Proc Natl Acad Sci U S A. 2025 Aug 12;122(32):e2423437122. doi: 10.1073/pnas.2423437122. Epub 2025 Aug 4.

ABSTRACT

During development, groups of cells generate shape by coordinating their mechanical properties through an interplay of self-organization and prepatterning. Hydra displays a striking planar pattern of actin fibers at the organism scale, and mechanics influence the morphogenesis of biological structures during its prepatterned regeneration. However, how mechanics participate in the formation of an ordered pattern from a totally disordered state remains unknown. To study this, we used cellular aggregates formed from dissociated Hydra cells, which initially lose all actin polarity yet regenerate a long-range actin pattern. We showed quantitatively that the actin meshwork evolves from a disordered symmetric state to an ordered state in which rotational symmetry is broken, and translation symmetry is partially broken, with the nematic and smectic order parameters increasing over days. During the first hours, the actin meshwork displayed spatial heterogeneity in the nematic order parameter, and ordered domains separated by line defects progressively grew and fused. This suggests that local cell-cell interactions drive the transition from disorder to order. To understand the mechanism of ordering, we perturbed the tissue's physical constraints. We showed that while topology and geometry do not have a direct effect, anisotropic stretch biases the emerging orientation of the actin meshwork within hours. Surprisingly, although a Wnt head organizer is expected to play a role in the actin ordering, the stretch-associated alignment happened without the prior formation of a head organizer. This demonstrates the role of tissue mechanics in the alignment of the actin fibers during the disorder-to-order transition.

PMID:40758890 | DOI:10.1073/pnas.2423437122

Proc Natl Acad Sci U S A. 2025 Aug 12;122(32):e2505217122. doi: 10.1073/pnas.2505217122. Epub 2025 Aug 4.

ABSTRACT

Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is indispensable for longevity in the nematode Caenorhabditis elegans. We show that Pelota mitigates premature senescence in cultured human cells, muscle aging in mice, and neuropathology in cellular and organoid models of Alzheimer's disease. Mechanistically, we demonstrate that Pelota maintains autophagy-mediated proteostasis, by preventing the hyperactivation of mechanistic target of rapamycin signaling. Overall, our work highlights the conserved functional significance of RQC, regulated by Pelota, in extending lifespan and protecting diverse species against age-associated disease phenotypes.

PMID:40758887 | DOI:10.1073/pnas.2505217122

PLoS Pathog. 2025 Aug 4;21(8):e1013371. doi: 10.1371/journal.ppat.1013371. Online ahead of print.

ABSTRACT

The zoonotic transmission of bat coronaviruses poses a threat to human health. However, the diversity of bat-borne coronaviruses remains poorly characterized in many geographical areas. Here, we recovered eight coronavirus genomes by performing a metagenomic analysis of fecal samples from hundreds of individual bats captured in Spain, a country with high bat diversity. Three of these genomes corresponded to potentially novel coronavirus species belonging to the alphacoronavirus genus. Phylogenetic analyses revealed that some of these viruses are closely related to coronaviruses previously described in bats from other countries, suggesting a shared viral reservoir worldwide. Using viral pseudotypes, we investigated the receptor usage of the identified viruses and found that one of them can use human ACE2, albeit with lower affinity than SARS-CoV-2. However, the receptor usage of the other viruses remains unknown. This study broadens our understanding of coronavirus diversity and identifies research priorities for the prevention of zoonotic viral outbreaks.

PMID:40758759 | DOI:10.1371/journal.ppat.1013371

J Vis Exp. 2025 Jul 18;(221). doi: 10.3791/66840.

ABSTRACT

Enhancers are DNA regions that regulate gene expression. Mutations within enhancers can result in abnormal gene regulation leading to disease. Therefore, identifying enhancers that regulate gene activity in specific tissues is crucial for understanding the genetic basis of disease. However, enhancers are difficult to identify as they do not encode proteins. While numerous enhancer repositories and identification tools are available, the complexity of these tools can present a challenge for biologists. To facilitate biologists in using these resources, we present a biologist-friendly protocol (https://github.com/Ramialison-Lab/EnhancerWorkflow) which leverages existing web-based genomics data such as H3K4me1 and H3K27ac histone marks and chromatin conformation analysis (Hi-C) data to discover enhancers associated with a gene of interest (GoI) in a target tissue where the enhancer is active. This protocol is entirely web-based and does not require programming skills from end-users. We demonstrated the utility of this approach by characterising candidate enhancers regulating TBX5, a gene critical for heart development. This protocol facilitates the identification of enhancers associated with this gene in the left ventricle.

