Biology subjects

Liao, G. Y.

Publications and source records attributed to Liao, G. Y..

8 recordsLinked to original sources

bioRxiv2026

Serum protein profiling reveals hallmark-level aging trajectories and strain-specific resilience in CB6F1J and C57BL/6J male mice.

Aging is characterized by coordinated molecular and physiological changes across multiple biological systems, yet the ability to quantify these processes non-invasively within individuals remains limited. Here, we establish a framework for quantifying hallmark-level features of aging in mice using serum protein array profiles obtained from a single blood draw. Serum protein expression was profiled in groups of CB6F1J and C57BL/6J male mice at 8 and 32 months of age and mapped to established hallmarks of aging. Hallmark-level analyses revealed coordinated, pathway-specific changes in inflammatory, vascular, intercellular signaling, metabolic, and regenerative processes, with distinct patterns observed between strains. CB6F1J mice exhibited directional shifts across multiple pathways, while C57BL/6J mice showed broader but more heterogeneous changes. Cross-strain comparisons demonstrated shared pathway-level trends alongside variable protein-level concordance. This approach enables non-terminal assessment of aging within individuals and resolves heterogeneity in aging trajectories using minimally invasive sampling. These findings support the use of circulating protein signatures to quantify biological aging and provide a framework for translating non-invasive proteome-based assessment of aging to human studies.

systems biology↗

bioRxiv2026

Middle-aged mice treated with GHK-Cu peptide administered intraperitoneally or intranasally show behavioral rescue but divergent hippocampal aging programs

Age-related cognitive decline (ARCD) is driven by conserved biological mechanisms of aging, yet no gerotherapeutic directly targets these processes in the brain. Glycyl-L-histidyl-L-lysine complexed with copper (GHK-Cu) is an endogenous peptide with regenerative and anti-inflammatory properties that declines with age. Whether its effects on cognitive aging depend on delivery route or exposure duration remains unclear. Aged C57BL/6J mice (20-21 months) received GHK-Cu (15 mg/kg) via short-term intraperitoneal (IP; 5 days) or longer-term intranasal (IN; 8 weeks) administration. Hippocampal-dependent escape learning was assessed using a spatial navigation task. Molecular effects were evaluated using hippocampal immunohistochemistry and bulk RNA sequencing. Differential gene expression was analyzed using DESeq2 with false discovery rate (FDR) correction, and pathway-level changes were assessed via gene set enrichment analysis (GSEA). IN GHK-Cu improved escape latency across Trials 2-4 in both sexes (P < 0.05), whereas IP dosing produced a transient improvement in males during Trial 2 (P < 0.05) without sustained effects or improvement in females. IN treatment increased synaptophysin in females (P < 0.001) and decreased GFAP in both sexes (P < 0.01), while IP treatment reduced TGF-{beta}, GFAP, and MCP-1 in males (P < 0.05) and decreased p21 in females (P < 0.0001). Transcriptomic analysis revealed distinct molecular programs. IN GHK-Cu induced coordinated suppression of oxidative phosphorylation (male NES -5.44, female NES -4.20; FDR < 0.0001) and MYC target pathways (female NES -4.31, FDR < 0.0001), with additional attenuation of PI3K-AKT-mTOR signaling in females (NES -3.15, FDR = 0.062). In contrast, IP treatment activated oxidative phosphorylation (female NES 4.97, FDR < 0.001), DNA repair (NES 5.58, FDR < 0.001), and MYC targets (NES 4.34, FDR = 0.002), indicating engagement of acute stress-response and repair pathways. GHK-Cu improves hippocampal-dependent learning in aged mice through distinct biological modes: IP exposure activates repair and stress-response pathways, whereas IN delivery induces sustained suppression of growth and mitochondrial metabolic signaling associated with aging biology. These findings demonstrate that functional cognitive improvement can arise from divergent molecular states and identify administrative route and exposure duration as key determinants of gerotherapeutic response.

pharmacology and toxicology↗

bioRxiv2026

A composite frailty index enables quantification of functional aging and identification of gerotherapeutic drugs in the house cricket.

