Biology subjects

Rhoads, T. W.

Publications and source records attributed to Rhoads, T. W..

4 recordsLinked to original sources

bioRxiv2026

Caloric restriction drives age-dependent and integrated remodeling of RNA processing and lipid composition in mouse brain

Caloric restriction (CR) extends lifespan and delays the onset of age-related diseases. Prior work has established numerous pathways that respond to CR, including growth signaling, metabolism, and inflammatory pathways. However, the molecular mechanisms that connect these pathways to enhanced lifespan and reduced disease risk remain unclear. Here, we demonstrate that RNA processing is altered in brains from mice on CR across adulthood and is linked to changes in lipid composition. Differential gene expression changes at each time point share a high degree of identity and functional overlap, with pathway enrichment including expected changes in metabolic pathways and neurotransmission related pathways. Differential splicing events were observed across adulthood; however, in contrast to the stable transcriptional program, RNA processing changes were dynamic and largely unique to each age group, suggesting regulatory mechanisms that were context specific. CR-induced changes in cortical lipid abundance profiles were highly coordinated across age groups, including increased abundance for lipids with higher degrees of unsaturation. Integrative analysis identified associations between specific lipid classes and transcripts, as well as particular categories of alternative splicing events. These data show that alternative RNA processing is a key mechanism harnessed by CR and linked to lipid homeostasis, providing new insight into metabolic reprogramming in the CR brain.

molecular biology↗

bioRxiv2025

Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism

Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/662412v3_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@33a57aorg.highwire.dtl.DTLVardef@b518ccorg.highwire.dtl.DTLVardef@16f2693org.highwire.dtl.DTLVardef@4daac4_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Caloric restriction reprograms adipose tissues in rhesus monkeys

Caloric restriction (CR) is a dietary intervention that delays the onset of age-related diseases and enhances survival in diverse organisms, and although changes in adipose tissues have been implicated in the beneficial effects of CR the molecular details are unknown. Here we show shared and depot-specific adaptations to life-long CR in subcutaneous and visceral adipose depots taken from advanced age male rhesus monkeys. Differential gene expression and pathway analysis identified key differences between the depots in metabolic, immune, and inflammatory pathways. In response to CR, RNA processing and proteostasis-related pathways were enriched in both depots but changes in metabolic, growth, and inflammatory pathways were depot-specific. Commonalities and differences that distinguish adipose depots are shared among monkeys and humans and the response to CR is highly conserved. These data reveal depot-specificity in adipose tissue adaptation that likely reflects differences in function and contribution to age-related disease vulnerability. In BriefRhesus monkey adipose tissues are highly responsive to long-term caloric restriction, although the response is depot-specific. Shared features include proteostasis and RNA processing pathways, whereas metabolic pathways, alterations in processes influenced by growth signaling, and changes in exon usage were depot-specific. The impact of CR on subcutaneous adipose tissue is highly conserved between monkeys and humans. HighlightsO_LIAt the transcript level, SAT and VAT taken from the same animals show modest specialization, primarily in metabolic and immune pathways. C_LIO_LIThe transcriptome of SAT is more responsive to CR than that of VAT, with depot-specific differences in metabolic adaptation and cell type composition. C_LIO_LIRNA processing pathways are engaged by CR and transcript isoforms are enriched in both depots, but differential exon usage is limited to SAT. C_LIO_LIAdipose reprogramming is linked to CR induced differences in body composition and systemic indices of health. C_LIO_LIThe impact of CR on subcutaneous adipose tissue is highly similar between monkeys and humans. C_LI

genomics↗

bioRxiv2023

Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging

The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.

cell biology↗