PMID:40758622 | DOI:10.3791/66840

Nanoscale. 2025 Aug 4. doi: 10.1039/d5nr02062j. Online ahead of print.

ABSTRACT

Cortisol plays a central role in maintaining physiological homeostasis, and both cortisol excess and deficiency are associated with life-threatening conditions. Accurate diagnosis, adequate treatment and monitoring of disorders of cortisol secretion are essential for good health, normal growth and development. Although commercially available lateral flow immunoassay (LFI) strips can be used to measure cortisol, they have limitations, especially low sensitivity and limited quantitative performance, inhibiting their use in clinical settings. Here, we present a novel LFI platform integrated with surface-enhanced Raman scattering (SERS), employing precisely size-controlled gold nanoparticle clusters functionalised with Raman reporter molecules to overcome these limitations. The approach achieves exceptional sensitivity, covering the relevant therapeutic range in humans, with a limit of detection (LOD) for cortisol of 0.014 pg mL-1, which is >500 times more sensitive than conventional LFI strips. The platform also showed high specificity for cortisol. The diagnostic potential was confirmed by testing with human saliva samples (n = 28), cross-validated with UPLC-MS/MS, showing excellent correlation (R2 = 0.9977). Bland-Altman analysis demonstrated strong agreement, with all samples falling within the 95% limits and yielding a mean bias of -3.5% ± 13.2% relative to UPLC-MS/MS. Given its sensitivity, specificity and simplicity, this LFI-SERS platform offers strong potential for clinical translation to enable convenient cortisol monitoring.

PMID:40758280 | DOI:10.1039/d5nr02062j

Mol Biol Rep. 2025 Aug 4;52(1):789. doi: 10.1007/s11033-025-10874-9.

ABSTRACT

BACKGROUND: Sanfilippo syndrome type B results from NAGLU mutations which cause progressive cognitive impairments and central nervous system degeneration. A 10-year-old boy presented with developmental regression, brain atrophy, intellectual disability, attention-deficit/hyperactivity disorder, and restlessness. His parents were non-consanguineous and asymptomatic.

METHODS: Whole-exome sequencing (WES) was performed, and variants were confirmed by Sanger sequencing. Downstream analyses integrated protein-protein interaction (PPI), gene-microRNA interaction (GMI), and drug-disease association (DDA) networks using STRING, NetworkAnalyst, and Enrichr.

RESULTS: Two missense variants were identified including rs1358994052 (NAGLU:c.874G > A; p.Gly292Arg) and rs768918822 (NAGLU:c.1004 A > G; p.Tyr335Cys [Y335C]), classified as pathogenic and likely pathogenic, respectively, by ACMG guidelines. Both variants localize to regulatory elements. The compound heterozygote network exhibited increased PPI connectivity and the absence of hsa-miR-27a-3p in GMI analysis. DDA highlighted carcinogenesis as the top-ranked term in the compound heterozygote network, contrasting with leukemia associations in homozygous contexts.

CONCLUSION: Compound heterozygous regulatory variants in NAGLU underlie diverse biochemical and neurodevelopmental phenotypes beyond enzymatic deficiency, emphasizing the value of integrative WES and systems biology approaches to refine pathogenicity assessments and guide targeted functional validation.

PMID:40758221 | DOI:10.1007/s11033-025-10874-9

Phys Rev Lett. 2025 Jul 18;135(3):038401. doi: 10.1103/jfm6-8h9s.

ABSTRACT

Microphase separation is common in active biological systems as exemplified by the separation of RNA- and DNA-rich phases in the cell nucleus driven by the transcriptional activity of polymerase enzymes acting similarly to amphiphiles in a microemulsion. Here we propose an analytically tractable model of an active microemulsion to investigate how the activity affects its structure and relaxation dynamics. Continuum theory derived from a lattice model exhibits two distinct regimes of the relaxation dynamics and is linked to the broken detailed balance due to intermittent activity of the amphiphiles.

PMID:40758004 | DOI:10.1103/jfm6-8h9s

Biotechnol J. 2025 Aug;20(8):e70091. doi: 10.1002/biot.70091.

