation is limited by cross-sectional design of the published reports, findings in the area of gene expression and synaptic function are promising and pave the way for future longitudinal studies needed to fully test this hypothesis.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction.

An in vitro model of premature ageing The premature ageing disorder Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic condition characterized by a rapid onset of signs associated with normal ageing, such as atherosclerosis and the degeneration of vascular smooth-muscle cells. Liu et al . report that the altered structure of the nuclear envelope and epigenetic modifications that accumulate during physiological ageing or under specific disease conditions can be restored to normalcy by reprogramming somatic cell lines established with fibroblasts from patients with HGPS as induced pluripotent stem (iPS) cells. Directed differentiation of the resulting iPS cells as vascular smooth-muscle cells then leads to the appearance of the premature senescence phenotypes associated with vascular ageing. This HGPS iPS cell model provides a way to study the mechanisms regulating premature and normal ageing in vitro . Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease 1 , 2 , 3 , 4 , 5 , characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs) 6 , 7 , 8 . HGPS is caused by a single point mutation in the lamin A ( LMNA ) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin 9 , 10 , 11 , 12 . Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs, also known as PRKDC) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological ageing. Because progerin also accumulates during physiological ageing 6 , 12 , 13 , our results provide an in vitro iPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.

Summary Hutchinson-Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single-nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high-resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC-1[alpha], a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial-targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.