Given the centralization of information flow, our analysis suggests that re-tuning just a few TFs could in principle rejuvenate information flow and restore gene expression. Aging may not be just cellular damage, but a gradual communication breakdown.

While signs of cellular aging may be varied, across all tissues, mutual information between TFs and TGs declines with age. Aged networks show input mismatch, higher centralization, and reduced stability, patterns reminiscent of aging brains and failing ecosystems.

We borrowed statistical physics/neuroscience models to study information transmission in noisy systems.
We treated transcription factors (TFs) → target genes (TGs) as a multi-input, multi-output communication channel, and measured its fidelity using mutual information.

We analyzed single-cell RNA-seq data from multiple mouse tissues across the lifespan. This dataset captures how thousands of genes are expressed in individual cells, letting us see how regulatory communication changes with age.

In our new paper led by Brooke Emison, in collaboration with Fabrisia Ambrosio, Andrew Mugler, and @chriswlynn.bsky.social, we show that as cells age, the flow of transcriptional information in gene regulatory networks breaks down.

We look forward to submitting our revision. As always, our experience with the new reviewing model of @elife.bsky.social has been wonderful! 6/n n =6

The implications?
It’s not just who binds tighter, but who survives the network's non-equilibrium processing.

Ligand-specificity is an emergent property of the entire network architecture not just binding thermodynamics 5/n

This behavior emerges only when the system is driven out of equilibrium. Energy dissipation (via dissociation and degradation) enables sharp ligand discrimination—not possible in equilibrium systems. 4/n

This means:
➡️Increasing ligand affinity can decrease signaling.
➡️The system has an optimal “sweet spot” for specificity and kinase activity
➡️Ligands with similar affinities can produce very different outputs depending on cellular parameters 3/n

We built a minimal model of receptor signaling that includes common signaling receptor features: Multi-site phosphorylation, rapid dissociation, and Ligand-dependent receptor degradation. Together, they create non-monotonic responses to ligand affinity and kinase activity. 2/n

It’s often assumed that stronger ligand binding = stronger signaling with non-equilibrium effects further enhancing this preference (a.k.a. kinetic proofreading). But often, thermodynamics preference is reversed! We asked: could non-equilibrium mechanisms help explain why? 1/n

What about accessible surface area? You get to choose the size of the "probe" which may be useful: en.wikipedia.org/wiki/Accessi...

Ugh that sucks! Let's hope for the best..

Thank you! We submitted one last December, so it technically is before the expiration date in Jan 2025.

Analysis of available signaling network parameters suggests that LAGS is widely applicable. Moreover, preferential degradation is just one mechanism for integral feedback control. Therefore, other habituation mechanisms e.g. activity induced inactivation, should also work the same way!

Additionally, when combined with receptor oligomerization, an increase in preferential degradation allows cells to sense relative ligand gradients over a larger range of background ligand concentrations. This is sometimes known as the Weber-Fechner law.

In LAGS, receptor activity is localized through receptor degradation or ligand unbinding. In contrast, uniform ligand sensitivity is maintained through receptor diffusion. Thus, increasing active receptor degradation and increasing diffusion of all receptors both sharpen receptor polarization.

This phenomenon can be summarized as a general principle: Localized Activity Global Sensitization (LAGS).

Many receptor families undergo activity-induced degradation. Additionally, receptors undergo lateral diffusion. Both these processes will blunt receptor polarization. Using a simple model, we show that two wrongs can make a right! The two processes in fact collaborate to enhance polarization.