ABSTRACT

Caffeic acid, a high-value natural phenolic compound synthesized through plant metabolism, plays a critical role in producing phenylpropanoid derivatives and serves as a direct precursor to several key phenolic acids. As a food additive and medicine, caffeic acid has garnered significant attention for its potential in various applications. Recent advances in synthetic biology and metabolic engineering have enabled its biosynthesis via microbial cell factories. This review summarizes five strategies for optimizing caffeic acid production: caffeic acid biosynthetic pathway, modification of metabolic pathway, systems biology and synthetic biology, cofactor engineering, and modular co-culture. However, caffeic acid production via microbial chassis faces bottlenecks such as limited precursor availability for biosynthesis, toxicity from metabolic intermediates, inefficient cofactor utilization, and over-reliance on conventional host microorganisms. Breaking through these bottlenecks by integrating the five strategies outlined is expected to further increase caffeic acid production.

PMID:40757780 | DOI:10.1002/biot.70091

CPT Pharmacometrics Syst Pharmacol. 2025 Aug 4. doi: 10.1002/psp4.70096. Online ahead of print.

ABSTRACT

Drug development in pediatric rare diseases is complicated by practical and ethical constraints on clinical trial design, stemming from small, highly heterogeneous, and vulnerable patient populations. Virtual patients (VPs) created with machine-learning (ML), mechanistically driven computational approaches, or hybrids thereof, have the potential to expedite and maximize the impact of trials. We discuss the potential of VPs to transform the efficiency and impact of clinical trials in pediatric rare diseases, based on adult and pediatric examples.

PMID:40757668 | DOI:10.1002/psp4.70096

Physiol Mol Biol Plants. 2025 Jun;31(6):863-876. doi: 10.1007/s12298-025-01621-2. Epub 2025 Jul 17.

ABSTRACT

Saffron (Crocus sativus L.) is a sterile triploid medicinal plant and is the world's most expensive cultivated herb. Its dried red stigmas accumulate important carotenoids, which produce apocarotenoids after oxidative cleavage. Saffron produces important apocarotenoids, crocin, picrocrocin and safranal, that provide color, flavor and aroma to it. To understand the expression pattern and stage specificity of apocarotenoid biosynthesis genes, we performed RNA sequencing at six different stages of stigma development (yellow, orange, red, two days before anthesis, at the day of anthesis and two days after anthesis) using Illumina platform. Differential expression analysis revealed preferential/specific expression of many genes at the different stages of stigma development. Functional annotation identified many genes encoding enzymes involved in different steps of apocarotenoid biosynthesis pathways expressed preferentially at red and later stages of stigma development. In addition, gene ontology enrichment analysis revealed several genes involved in primary/secondary metabolic processes and reproductive development pathways, exhibiting higher transcript abundance at the later stages of stigma development. Overall, the data and results presented in this study can serve as a rich resource for understanding the apocarotenoid biosynthesis in C. sativus during stigma development.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-025-01621-2.

PMID:40756438 | PMC:PMC12314296 | DOI:10.1007/s12298-025-01621-2

Gut Microbes. 2025 Dec;17(1):2539450. doi: 10.1080/19490976.2025.2539450. Epub 2025 Aug 3.

ABSTRACT

The mucosal virome is increasingly recognized for its potential role in shaping intestinal health and disease. Building on previous findings, we analyzed the mucosal virome from 51 individuals, including newly diagnosed treatment naïve participants with ulcerative colitis (UC), Crohn's disease (CD), and non-inflammatory bowel disease (non-IBD) controls, incorporating longitudinal sampling for a subset of the participants. Viromes were highly individualized, with no shared or core components across participants. Unlike fecal virome studies, we observed no significant associations between mucosal virome diversity and mucosal inflammation, disease subtype, or sampling site. However, there was positive correlation between virome and bacteriome diversity, particularly in CD, suggesting the presence of dynamic interactions that influence microbial community structure. Crassvirales was abundant in the mucosa layer and, consistent with prior studies, Crassvirales abundance was reduced in IBD, irrespective of inflammation status or IBD subtype. These findings highlight their potential as biomarkers of virome health. Our data also revealed the potential presence of altered bacteriome-virome interactions and longitudinal sampling revealed a persistent subset of viruses, potentially shaping disease progression and remission dynamics. Our study underscores the importance of distinguishing microbial community dynamics across IBD subtypes and highlights Crassvirales as key players in mucosal immunity.