Frailty, defined by progressive loss of physiological resilience, neuromuscular function, and cognitive capacity, is a central manifestation of biological aging yet remains difficult to quantify in scalable experimental systems. Here, we introduce a Composite Frailty Index (CFI) in the house cricket (Acheta domesticus) that integrates automated measures of locomotion, exploratory behavior, and freezing into a unified, quantitative framework of functional decline. Ten behavioral parameters derived from automated open-field tracking, including locomotor performance, exploratory behavior, and freezing were integrated into the CFI. Locomotor states were classified using k-means clustering (k = 2) of velocity distributions, and all features were normalized to age- or treatment-matched reference populations, discretized into quintiles, and summed to generate a 0-40 frailty score. Aging cohorts (young adult: 4-6 weeks; geriatric: 10-12 weeks, N = 103) and pharmacological cohorts treated at mid-life (8-10 weeks) with rapamycin (14 ppm), acarbose (1000 ppm), or phenylbutyrate (1000 ppm) were evaluated (N = 122). Across chronological aging cohorts, CFI increased from young adults to geriatrics in both females (d = 1.14 [95% CI: 0.53, 1.76], P = 0.0003) and males (d = -1.17 [95% CI: -1.75 to -0.59], P < 0.0001). Using pharmacological intervention cohorts, mid-life rapamycin treatment reduced late-life frailty relative to controls in both females (d = -1.31 [95% CI: -2.09, -0.53], P = 0.0017) and males (d = -1.33 [95% CI: -2.09, -0.58], P = 0.0004), whereas acarbose and phenylbutyrate produced inconclusive effects (ds = -0.54 to -0.03; Ps > 0.05). Together, these findings establish the cricket CFI as a scalable, high-throughput platform for quantifying multidimensional functional aging and prioritizing candidate geroprotective interventions based on clinically relevant endpoints beyond lifespan.

animal behavior and cognition↗

bioRxiv2025

The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets.

The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs (ds = -1.82 to -1.28, Ps < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity (d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios (d = -0.75, P < 0.05). Rapamycin increased central exploration and freezing (d = -1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing (d = -0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time (ds = -2.30 to -1.32, Ps < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin (HR = 0.42, P < 0.001) and reduced by acarbose in females (HRs = 2.92 to 3.03, Ps < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.

pharmacology and toxicology↗

bioRxiv2025

Age-related cognitive decline in house crickets reveals conserved patterns of sensory and learning deficits across the lifespan

Cognitive decline with age is characterized by impairments in learning, sensory discrimination, and decision-making. While mammalian models have advanced understanding of the neural substrates of aging, their use in large-scale behavioral studies is limited. Invertebrate models, such as the house cricket (Acheta domesticus), offer short lifespans, high throughput, and conserved neurobiological pathways but remain underexplored in geroscience. We developed a dual behavioral paradigm integrating an olfactory discrimination Y-maze and an escape learning task requiring crickets to override innate odor preferences. Adult, mid-age, and geriatric crickets were tested for sensory discrimination, associative learning, and decision speed. Morphological traits, including antennal and femoral metrics, were quantified to evaluate their influence on cognitive outcomes. Data were analyzed using ANOVA, ANCOVA, and logistic regression models. Aging impaired olfactory preference and learning success, with geriatric crickets showing reduced task acquisition and memory retention. Mid-age individuals exhibited the slowest decision-making, suggesting an early onset shift in behavioral strategy. Morphological traits predicted aspects of sensory performance and physiological resilience, such as reduced weight loss in crickets with larger femoral dimensions but did not explain age-related cognitive deficits. Olfactory decline was particularly pronounced in males, mirroring sex differences observed in human cognitive aging. House crickets exhibit hallmark features of cognitive aging, including sensory decline, learning impairments, and reduced resilience, independent of morphological deterioration. These findings establish the house cricket as a scalable invertebrate model for dissecting conserved mechanisms of neural aging and testing interventions to promote cognitive health.

