Biology subjects

Luciano, A.

Publications and source records attributed to Luciano, A..

7 recordsLinked to original sources

bioRxiv2026

Circulating extracellular vesicles in plasma carry accessible molecular signatures of aging in mice

Cells release membrane-bound extracellular vesicles into the bloodstream laden with proteins that may reflect their physiological state. How this circulating EV proteome changes across life remains poorly understood. Identifying molecular signatures of aging in accessible biofluids could facilitate earlier intervention and monitoring of age-related disease. Many circulating aging proteome studies rely on affinity-based platforms which suffer from poor cross-species translation, ambiguous signal attribution, and inconsistent agreement between platforms. Here, we present a characterization of the aging plasma EV proteome from a cross-sectional cohort of 86 male and female C57BL/6J mice (5-31 months). We leveraged a species-agnostic EV enrichment (Mag-Net) and mass spectrometry to detect 2,575 protein groups from 15,969 peptides. Protein abundance heterogeneity increased with age and the abundance of 272 proteins were significantly correlated with chronological age including established senescence and frailty markers. Proteins increasing with age were enriched in genome maintenance pathways, while those decreasing were associated with the extracellular matrix organization and lipid metabolism. Notably, several of the strongest age-increased proteins converged on Alzheimers and Parkinsons disease pathology. We observed sexual divergence in the aging EV proteome not previously characterized at this resolution. A proteomic clock built from this data accurately predicts chronological age, and peptide-level analysis reveals aging signals invisible at protein-level. These findings demonstrate that EV-enriched plasma proteomics can identify known aging markers, reveal novel sex-specific age-related changes, and generate predictive models of chronological age. This study provides a species-agnostic foundation for proteomic clocks that complement epigenetic approaches to monitor aging and evaluate healthspan.

molecular biology↗

bioRxiv2026

A multiomic lifespan signature in genetically diverse, diet-restricted mice

Dietary restriction extends lifespan across model organisms, but the plasma molecular changes mediating this effect remain incompletely characterized. We present a longitudinal multiomic analysis of 2,234 plasma samples from 960 Diversity Outbred mice subjected to intermittent fasting or caloric restriction and followed to natural death. Using mass spectrometry, we quantified 1,512 metabolites, lipids, and proteins and mapped their associations with diet, age and longevity. DR-induced molecular changes scale with caloric intake and modulate inflammatory, lipid catabolism, and oxidative stress pathways. Aging showed a biphasic signature with sharp acceleration beyond 85% of lifespan, demarcating terminal decline. Mediation and survival modeling both identified superoxide dismutase (SODE) and vascular cell adhesion molecule (VCAM1) as top lifespan predictors. Genetic analysis revealed 9,599 QTL, nine of which coincided with previously identified lifespan QTLs, and were largely related to immune regulation. These findings provide a rich multiomic and genetic resource for the aging research community.

systems biology↗

bioRxiv2026

Multimodal analysis of molecular remodeling in aging spleen identified global and cell type specific changes

Aging reshapes the cellular and molecular landscape of mammalian tissues. These changes can be progressive, preceding linearly with age, or occur as abrupt transitions of the course of lifespan. To investigate the age-dependent cellular and molecular shifts we profiled matched proteomes and transcriptomes from male and female murine spleens across eight time points, from stable adults through late life. The spleen was chosen to integrate understanding of age-dependent changes associated with immune surveillance, inflammaging, and immune-related proteostasis. Male and female mice follow distinct aging trajectories particularly in protein-RNA correlation in late life, reflecting both compositional shifts and failure of post-transcriptional buffering. To investigate whether these changes could be attributed to specific cell-types within the spleen, we developed Celestial, a machine-learning framework to identify cell-type-specific changes in bulk tissue samples. We found that age-related bulk molecular changes could be attributed in part to compositional remodeling of cell-types--expansion of GZMK+ CD8+ T cells and C1Q+ macrophages alongside naive T cell and global B cell loss. These results demonstrate that cell-type-aware interpretation can inform bulk multi-omic data for accurate mechanistic inference in heterogeneous tissues undergoing complex molecular remodeling.

