Biology subjects

Borrus, D. S.

Publications and source records attributed to Borrus, D. S..

5 recordsLinked to original sources

bioRxiv2025

TranslAGE: A Comprehensive Platform for Systematic Validation of Epigenetic Aging Biomarkers

Epigenetic clocks are powerful biomarkers of biological aging, however, their performance varies across studies and contexts. Current limitations include siloed datasets, inconsistent validation methods, and the absence of a standardized framework for systematic comparison. Here, we introduce TranslAGE: a publicly available online resource that addresses this gap by harmonizing 179 human blood DNA methylation datasets and precalculating a suite of 41 epigenetic biomarker scores for each of the >42,000 total samples. Users can explore these data through interactive dashboards that evaluate four fundamental performance domains: Stability, Treatment response, Associations, and Risk, collectively forming the STAR framework. Stability quantifies robustness to multiple types of technical and biological noise. Treatment response measures biomarker sensitivity to aging interventions and environmental exposures. Associations capture cross-sectional relationships with age, demographics, disease, and other phenotypes, and Risk assesses predictive power for future functional decline, morbidity and mortality. The STAR framework unifies these test metrics into a single composite scoring system that enables researchers to identify, benchmark, and validate biomarkers best suited to their scientific or clinical applications. TranslAGE will be continually updated, with rapid scaling by adding datasets, biomarkers, or analyses. By providing harmonized datasets, precomputed biomarker scores, and interactive data tools, TranslAGE establishes the first standardized, reproducible framework for benchmarking epigenetic aging biomarkers across populations, and accelerates the translation toward clinical use.

genomics↗

bioRxiv2024

When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.

Recent human studies have suggested that aging interventions can reduce aging biomarkers related to morbidity and mortality risk. Such biomarkers may potentially serve as early, rapid indicators of effects on healthspan. An increasing number of studies are measuring intervention effects on epigenetic clocks, commonly used aging biomarkers based on DNA methylation profiles. However, with dozens of clocks to choose from, different clocks may not agree on the effect of an intervention. Furthermore, changes in some clocks may simply be the result of technical noise causing a false positive result. To address these issues, we measured the variability between 6 popular epigenetic clocks across a range of longitudinal datasets containing either an aging intervention or an age-accelerating event. We further compared them to the same clocks re-trained to have high test-retest reliability. We find the newer generation of clocks, trained on mortality or rate-of-aging, capture aging events more reliably than those clocks trained on chronological age, as these show consistent effects (or lack thereof) across multiple clocks including high-reliability versions, and including after multiple testing correction. In contrast, clocks trained on chronological age frequently show sporadic changes that are not replicable when using high-reliability versions of those same clocks, or when using newer generations of clocks and these results do not survive multiple-testing correction. These are likely false positive results, and we note that some of these clock changes were previously published, suggesting the literature should be re-examined. This work lays the foundation for future clinical trials that aim to measure aging interventions with epigenetic clocks, by establishing when to attribute a given change in biological age to a bona fide change in the aging process.

genomics↗

bioRxiv2022

Minimal models of the inspiratory and sigh breathing rhythms of the preBötzinger complex

The preBotzinger complex of the lower brainstem generates two breathing-related rhythms: one for inspiration on a timescale of seconds, and another that produces larger amplitude sighs on the order of minutes. We hypothesize that these two disparate rhythms emerge in tandem wherein recurrent excitation gives rise to the inspiratory rhythm while a calcium oscillator generates sighs; distinct neuronal populations are not required. We present several mathematical models that instantiate our working hypothesis including: (1) an activity (firing rate) model and (2) a minimal spiking network model. Both modeling frameworks corroborate the single-population rhythmogenic hypothesis.

neuroscience↗

bioRxiv2022

Sigh breathing rhythm depends on intracellular calcium oscillations in a population of inspiratory rhythmogenic preBötzinger complex neurons in mice

The preBotzinger Complex (preBotC) of the lower brainstem generates two breathing-related rhythms: one for inspiration on a timescale of seconds and another that produces larger amplitude sighs on the order of minutes. Their underlying mechanisms and cellular origins remain incompletely understood. We resolve these problems via a joint experiment and modeling approach. Blocking purinergic gliotransmission does not perturb either rhythm and imaging experiments show that both rhythms emanate from the same glutamatergic neuron population. We hypothesized that these two disparate rhythms emerge in tandem wherein recurrent excitation gives rise to inspiratory rhythm while a calcium oscillator generates sighs; there is no obligatory role for gliotransmission, hyperpolarization activated mixed cationic current (Ih) in neurons, or synaptic inhibition-mediated coupling of separate populations. We developed a mathematical model that instantiates our working hypothesis. Tests of model predictions validate the single-population rhythmogenic framework, reproducing disparate breathing-related frequencies and the ability for inspiratory and sigh rhythms to be separately regulated in support of respiration under a wide array of conditions. Here we show how a single neuron population exploits two cellular tool-kits: one involving voltage-dependent membrane properties and synaptic excitation for inspiratory breathing (eupnea) and an intracellular biochemical oscillator for sighs, which ventilate and maintain optimal function in the compliant mammalian lung. SIGNIFICANCE STATEMENTBreathing consists of two vital rhythms: one for eupnea that serves periodic physiological gas exchange and the other for sighs, which are larger breaths that occur minutes apart and serve to optimize pulmonary function. These rhythms with disparate frequencies emerge via a mechanism that is simpler than previously envisaged: it results from one neuron population (not two as previously thought) without need for gliotransmission or synaptic inhibition-mediated coupling of neuronal populations. We show that a low-frequency intracellular calcium oscillation underlies sighs and functions in parallel with the higher-frequency voltage-dependent network oscillation that drives eupnea. Exploiting two separate cellular tool kits enables quasi-independent breathing rhythms, which are unique features of breathing in mammals with compliant lungs.

neuroscience↗

bioRxiv2019

Role of synaptic inhibition in the coupling of the respiratory rhythms that underlie eupnea and sigh behaviors

The preBotzinger Complex (preBotC) gives rise to two types of breathing behavior: eupnea and sighing. Here, we examine the neural mechanisms that couple their underlying rhythms by recording from the preBotC in neonatal mouse brainstem slice preparations. It has been proposed that chloride-mediated synaptic inhibition couples inspiratory (eupnea-related) bursts and sigh bursts, but we find no evidence to support that notion. First, we characterize a fluctuating temporal relationship between sigh bursts and their preceding inspiratory bursts; their coupling is far weaker than previously described. Surprisingly, selective blockade of inhibitory synapses strengthened (rather than weakened) that phasic inspiratory-sigh burst relationship. Furthermore, pharmacological disinhibition did not alter the duration of the prolonged interval that follows a sigh burst prior to resumption of the inspiratory rhythm. These results demonstrate that coupling between inspiratory and sigh rhythms does not depend on synaptic inhibition.\n\nSIGNIFICANCE STATEMENTBreathing consists of eupnea and sigh breaths, which differ in their magnitude and frequency. Both breath types emerge from a brainstem microcircuit that coordinates their timing. Here, we advance understanding of these rhythms by assessing the nature and strength of their coordination, and by showing that synaptic inhibition does not enforce their temporal coupling in contrast to conventional understanding. This study provides insights into the basic neural mechanisms that link oscillations of different amplitude and frequency in a core oscillator.

neuroscience↗