PMID:40754936 | DOI:10.1080/19490976.2025.2539450

Gut Microbes. 2025 Dec;17(1):2526719. doi: 10.1080/19490976.2025.2526719. Epub 2025 Aug 3.

ABSTRACT

The associations of the gut microbiome and virome with human health and disease are increasingly numerous and clear. The mechanistic roles of bacteriophages (phages) in the microbiome, however, are especially unclear, as their cultivation is exceedingly difficult and their diversity so immense. We use viral tagging (VT), a technique wherein fluorescently stained uncultivated viruses are allowed to adsorb to host cells and then host cells are singly sorted. This method identifies interacting phage-bacteria pairs to better sample and characterize the phages in human stool samples from healthy and inflammatory bowel disease (IBD)-affected patients. First, we apply VT to uncultivated bacteria from a healthy human sample, demonstrating far-reaching ability to observe diverse bacteria and phages alike. We also use VT with a cultured Faecalibacterium prausnitzii isolate, a bacterial host of interest due to its anti-inflammatory effects and strong negative correlation with IBD. Comparing VT with virome sequencing and phage identification from single amplified genomes shows that it is a practical technique for phage discovery, especially when it is used to focus on individual bacterial cultivars for which genomes have been sequenced. VT can detect phages so rare as to be undetectable in standard virome sequencing, which is biased toward the most abundant phage species even at high sequencing depth. Remarkably, VT also identified novel prophage integration events in F. prausnitzii, demonstrating that VT interactions can extend beyond the level of surface attachment and constitute active infection events. In total, VT identified at least 328 unique and highly diverse phage-host pairs, almost all of which are entirely uncharacterized, and several phages that are differentially abundant in IBD patients compared to healthy controls. Taken together, we show that VT is an extremely powerful tool to move beyond the cultivation and abundance biases inherent to current techniques and suggest that the phage-host pairs identified by VT here are crucial first step to enable future mechanistic studies of phage-bacteria-human interactions.

PMID:40754853 | DOI:10.1080/19490976.2025.2526719

Immunology. 2025 Aug 3. doi: 10.1111/imm.70024. Online ahead of print.

ABSTRACT

Tissue-resident memory T (TRM) cells are a specialised subset of immune cells that remain within tissues, playing a vital role in localised immune defence and long-term immunity. Unlike circulating memory T cells, TRM cells do not recirculate to provide rapid and effective responses against previously encountered pathogens at the tissue level. The formation of TRM cells is driven by tissue-specific cues, guiding their differentiation and retention within organs such as the skin, lungs and gut. They are characterised by the expression of unique markers, including CD69 and CD103, which facilitate their retention and longevity in tissues. TRM cells are essential for immune surveillance, effectively detecting and responding to different infections and contributing to tumour suppression. However, TRM cells are also implicated in chronic inflammatory and autoimmune diseases, where persistent activation by resident and autoantigens can lead to tissue damage. This pathogenic role is evident in chronic inflammatory conditions such as psoriasis, vitiligo and inflammatory bowel disease (IBD), where TRM cells may drive persistent localised inflammation and contribute to disease progression and severity. Emerging therapeutic strategies seek to modulate TRM cells to balance their protective and pathogenic roles in these inflammatory diseases. Approaches such as checkpoint inhibitors, cytokine modulation and cell-depletion therapies aim to enhance TRM cells' beneficial immune functions while minimising their role in autoimmunity. A deeper understanding of TRM cell development, maintenance and functional diversity is critical for advancing treatments for infectious diseases, chronic inflammation, autoimmune conditions and cancer.

PMID:40754695 | DOI:10.1111/imm.70024

Biol Pharm Bull. 2025;48(8):1165-1171. doi: 10.1248/bpb.b25-00330.

