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Results for “Phenotype modifier”

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PubMed2026

Single-cell vector copy number analysis of phenotypically defined long-term hematopoietic stem cells for gene therapy safety assessment.

Hematopoietic stem cell (HSC)-based gene therapy has emerged as a transformative approach for the treatment of genetic diseases; however, accurate evaluation of vector copy number (VCN) remains critical for ensuring safety. Conventional bulk VCN assays, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR), do not resolve clonal heterogeneity and cannot identify rare high-VCN cells that may contribute disproportionately to insertional mutagenesis risk. Here, we developed an accessible single-cell VCN profiling method by combining fluorescence-activated cell sorting (FACS) of phenotypically defined long-term HSCs (Lineage- CD34+ CD38- CD90+ CD45RA- cells) with whole-genome amplification followed by conventional qPCR. This approach enabled resolution of VCN distributions at single-cell level using standard laboratory techniques. Notably, single-cell analysis revealed a high VCN tail that bulk VCN analysis could not resolve. Furthermore, in a humanized mouse transplantation model, single-cell VCN profiling demonstrated that overall VCN distributions could be analyzed after engraftment, although inter-donor and inter-mouse variability was observed. Collectively, this method provides a rapid, cost-effective, and phenotypically resolved strategy for assessing VCN heterogeneity in gene-modified HSCs. Single-cell VCN profiling offers complementary insights beyond conventional bulk assays and may enhance preclinical safety evaluation of gene and cell therapy products.

lentiviral vector↗

PubMed1979

Microenvironmental influences on the in vivo behavior of neoplastic lymphocytes.

A transplantable hamster lymphocytic neoplasma of probable monoclonal derivation, induced by the oncogenic DNA simian virus 40, has been adapted to grow in the allogeneic host either as leukemia (characterized by dissemination and poor prognosis) or as lymphoma (characterized by localization and favorable prognosis) [Diamandopoulos, G. Th. (1978) Proc. Natl. Acad. Sci. USA 75, 2011-2015]. In the present experiments the circumstances under which neoplastic lymphocytes that are transplanted in allogeneic animals retain, lose, or regain the capacity for dissemination or localization are assessed. Results indicate that the in vivo behavior of neoplastic lymphocytes is not a stable, irreversible characteristic that is transmitted to the cell progeny. On the contrary, it can be altered by the origin/tissue microenvironment in which the cells proliferate. It is suggested that, whereas neoplastic cell mutation followed by host selection could be responsible for changes in cell behavior, a more likely explanation is that the proliferating neoplastic lymphocytes acquire reversible nonmutational phenotypic characteristics during their interaction with the host microenvironment, which modify their behavior and, as a result, the prognosis of the neoplastic process.

Animals↗

PubMed1977

Growth of murine sarcoma virus-transformed rat kidney cells in nude mice: absence of induction of host endogenous viruses.

Clonal isolates of the normal rat kidney cell line (NRK) transformed by a defective murine sarcoma virus (Kirsten strain) were injected into nude mice of BALB/c background to determine whether the growth of these cells as tumors was accompanied by the induction of host endogenous type C viruses. All the virus-transformed clones produced rapidly growing tumors in nude mice, but neither the induction of mouse endogenous viruses nor the rescue and spread of the transforming sarcoma virus were observed during the growth of tumors. The degree of expression of the tumor virus structural proteins in the transformed cells did not determine the cellular phenotype with regard to tumorigenicity in nude mice, nor did it modify the cellular growth properties in vitro. Consistent with earlier observations with simian virus 40-transformed mouse and rat cells, the ability of sarcoma virus-transformed NRK cells to initiate tumor growth in nude mice appeared to be correlated with anchorage-independent growth in vitro.

Animals↗

PubMed2026

Expert consensus on the reporting and clinical follow up of individuals with incidentally discovered germline RET variants in the UK.

Incidentally discovered pathogenic germline genetic variants refer to the finding of a pathogenic variant in a gene that is unrelated to the reason for the initial test and is not actively sought. Our clinical understanding of the risk of developing a particular medical condition and the required clinical action for a specific pathogenic gene variant is predominantly based on knowledge and information acquired from cases ascertained through a 'phenotype-first approach' rather than in clinically unselected individuals. Therefore, a modified approach is required for incidentally discovered gene variants. Data from large UK and US population-based cohorts have demonstrated that RET variants classified as moderate-risk RET variants as per the American Thyroid Association (ATA) classification have a low penetrance for medullary thyroid cancer and other RET-related conditions (e.g. phaeochromocytoma) and are not associated with excess mortality when identified incidentally in clinically unselected adult individuals. Here, we provide guidance based on multidisciplinary expert consensus opinion for the reporting and subsequent clinical surveillance and management of patients with incidentally discovered RET gene variants in the UK.