neuroscience↗

bioRxiv2025

Morphological features of the domestic house cricket (Acheta domesticus) for translational aging studies

Aging alters morphology and locomotor function in diverse organisms, yet standardized model systems for studying these changes remain limited to a relatively few species. Here, we present a comprehensive analysis of age- and sex-dependent morphological variations in house crickets (Acheta domesticus), integrating refined husbandry protocols to enhance reproducibility and translational relevance. We observed progressive increases in body weight, length, and appendage dimensions with age, with pronounced sexual dimorphism emerging post-maturity. Structural adaptations, including increased femoral volume and cross-sectional area, suggest compensatory mechanisms for age-related declines in muscle efficiency, while reduced hind leg-to-body length ratios indicate potential biomechanical constraints on locomotion. Antennal growth patterns highlight prolonged sensory investment, potentially offsetting declining mobility in aging individuals. To ensure data consistency, we implemented a standardized husbandry framework incorporating self-determined photoperiods, co-housing both sexes, and controlled diet and hydration strategies. Our results underscore the necessity of harmonizing environmental conditions in gerontological research, as variations in lighting, substrate availability, and microbiome exposure may significantly impact physiological resilience and behavioral fidelity. Future work should explore the influence of microbiome diversity on lifespan and stress resilience while refining methodologies for cricket rearing from egg to adulthood. By bridging invertebrate and vertebrate aging research, this study positions house crickets as a scalable, high-throughput model for investigating age-related functional decline, behavioral plasticity, and lifespan-extending interventions. Integrating behavioral assays, biomechanical analyses, and molecular markers of aging will further elucidate the interplay between morphology, function, and longevity, advancing the utility of crickets in comparative geroscience.

animal behavior and cognition↗

bioRxiv2024

Comparison of Age-Related Decline and Behavioral Validity in C57BL/6 and CB6F1 Mice

Variability in physical resilience to aging prompts a comprehensive examination of underlying mechanisms across organs and individuals. We conducted a detailed exploration of behavioral and physiological differences between C57BL/6 and CB6F1 mice across various age groups. In behavioral assays, B6 mice displayed superior performance in rotarod tasks but higher anxiety while CB6F1 mice exhibited a decline in short-term memory with age. Grip strength, long-term memory, and voluntary wheel running declined similarly with age in both strains. Examining physiological phenotypes, B6 mice exhibited lower body fat percentages across ages compared to CB6F1 mice, though cataract severity worsened with age in both strains. Analysis of cardiac functions revealed differences between strains, with worsening left ventricular hypertrophy and structural heart abnormalities with age in CB6F1 mice along with higher blood pressure than B6. Lesion scores showed an age-related increase in heart, kidney, and liver lesions in both strains, while lung lesions worsened with age only in CB6F1 mice. This study underscores the validity of behavioral assays and geropathology assessment in reflecting age-related decline and emphasizes the importance of considering strain specificity when using mouse models to study human aging.

animal behavior and cognition↗

bioRxiv2023

Behavioral and neuropathological features of Alzheimer's disease are attenuated in 5xFAD mice treated with intranasal GHK peptide

Efforts to find disease modifying treatments for Alzheimers disease (AD) have met with limited success in part because the focus has been on testing drugs that target a specific pathogenic mechanism. Multiple pathways have been implicated in the pathogenesis of AD. Hence, the probability of more effective treatment for AD is likely increased by using an intervention that targets more than one pathway. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), as a GHK-Cu complex, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. In order to test GHK-Cu as a neurotherapeutic for AD, male and female 5xFAD transgenic mice on the C57BL/6 background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered inflammation levels in the frontal cortex and hippocampus. These observations suggest additional studies are warranted to investigate the potential of GHK-Cu peptide as a promising treatment for AD.

neuroscience↗