ABSTRACT

One of the most significant conceptual changes brought about by the discovery of clock genes and development of circadian-clock mutant mice is the recognition that impaired circadian rhythmicity extends its impact far beyond sleep, driving pathogenesis of a wide variety of disorders such as cancer, obesity, and hypertension. However, despite this growing clinical evidence, chronobiology still lacks a coherent answer to the converse question: can restoration of circadian rhythms ameliorate-or even reverse-such diseases? In this review, three complementary pharmacological strategies-each still in preclinical development-are explored. First, direct modulation of the transcription-translation feedback loop (TTFL)-the core gene-regulatory circuit that generates 24-h rhythms in almost all nucleated cells-is reviewed as an approach to manipulation of cellular circadian biology. Second, the suprachiasmatic nucleus (SCN)-enriched G-protein-coupled receptor Gpr176 is highlighted as a central-clock target, given its ligand-independent, Gz-mediated control of cAMP signaling and demonstrated ability to reset the master pacemaker. Third, the concept of rhythmic enhancement of output function is introduced and exemplified by describing re-activation of circadian oxidized form of nicotinamide adenine dinucleotide (NAD+)-dependent 3β-hydroxy-steroid dehydrogenase (3β-HSD) activity in the meibomian gland-using nicotinamide mononucleotide (NMN)-to restore peripheral clock-driven steroidogenesis in this tissue, which leads to amelioration of meibomian gland dysfunction, a leading cause of dry eye disease. This review aims to highlight the molecular logic of each strategy; both mechanistic insights and safety/efficacy considerations are discussed.

PMID:40754455 | DOI:10.1248/bpb.b25-00330

Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Aug 1:S2451-9022(25)00226-5. doi: 10.1016/j.bpsc.2025.07.010. Online ahead of print.

ABSTRACT

BACKGROUND: Neuroanatomical variation in individuals with bipolar disorder (BD) has been previously described in observational studies. However, the causal dynamics of these relationships remain unexplored.

METHODS: We performed Mendelian Randomization of 297 structural and functional neuroimaging phenotypes from the UK Biobank and BD using GWAS summary statistics. We carried out a suite of sensitivity analyses and examined phenotypic categories with the greatest effect on BD. We applied a novel inverse sparse regression model which accounts for covariance between sets of correlated effects to estimate 'direct causal effects' (DCE), representing the effect of one phenotype conditional on all other effects. We used DCE weights to create causal scores for BD using neuroimaging data from three clinical cohorts.

RESULTS: We found 28 significant causal relationship pairs after multiple testing corrections containing BD as a term, 27 of which described neuroimaging phenotype effects on BD. White matter tract phenotypes have larger absolute effects on BD than vice versa in MR tests and estimated direct causal effect solutions. We found that white matter phenotypes had significantly larger out-degrees than non-white matter tract phenotypes across network solutions. A causal score constructed using neuroimaging causal estimates was a significant predictor of BD in an adolescent cohort (O.R.=0.79).

CONCLUSION: Mendelian randomization analyses suggest that neuroanatomical variation, specifically in white matter tracts such as the longitudinal fasciculi, is likely a cause rather than a consequence of BD. Verification of estimated causal relationships requires replication and triangulation of evidence approaches using other study designs.

PMID:40754166 | DOI:10.1016/j.bpsc.2025.07.010

J Mol Biol. 2025 Aug 1:169370. doi: 10.1016/j.jmb.2025.169370. Online ahead of print.

ABSTRACT

Polyprotein processing is a common strategy in many positive sense single-stranded RNA ((+)ssRNA) viruses. This highly regulated process is crucial for viral progeny and ensures the release of functional replicase proteins in the correct location and at the right time. Coronaviruses (CoVs) have one of the largest genomes on average among (+)ssRNA viruses requiring a unique replication-transcription complex (RTC) with proofreading function that prevents error catastrophe. Two thirds of the CoV genome encode for the non-structural proteins (nsps) that drive replication. These are directly synthesized by RNA genome translation after infection as two large polyproteins pp1a and pp1ab. A regulated polyprotein proteolytic auto-processing is essential for viral growth and always has been an interesting target for therapeutics. Here, we present an overview of polyprotein processing and RTC research in CoVs in vitro and in vivo over the last 30 years. We highlight cutting-edge methodologies such as super resolution microscopy or structural mass spectrometry approaches and demonstrate how these have contributed to polyprotein research, e.g. by providing comprehensive structural models. We illustrate exciting examples of polyprotein processing in other viruses that could be transferred to CoVs, too. Additionally, we identify critical knowledge gaps in polyprotein processing and RTC assembly, proposing future perspectives to address these limitations.

PMID:40754154 | DOI:10.1016/j.jmb.2025.169370

Nat Commun. 2025 Aug 2;16(1):7123. doi: 10.1038/s41467-025-62522-2.