Humans↗

PubMed2026

Mendelian randomisation for rheumatology: beyond hype-what it's good for, what it can't do, and how to read it critically.

Mendelian randomisation (MR) has become abundant in the literature, with variation in quality and frequent overinterpretation of causality. This creates a problem for clinical readers, reviewers, and editors: some MR studies can sharpen causal thinking, prioritise drug targets, and challenge misleading observational claims, whereas others are little more than automated exposure-outcome scans with causal claims disproportionate to the evidence. MR can strengthen causal inference when randomised trials are impractical and conventional observational studies are vulnerable to confounding, reverse causation, or selection bias. In rheumatology, credible MR can contribute to questions about disease aetiology, modifiable risk factors, therapeutic target validation, adverse-effect anticipation, and phenotype validation. However, its interpretation depends on whether the exposure is plausibly instrumentable, whether the genetic instruments are biologically defensible, whether assumptions are interrogated in ways appropriate to the design, and whether findings are triangulated with clinical, observational, experimental, and mechanistic evidence. Instead of recapitulating all methodological issues of MR, this review aims to help rheumatologists distinguish robust MR from weak or overinterpreted analyses quickly. We provide an accessible framework for reading and triaging MR studies in rheumatology. Papers that use poorly justified instruments, treat medication use as drug-target evidence, interpret genetic liability as diagnosis, rely on mechanical sensitivity analyses, ignore prior evidence or ask no clinically meaningful question can often be passed over by readers. The goal is not to discourage MR in rheumatology, but to raise the standard; useful MR should clarify causal reasoning rather than simply generate another statistically significant association.

Journal Article↗

PubMed2026

Genomic insights into stroke recovery: cross-phenotype associations.

Stroke is a major cause of long-term disability with variable recovery. While clinical factors such as initial severity play a role, genetic factors are increasingly recognized as important contributors to stroke recovery. Genotype studies are generally focused on a single post-stroke behavioural domain, but some genes might relate to broad mechanisms of plasticity. This study therefore aimed to identify cross-phenotypic genetic variants associated across two or more stroke recovery domains. DNA from Stroke, Stress, Rehabilitation, and Genetics study participants was genotyped, resulting in 9 814 610 variants. In order to examine cross-phenotypic results, we first conducted genome-wide association studies on the six recovery domains: motor (grip force), cognition (Telephone Montreal Cognitive Assessment), depression (Patient Health Questionnaire-8), stress (Primary Care Post-Traumatic Stress Disorder Screen), functional status (Stroke Impact Scale-Activities of Daily Living), and disability (modified Rankin Scale 0-2 versus 3-6), some of which were tested longitudinally, yielding nine phenotypes. Models were adjusted for age, sex, initial severity (NIH Stroke Scale score), and ancestry. Cross-phenotype associations were identified by evaluating single nucleotide polymorphisms (SNPs) associated (P < 5e-5) with multiple phenotypes. To determine how these genetic variants may relate to biological mechanisms of recovery, we conducted gene enrichment analyses. Participants (n = 565, 59% male) had mild-moderate initial stroke severity (median acute NIH Stroke Scale score = 4). After accounting for the correlation structure among the nine phenotypes, we observed 319 cross-phenotypic SNPs, 3.45 times the expected number. Five of the cross-phenotypic SNPs were linked to genes relevant to neural development, function and plasticity, e.g. ERICH1 (rs11778883-C), FOX3 (rs55726768-G), LIFR-AS1 (rs76401391-T), RPS6KA2 (rs113518460-C) and TUBGCP2 (rs147150392-C), as were enrichments in RAB5-EEA1, CTNNA1-CTNNB1, CIN85-SH3GL2 and ELMO1-DOCK2 complexes. Multiple gene enrichments were found, e.g. Stroke Impact Scale-Activities of Daily Living and Patient Health Questionnaire 8 at 3 months were enriched for CREB phosphorylation, which is important for long-term potentiation. We identified cross-phenotypic SNPs associated with multiple behavioural domains of stroke recovery. Some of these genes encode, or regulate, druggable proteins. These genetic factors are not well captured by clinical or neuroimaging assessments and so provide a unique window into stroke recovery. These findings, if validated, suggest that some genes may be broadly important to stroke recovery.

