Hypothesis

The loss of persistent topological features in immune cell transcriptomes precedes and drives the global simplification of gene expression manifolds seen in aging.

Mechanistic reasoning

Single‑cell RNA‑seq data form high‑dimensional point clouds where persistent homology captures loops (H1) that reflect feedback‑rich regulatory circuits, such as cytokine‑signaling networks and antigen‑receptor repertoires. In youthful immune tissues these loops are long‑lived, indicating robust, oscillatory signaling that enables rapid pathogen clearance and senescent‑cell surveillance. With age, thymic involution and hematopoietic skewing reduce the diversity of T‑cell clones and destabilize cytokine circuits, causing early death of H1 features. This topological collapse diminishes the immune system’s ability to detect and eliminate senescent neighbors, allowing their accumulation and the secretion of SASP factors that scar surrounding tissue. The resulting inflammatory milieu then feeds back onto non‑immune tissues, accelerating the loss of their own persistent components (H0 diversity, H1 loops) and manifesting as the transcriptional "decay" measured by TDA across the organism.

Testable predictions

1. Temporal precedence – Computing persistence diagrams from the Human Cell Aging Transcriptome Atlas (ages 0‑103, 50+ tissues) will show a statistically significant decline in H1 persistence (average lifetime and persistence entropy) in immune compartments (bone marrow, thymus, spleen, peripheral blood) beginning at least one decade before comparable declines in non‑immune tissues such as liver, muscle or cortex.
2. Causal link – Interventions that boost immune topological complexity (e.g., IL‑7 therapy to expand naïve T‑cell pools, or transgenic overexpression of Notch ligands in thymic epithelium) should delay the onset of H1 loss in immune tissues and consequently slow the topological decay observed in distal tissues measured by the same TDA pipeline.
3. Falsifiable outcome – If immune tissues do not exhibit earlier H1 loss than other tissues, or if enhancing immune complexity fails to alter systemic topological trajectories, the hypothesis is refuted.

Analytical approach

• Map single‑cell profiles to a gene‑expression metric space (e.g., PCA‑reduced but retaining sufficient dimensions for homology).
• Build Vietoris–Rips filtrations and compute persistence diagrams for H0 and H1 using tools like GUDHI or Dionysus.
• Summarize diagrams with persistence entropy and average lifetime; compare across tissues and ages using mixed‑effects models.
• Validate findings in the voyAGEr GTEx subset and in murine models where immune topology can be experimentally manipulated.

By linking a concrete, measurable topological metric to immune function and systemic aging, this hypothesis converts a compelling narrative into a falsifiable, data‑driven claim that can be pursued with existing single‑cell atlases and targeted immunological interventions.