ABSTRACT

The C. elegans-Orsay virus pathosystem provides a powerful model for investigating the mechanisms that govern viral infection and immunity. Here, we focus on two key aspects of this interaction: the impact of lifelong latent infections and the dynamics of superinfection. By tracking the course of a lifelong infection, we demonstrate that the infection remains latent, with animals maintaining control over viral replication for most of their lifespan. Furthermore, we show that animals previously exposed to the virus can suppress viral replication following a second inoculation, indicative of an acquired immune response. Primary infections led to changes in transcriptomic and small RNA profiles, which varied depending on the developmental stage of the host and the timing of analysis. In contrast, superinfection disrupted multiple sRNA classes. Over time, the ability to control repeated viral reactivations declined, whereas resistance to superinfection was stable, ultimately favoring the primary infecting virus. This phenomenon was dependent on a functional RNA interference pathway.

PMID:40753171 | DOI:10.1038/s41467-025-62522-2

Biochim Biophys Acta Proteins Proteom. 2025 Jul 31:141091. doi: 10.1016/j.bbapap.2025.141091. Online ahead of print.

ABSTRACT

Pancreatic cancer remains a severe malignancy with a dismal 5-year survival rate, and most pancreatic cancer patients harbor KRAS mutations, which are critical targets for anti-cancer drug development. However, the structural characteristics of KRAS present challenges for therapeutic targeting. In this study, we developed a novel peptide derived from TIG3 protein, a type II tumor suppressor, and confirmed its moderate affinity binding to KRAS G12V. X-ray crystallography revealed that this peptide binds near the Switch II domain of KRAS G12V, causing conformational changes likely to affect its activity. Furthermore, the peptide reduced the viability of cancer cell lines harboring the KRAS G12V mutation, thus demonstrating its potential as a KRAS G12V inhibitor. Our results indicate that the developed novel TIG3 peptide is a promising candidate for KRAS-targeted therapy and provide structural insights useful for the development of pancreatic ductal adenocarcinoma therapeutics.

PMID:40752582 | DOI:10.1016/j.bbapap.2025.141091

STAR Protoc. 2025 Aug 1;6(3):103986. doi: 10.1016/j.xpro.2025.103986. Online ahead of print.

ABSTRACT

Vertical-looking radars (VLRs) detect individual flying animals up to ∼2 km above ground and characterize their flight track, timing, wing movement, size, and shape. We present a protocol for calculating individual vertical movement characteristics and producing diel vertical movement profiles using the BirdScan MR1 VLR, based on flight altitude detection and timing. The protocol includes steps for data preparation and analysis. This protocol promotes a more detailed understanding of migration ecology, stopover behavior, and movement phenology. For complete details on the use and execution of this protocol, please refer to Werber and Sapir.1.

PMID:40751920 | DOI:10.1016/j.xpro.2025.103986

Sex Med Rev. 2025 Aug 2:qeaf043. doi: 10.1093/sxmrev/qeaf043. Online ahead of print.

ABSTRACT

INTRODUCTION: Since its proposal in 2002, late-onset hypogonadism (LOH) has been a subject of considerable controversy. Although its status as a pathophysiological entity is undisputed, the underlying mechanisms remain contentious and are not fully understood.

OBJECTIVES: To evaluate current therapies for LOH, such as testosterone replacement therapy (TRT) and weight loss interventions, and to explore innovative anti-aging strategies aimed at counteracting age-related factors contributing to LOH.

METHODS: A comprehensive literature review was conducted to explore the ongoing controversies and challenges in the clinical diagnosis of LOH. Additionally, the efficacy and limitations of current therapeutic approaches, including novel anti-aging strategies and combination therapies were critically examined.

RESULTS: Current therapies address specific aspects of LOH, such as TRT for low testosterone levels and weight loss interventions for obesity, which is the strongest risk factor. However, these therapies have shortcomings, including potential health hazards associated with TRT and disputed efficacy of weight loss interventions. Recent discoveries have led to the development of innovative anti-aging strategies, which show promise in overcoming the limitations of existing methods. Several clinical trials have substantiated the efficacy of these novel approaches, particularly when used in combination therapies.

CONCLUSIONS: While further clinical trials are necessary, novel anti-aging strategies hold promise for enhancing the efficacy of existing LOH treatments and overcoming their limitations. These innovative approaches could potentially offer more effective solutions for managing LOH.

PMID:40751587 | DOI:10.1093/sxmrev/qeaf043