GWAS↗

PubMed2026

Maize Gametophytic factor loci Ga3 through Ga11 modify reproductive barriers.

Gametophytic factor (Ga) barriers are maize (Zea mays ssp. mays) reproductive barriers controlled by molecular incompatibilities between pollen and silks. Twelve distinct Ga loci have been identified in maize populations since the first genetic evidence of a Ga barrier was reported in 1901. Of the twelve, however, only three have been validated by modern molecular, functional and genomic studies: Ga1, Ga2, and Tcb1. The remaining "higher" Ga loci, spanning Ga3 to Ga11, were reported in the historical literature, but their associated phenotypes segregated in unexpected ways or disappeared over subsequent generations. Here we introduce and explore the hypothesis that the higher Ga loci represent modifiers of Ga1, Ga2, and Tcb1 barrier functions. By revisiting the historical literature, we found that barrier phenotypes fall into two phenotypic and functional categories. Phenotypically, the two categories represented healthy pollen with a silk-length effect and unhealthy pollen without a silk-length effect. These phenotypic categories were supported by genomic data; we identified candidate genes in each higher Ga locus by comparing historical linkage mapping data to the corresponding genomic sequence of maize reference line B73. We discovered candidate genes related to two broad pathways: pollen tube growth and RNA-directed DNA methylation. We conclude that the past century of evidence aligns with our hypothesis that maize loci Ga3 through Ga11 modify rather than directly control Ga barriers. This brief investigation provides a starting point for geneticists and evolutionary biologists to explore how strong reproductive barriers are shaped by epistatic interactions.

Epistasis↗

PubMed2026

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Molecular mechanisms↗

PubMed1979

Suppression of mitochondrially-determined resistance to chloramphenicol and paromomycin by nuclear genes in Saccharomyces cerevisiae.

Phenotypic "revertants" of a drug resistant strain of Saccharomyces cerevisiae were induced by mutgenesis with manganese. Several of these drug sensitive mutants have been shown to result from mutations in the nuclear genome that cause phenotypic modification (suppression) of the mitochondrially-determined drug resistant genotype. Four mutants carrying a single recessive nuclear gene capable of modifying mitochondrial chloramphenicol resistance are described; these may be assigned to three complementation groups. Chloramphenicol resistant mutants mapping at five separate mitochondrial loci are described. At least two of the nuclear genes cause modification of mitochondrial chloramphenicol resistance determined by mutations at three of these loci, but the other two loci are apparently non-suppressible by these nuclear alleles. This indicates that these modifiers do not act by causing a general decrease in cellular or mitochondrial permeability to the drug. A single dominant nuclear modifier of mitochondrial paromomycin resistance has been identified. It is non-allelic to and does not interact with the genes modifying mitochondrial chloramphenicol resistance.

Chloramphenicol↗

PubMed1977

Lysogenic conversion for multiple characters in a strain of Staphylococcus aureus.

Lysogenization of nonlysogenic strains of Staphylococcus aureus was performed with two different bacteriophages, LS1 and LS2, that were unable to plaque on any of the strains of S. aureus tested. Infection of recipient strains was achieved when protoplasts were inoculated with LS1 or LS2 or when bacterial cultures were simultaneously inoculated with a virulent phage together with LS1 or LS2. Lysogenization was demonstrated by changes in phenotypic characters of the host strain and by liberation of bacteriophages from the modified strains as shown by electron microscopic examination. The lysogenic strains differed from the host strains by the following characters: they were coagulase, deoxyribonuclease, and lipase negative; they were untypable by the basic set of phages; they did not ferment mannitol under anaerobic conditions; and they produced only l-(+)-lactic acid by glucose fermentation. Their cell walls contained less glycine and concomitantly more serine than those of the host strains. Furthermore, they were devoid of protein A. Conversely, some antigenic factors as well as the presence of ribitol in the cell wall teichoic acid, indicated a parental relationship between the host strains and the derived lysogenic ones. Phages LS1 and LS2 could be excluded from the lysogenic strains by invading phages, and the revertant nonlysogenic strains recovered all of the characteristics of the initial host strains. It was thus concluded that the phenomenon described was due to lysogenic conversion. The origin of phages LS1 and LS2 is discussed.

Cell Wall↗

PubMed2025

Efficient and versatile rapeseed transformation for new breeding technologies.