systems biology↗

bioRxiv2025

Genetic regulation of fasting-induced longevity effects

Research methods for the investigation of the biology of aging have often implicitly generalized strain-specific results. Dietary interventions, such as caloric restriction and periodic fasting, have been shown to enhance metabolic health and extend lifespan in preclinical models. However, inter-individual variation in physiological responses to these interventions, which affects their safety and efficacy when translated to humans, remains poorly understood despite being observed in multiple studies. In this study, we implemented intermittent fasting (IF) for two days per week in 10 inbred strains (n = 800 mice) from the Collaborative Cross (CC). The CC is a multiparent recombinant inbred strain panel that offers a diverse collection of reproducible models to study the genetic control of heterogeneous intervention responses. We conducted longitudinal phenotyping to characterize hundreds of traits, including lifespan, in the CC mice. We demonstrate that sex and genetic background induce variable responses to intermittent fasting across multiple physiological outcomes, including metabolic, hematologic, and immunologic health. Effects of IF on lifespan were sex-specific and variable across genetic backgrounds. Thus we establish that response to IF is genetically determined in an animal model with physiological features similar to humans. We compared our findings in the CC with those from a parallel study of Diversity Outbred (DO) mice, highlighting common predictors of health and lifespan, as well as key differences between the genetically diverse inbred and outbred models. These findings underscore the importance of genetic factors in dietary intervention responses, offering valuable insights for translating intermittent fasting benefits to human health and longevity. Keywords: multiparental populations; gene-by-treatment interaction

genetics↗

bioRxiv2024

Quantifying the Impact of Co-Housing on Murine Aging Studies

Analysis of preclinical lifespan studies often assume that outcome data from co-housed animals are indepen-dent. In practice, treatments, such as controlled feeding or putative life-extending compounds, are applied to whole housing units, and as a result the outcomes are potentially correlated within housing units. We consider intra-class (here, intra-cage) correlation in three published and two unpublished lifespan studies of aged mice encompassing more than 20 thousand observations. We show that the independence assumption underlying common analytic techniques does not hold in these data, particularly for traits associated with frailty. We describe and demonstrate various analytical tools available to accommodate this study design and highlight a limitation of standard variance components models (i.e., linear mixed models) which are the usual statisti-cal tool for handling correlated errors. Through simulations, we examine the statistical biases resulting from intra-cage correlations with similar magnitudes as observed in these case studies and discuss implications for power and reproducibility.

bioinformatics↗

bioRxiv2024

Longitudinal Fragility phenotyping predicts lifespan and age-associated morbidity in C57BL/6 and Diversity Outbred mice

Aging studies in mammalian models often depend on natural lifespan data as a primary outcome. Tools for lifespan prediction could accelerate these studies and reduce the need for veterinary intervention. Here, we leveraged large-scale longitudinal frailty and lifespan data on two genetically distinct mouse cohorts to evaluate noninvasive strategies to predict life expectancy in mice. We applied a modified frailty assessment, the Fragility Index, derived from existing frailty indices with additional deficits selected by veterinarians. We developed an ensemble machine learning classifier to predict imminent mortality (95% proportion of life lived [95PLL]). Our algorithm represented improvement over previous predictive criteria but fell short of the level of reliability that would be needed to make advanced prediction of lifespan and thus accelerate lifespan studies. Highly sensitive and specific frailty-based predictive endpoint criteria for aged mice remain elusive. While frailty-based prediction falls short as a surrogate for lifespan, it did demonstrate significant predictive power and as such must contain information that could be used to inform the conclusion of aging experiments. We propose a frailty-based measure of healthspan as an alternative target for aging research and demonstrate that lifespan and healthspan criteria reveal distinct aspects of aging in mice.

bioinformatics↗

bioRxiv2023

Regulators of health and lifespan extension in genetically diverse mice on dietary restriction

Caloric restriction (CR) delays aging and extends healthy lifespan in multiple species. Alternative forms of dietary restriction (DR) such as intermittent fasting (IF) have drawn significant interest as a more sustainable regimen, but the landscape of longevity-promoting dietary interventions remains largely unexplored. Identifying the most robust, efficacious, and experimentally tractable modes of DR is key to better understanding and implementing effective longevity interventions for human healthspan. To that end, we have performed an extensive assessment of DR interventions, investigating the effects of graded levels of CR (20% and 40%) and IF (1 day and 2 days of fasting per week) on the health and survival of 960 genetically diverse female mice. All interventions extended lifespan, although only CR significantly reduced the mortality doubling time. Notably, IF did not extend lifespan in mice with high pre-intervention bodyweight. We carried out extensive phenotyping to determine the health effects of long-term DR and to better understand the mechanisms driving within-diet heterogeneity in lifespan. The top within-diet predictor of lifespan was the ability of mice to maintain bodyweight through periods of handling, an indicator of stress resilience. Additional predictors of long lifespan include specific changes in immune cells, red blood cell distribution width (RDW), and retention of adiposity in late life. We found that lifespan is heritable (h2 = 0.24), and that genetic background has a larger influence on lifespan than dietary interventions. We identified a significant association for lifespan and RDW on chromosome 18 that explained 4.3% of the diet-adjusted variation in lifespan. Diet-induced changes on metabolic traits, although beneficial, were relatively poor predictors of lifespan, arguing against the long-standing notion that DR works by counteracting the negative effects of obesity. These findings indicate that improving health and extending lifespan are not synonymous and that metabolic parameters may be inappropriate endpoints for evaluating aging interventions in preclinical models and clinical trials.

genetics↗