Cargando…

Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes

Bistability is a fundamental biological phenomenon associated with “switch-like” behavior reflecting the capacity of a system to exist in either of two stable states. It plays a role in gene regulation, cell fate switch, signal transduction and cell oscillation, with relevance for cognition, hearing...

Descripción completa

Detalles Bibliográficos
Autores principales: Schaumburger, Nathan, Pally, Joel, Moraru, Ion I., Kositsawat, Jatupol, Kuchel, George A., Blinov, Michael L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192762/
https://www.ncbi.nlm.nih.gov/pubmed/37216041
http://dx.doi.org/10.3389/fnetp.2023.1079070
_version_ 1785043695826894848
author Schaumburger, Nathan
Pally, Joel
Moraru, Ion I.
Kositsawat, Jatupol
Kuchel, George A.
Blinov, Michael L.
author_facet Schaumburger, Nathan
Pally, Joel
Moraru, Ion I.
Kositsawat, Jatupol
Kuchel, George A.
Blinov, Michael L.
author_sort Schaumburger, Nathan
collection PubMed
description Bistability is a fundamental biological phenomenon associated with “switch-like” behavior reflecting the capacity of a system to exist in either of two stable states. It plays a role in gene regulation, cell fate switch, signal transduction and cell oscillation, with relevance for cognition, hearing, vision, sleep, gait and voiding. Here we consider a potential role for bistability in the existence of specific frailty states or phenotypes as part of disablement pathways. We use mathematical modeling with two frailty biomarkers (insulin growth factor-1, IGF-1 and interleukin-6, IL-6), which mutually inhibit each other. In our model, we demonstrate that small variations around critical IGF-1 or IL-6 blood levels lead to strikingly different mobility outcomes. We employ deterministic modeling of mobility outcomes, calculating the average trends in population health. Our model predicts the bistability of clinical outcomes: the deterministically-computed likelihood of an individual remaining mobile, becoming less mobile, or dying over time either increases to almost 100% or decreases to almost zero. Contrary to statistical models that attempt to estimate the likelihood of final outcomes based on probabilities and correlations, our model predicts functional outcomes over time based on specific hypothesized molecular mechanisms. Instead of estimating probabilities based on stochastic distributions and arbitrary priors, we deterministically simulate model outcomes over a wide range of physiological parameter values within experimentally derived boundaries. Our study is “a proof of principle” as it is based on a major assumption about mutual inhibition of pathways that is oversimplified. However, by making such an assumption, interesting effects can be described qualitatively. As our understanding of molecular mechanisms involved in aging deepens, we believe that such modeling will not only lead to more accurate predictions, but also help move the field from using mostly studies of associations to mechanistically guided approaches.
format Online
Article
Text
id pubmed-10192762
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-101927622023-05-19 Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes Schaumburger, Nathan Pally, Joel Moraru, Ion I. Kositsawat, Jatupol Kuchel, George A. Blinov, Michael L. Front Netw Physiol Network Physiology Bistability is a fundamental biological phenomenon associated with “switch-like” behavior reflecting the capacity of a system to exist in either of two stable states. It plays a role in gene regulation, cell fate switch, signal transduction and cell oscillation, with relevance for cognition, hearing, vision, sleep, gait and voiding. Here we consider a potential role for bistability in the existence of specific frailty states or phenotypes as part of disablement pathways. We use mathematical modeling with two frailty biomarkers (insulin growth factor-1, IGF-1 and interleukin-6, IL-6), which mutually inhibit each other. In our model, we demonstrate that small variations around critical IGF-1 or IL-6 blood levels lead to strikingly different mobility outcomes. We employ deterministic modeling of mobility outcomes, calculating the average trends in population health. Our model predicts the bistability of clinical outcomes: the deterministically-computed likelihood of an individual remaining mobile, becoming less mobile, or dying over time either increases to almost 100% or decreases to almost zero. Contrary to statistical models that attempt to estimate the likelihood of final outcomes based on probabilities and correlations, our model predicts functional outcomes over time based on specific hypothesized molecular mechanisms. Instead of estimating probabilities based on stochastic distributions and arbitrary priors, we deterministically simulate model outcomes over a wide range of physiological parameter values within experimentally derived boundaries. Our study is “a proof of principle” as it is based on a major assumption about mutual inhibition of pathways that is oversimplified. However, by making such an assumption, interesting effects can be described qualitatively. As our understanding of molecular mechanisms involved in aging deepens, we believe that such modeling will not only lead to more accurate predictions, but also help move the field from using mostly studies of associations to mechanistically guided approaches. Frontiers Media S.A. 2023-05-04 /pmc/articles/PMC10192762/ /pubmed/37216041 http://dx.doi.org/10.3389/fnetp.2023.1079070 Text en Copyright © 2023 Schaumburger, Pally, Moraru, Kositsawat, Kuchel and Blinov. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Network Physiology
Schaumburger, Nathan
Pally, Joel
Moraru, Ion I.
Kositsawat, Jatupol
Kuchel, George A.
Blinov, Michael L.
Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes
title Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes
title_full Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes
title_fullStr Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes
title_full_unstemmed Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes
title_short Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes
title_sort dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes
topic Network Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192762/
https://www.ncbi.nlm.nih.gov/pubmed/37216041
http://dx.doi.org/10.3389/fnetp.2023.1079070
work_keys_str_mv AT schaumburgernathan dynamicmodelassumingmutuallyinhibitorybiomarkersoffrailtysuggestsbistabilitywithcontrastingmobilityphenotypes
AT pallyjoel dynamicmodelassumingmutuallyinhibitorybiomarkersoffrailtysuggestsbistabilitywithcontrastingmobilityphenotypes
AT moraruioni dynamicmodelassumingmutuallyinhibitorybiomarkersoffrailtysuggestsbistabilitywithcontrastingmobilityphenotypes
AT kositsawatjatupol dynamicmodelassumingmutuallyinhibitorybiomarkersoffrailtysuggestsbistabilitywithcontrastingmobilityphenotypes
AT kuchelgeorgea dynamicmodelassumingmutuallyinhibitorybiomarkersoffrailtysuggestsbistabilitywithcontrastingmobilityphenotypes
AT blinovmichaell dynamicmodelassumingmutuallyinhibitorybiomarkersoffrailtysuggestsbistabilitywithcontrastingmobilityphenotypes