Many gene functions are widely studied and understood in Arabidopsis; however, the lack of efficient transformation systems often limits the application and verification of this knowledge in crop plants. Brassica napus L., a member of the Brassicaceae family, is usually transformed by Agrobacterium-mediated hypocotyl transformation, but not all growth types are equally amenable to transformation. In particular, winter rapeseed, which requires vernalization to initiate flowering, is recalcitrant to in vitro regeneration and transformation. The analysis of gene functions in rapeseed is further complicated by the allotetraploid nature of its genome and the genome triplication within the Brassica genus, which has led to the presence of a large number of gene homologs for each Arabidopsis ortholog. We have established a transformation method that facilitates the regeneration of winter rapeseed by using the WUSCHEL gene from Beta vulgaris. This allowed us to efficiently transform a winter and spring rapeseed genotype in small-scale experiments. As proof of principle, we targeted BnCLV3 and BnSPL9/15 with CRISPR/Cas9 and showed that entire gene families are effectively edited using this transformation protocol. This allowed us to simultaneously study many redundantly acting homologous genes in rapeseed. We observed mutant phenotypes for BnCLV3 and BnSPL9/15 in primary transformants, indicating that biallelic knockouts were obtained for up to eight genes. This allowed an initial phenotypic characterization to be performed already a few months after starting the experiment.

Brassica napus↗

PubMed2026

Genetic diversity and molecular mechanisms in hypertrophic cardiomyopathy: toward personalized therapy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder, yet contemporary genomic and mechanistic research still lacks a cohesive model explaining how diverse genetic architectures give rise to heterogeneous phenotypes. This review synthesizes advances across sarcomeric and nonsarcomeric mutations, including intermediate-effect variants, polygenic modifiers, and ancestry-dependent sources of variant misclassification to elucidate how these factors govern disease penetrance and clinical expression. It critically evaluates how genetic diversity intersects with key molecular pathways, including sarcomeric hypercontractility, calcium dysregulation, mitochondrial energy deficiency, and transforming growth factor-β (TGF-β) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, to drive hypertrophic and fibrotic remodeling. Emerging mechanism-based therapies, such as myosin inhibition, allele-specific silencing, clustered regularly interspaced short palindromic repeats (CRISPR)-based correction, and metabolic modulation, are examined with respect to their capacity to modify upstream molecular drivers rather than downstream hemodynamic consequences. Persistent challenges, including variants of uncertain significance classification, ancestry-biased databases, inequitable access to genetic testing, and unresolved safety concerns for gene-based therapies, are critically assessed as major barriers to precision-medicine integration. By linking genetic architecture, molecular pathogenesis, and targeted interventions, this review advances a contemporary, mechanistically grounded framework that informs both individualized management and future research directions. Future research should prioritize pathway-specific therapeutics, functional and mechanistic validation of emerging variants, deeper physiologic phenotyping to refine disease modeling, and accelerate translation throughout the continuum of HCM pathophysiology.

Humans↗

PubMed1979

Properties of inbred strains and outbred stocks, with special reference to toxicity testing.

Genetically uniform or isogenic strains (inbred strains and F1 hybrids) have a number of properties that make them valuable in toxicity testing, provided the experimental design can be modified to include more than one such strain. Isogenicity and homozygosity lead to great phenotypic uniformity, high long-term genetic stability, high identifiability, large differences between strains (individuality), and the possibility of setting up daughter colonies genetically identical to the parents. This in turn means that many isogenic strains are internationally distributed, and that considerable background data exist on the characteristics of the common strains. Toxicity testing usually involves the calculation of dose-response curves. Use of phenotypically variable nonisogenic stocks reduces the precision with which such curves can be estimated, without many other benefits. A single isogenic strain may not be satisfactory as it may be resistant to the drug being tested. However, the use of several isogenic strains with a factorial experimental design would overcome this problem, would give high statistical precision, and would provide a better basis for extrapolation to humans than the use of a single stock. Such a design would make it possible to choose a range of strains on the basis of known drug sensitivities, it would be highly repeatable, it would allow comparison of different drugs, and it would show whether the response was genetically determined. The benefits of such an experimental design far outweigh the disadvantages, which are mostly of a practical nature.

Animals↗

PubMed2026

Maternal genetic variants associated with aneuploid conception: a narrative review.

BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE: This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS: We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [≤50 bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle-Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES: From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS: This review proposes that 'aneuploidy predisposition' constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER: CRD42025636217.

Humans↗

PubMed2026

DNA methylation signatures in skeletal muscle associated with physical function in healthy older adults.

Despite the substantial variability in physical function among older adults, the molecular mechanisms remain poorly characterized, particularly within skeletal muscle. This study aimed to determine the patterns of DNA methylation in skeletal muscle associated with physical function in healthy older adults. We analyzed DNA methylation (EPIC v2 array; 875,554 CpG sites) in skeletal muscle from 92 healthy older adults (median age 74; 62% female). Associations were examined across five phenotypes: Short Physical Performance Battery (SPPB), 6-min walk test (6MWT), handgrip strength, perceived disability (PAT-D), and lifestyle health (modified Life's Essential 8). Linear regression models adjusted for age, sex, race, BMI, and muscle fiber composition. Genomic inflation corrected via the BACON method (FDR < 0.05). Gene set enrichment analysis was performed on suggestive hits (FDR < 0.1). We identified significant differentially methylated probes (DMPs) and regions (DMRs) across all phenotypes: SPPB (70 DMPs, 22 DMRs), 6MWT (16 DMPs, 566 DMRs), handgrip strength (2 DMRs), PAT-D (19 DMPs, 1 DMR), and lifestyle health (2 DMPs). DMRs largely overlapped promoters. Identified genes overlapped known musculoskeletal and neurological GWAS hits, including RUNX2 and FOXL1 (bone mineral density), IGFBP3 (muscle mass), and NEK1 and SHANK1 (neurological function). Enrichment analysis revealed that 6MWT-associated genes relate to nervous and skeletal system development, while handgrip-associated genes involve cytoskeletal dynamics and protein assembly. Epigenetic variation in aging skeletal muscle is associated with physical function. The enrichment of pathways related to nervous and musculoskeletal development suggests specific epigenetic mechanisms underlying functional decline, offering potential targets for intervention in older adults.

DNA methylation↗

PubMed2025

Species-wide gene editing of a flowering regulator reveals hidden phenotypic variation.

Genes do not act in isolation, and the effects of a specific variant at one locus can often be greatly modified by polymorphic variants at other loci. A good example is FLOWERING LOCUS C (FLC), which has been inferred to explain much of the flowering time variation in Arabidopsis thaliana. We use a set of 62 flc species-wide mutants to document pleiotropic, genotype-dependent effects for FLC on flowering as well as several other traits. Time to flowering was greatly reduced in all mutants, with the remaining variation explained mainly by allelic variation at the FLC target FT. Analysis of FT sequence variation suggested that extremely early combinations of FLC and FT alleles should exist in the wild, which we confirmed by targeted collections. Our study provides a proof of concept on how pan-genetic analysis of hub genes can reveal the true extent of genetic networks in a species.

Gene Editing↗

PubMed1979

Sampling considerations in the gathering and analysis of pedigree data.

A general expression for the likelihood of a set of phenotypic observations on a randomly sampled pedigree, suitable for a wide variety of genetic models, has been previously modified to allow for independent ascertainments via probands. In this paper, further allowance is made for the fact that a pedigree usually contains some individuals who, whatever their phentoype, could never be probands, and we derive the limiting form of the likelihood appropriate for single ascertainment. The case when the sampling frame is ill-defined is discussed, and suggestions made for how to proceed in such a case.

Genetic Techniques↗

PubMed2026

Sex-specific aging clocks from a large-scale human phenome reveal distinct aging transitions and circulating signatures.

Aging is a primary risk factor for chronic diseases, yet its progression varies among individuals and between sexes. Here, under the X-Age Project, we profiled the clinical aging phenome of the Multicentric Chinese Aging Study (mCAS) through a cross-sectional analysis of 172 clinical measures from more than 100,000 participants aged 18-98 years across three centers. These profiles enabled sex-specific clinical aging clocks that revealed divergent aging trajectories between women and men during midlife that converged in later life. Phenome-wide analyses revealed age-related accumulation of metabolic factors, including low-density lipoprotein, triglycerides, glucose and uric acid, and tumor markers, such as carcinoembryonic antigen and human epithelial protein 4. These age-accumulating factors induced senescence-related phenotypes in human endothelial cells. Furthermore, a high-fat diet mouse model with dietary reversal supported the modifiability of metabolic burden-induced aging. Together, this work establishes metabolic and tumor marker accumulation as actionable drivers of human aging, paving the way for personalized, sex-stratified geroprotective interventions.

Humans↗