Two Beats Within One Heart: Autonomic and Vascular Biological Aging in Obesity and Exercise

Abstract

The Autonomic–Vascular Paradox and Rigid Senescence of Inflammatory Resolution: Two Studies on the Systems Biology of Insulin Resistance and Cardiovascular Aging Loukman Omarjee, MD, MEng, MSc, PhD Master of Medical Sciences in Clinical Investigation Harvard Medical School This thesis presents two investigations into how insulin resistance reshapes cardiovascular regulatory systems, examined through the lens of dynamical systems theory, causal discovery, and multi-omics integration. Paper 1 analyzed N = 854 subjects (analytical cohort: combined ECG∩BP quality gate; 1,018 passed the ECG gate alone) from the PhysioNet Autonomic Aging Database, extracting 218 features from electrocardiographic and continuous blood pressure recordings to build domain-specific biological age estimators across seven machine-learning architectures. The central finding is differential domain aging sensitivity (the autonomic–vascular paradox, reframed): higher BMI is associated with advanced autonomic biological aging (positive autonomic aging gap, βstd = +0.126 [95% CI: +0.069, +0.183], P = 1.46 × 10−5; cross-sectional association only; no longitudinal aging trajectory is inferred), while vascular biological age is BMI independent at the population scale (vascular aging gap, βstd = −0.002 [95% CI: −0.055, +0.052], P = 0.955 n.s.); sign-level dissociation between domains is confirmed by Taguchi L9 9/9 trials across all hyperparameter configurations, and by directional extremes in the obese stratum (autonomic gap +1.90 yr vs. vascular gap −0.51 yr). Baroreflex sensitivity (BRS) explains 57–66% of the BMI–autonomic gap association (Natural Indirect Effect [NIE] = −0.074 [95% BCa CI: −0.131, −0.028]; BCa bootstrap n = 5,000), identifying vagal withdrawal as the primary statistical pathway through which adiposity is cross-sectionally associated with more advanced autonomic biological decline. The autonomic–vascular dissociation resolves through the conductor metaphor: the sinoatrial node acts as a conductor of cardiovascular homeostasis, and BMI-driven vagal withdrawal removes its regulatory authority, producing selective autonomic degradation while vascular aging remains BMI independent at the population level. Paper 2 analyzed N = 35 subjects (IS = 16, IR = 19) from the Stanford iPOP Exercise Sub-Study across 5 timepoints and 5 omics layers (proteomics, metabolomics, lipidomics, transcriptomics, immunomics), directly extending Contrepois et al. (Cell, 2020). The eight-axis Resolution Capacity Index (RCI) reveals that insulin resistance produces a precision enzymatic lesion, not a global immune deficit: only the Lipid Degradation-to-Detoxification Score (LDDS = log2(CYP4F3/PTGR2); Hedges’ g = +0.944, p = 0.007) separates groups, while seven remaining axes and the composite RCI are null (g = +0.023 [95% BCa CI: −0.642, +0.688], P = 0.944). Constraint-based causal discovery (J-PCMCI+) reveals that IS subjects operate under a directed causal cascade (45.5% directed edges at primary threshold α = 0.10; logRCI as terminal sink; IS>IR at 4/4 α thresholds), whereas IR subjects exhibit weaker causal ordering (41.7% directed). Ensemble SINDy (2-equation autonomous system; 7-term core library; identifiability ratio N/coeff = 2.19) recovers k = 3/6 governing terms for IS (epiplexity k = 9; dual enzymatic forcing [ECI, EIC]) and k = 1 near-null plus SPM SINDy identification failure for IR (CV R2 = −0.150 0; Rigid Senescence of SPM self-regulation; perm p = 0.203 n.s.); Liouville analysis confirms IS is strongly dissipative (tr(J) = −0.1285; t1/2 ≈ 5.39 min; volume≈ 0.04% at 60 min) while IR is near-zero divergence (tr(J) ≈ −0.0479; J22 = 0 from SPM failure; t1/2 ≈ 14.47 min; volume≈ 5.6%; IS/IR ratio≈ 2.7×). The SDRE Riccati analysis: IS controllable at finite cost (ΩIS = 1.47); IR formally less controllable (ΩIR = 1.54; ΔΩ = +0.07). This dynamical phenotype is termed Rigid Senescence: molecular components present, SPM system-level organization absent. The bridge between the two papers is the conductor metaphor itself. Paper 1 shows that vagal withdrawal removes the sinoatrial node’s authority over cardiovascular timing. Paper 2 shows that the same cholinergic deficit (the ANS axis, Hedges’ g = 0.41, underpowered at N = 35) accompanies the enzymatic resolution failure. The vagus nerve does not merely pace the heart; it governs the inflammatory reflex (Tracey, 2002) and the release of pro-resolving mediators (Mirakaj & Serhan, 2014). Vagal withdrawal removes the conductor from two orchestras simultaneously: the cardiovascular and the immunological. The autonomic–vascular paradox of Paper 1 and the Rigid Senescence of Paper 2 are two manifestations of a single upstream lesion. Insulin resistance does not merely associate with poorer cardiovascular aging or suppressed immune capacity. It associates with the loss of the dynamical laws that organize physiology into function. Paper 1 and Paper 2 document this loss at two scales: at the systems level, the cardiovascular autonomic age gap diverges by domain, a paradox invisible to composite metrics; at the molecular level, the resolution cascade loses its governing equations (IS epiplexity k = 9; IR near-null plus SPM SINDy failure). The analytical methods used here, the Riemannian age-gap geometry, SINDy, J-PCMCI+, and Schrödinger bridge optimal transport, supply a mathematical vocabulary for precision medicine: diagnosing not what the body contains, but how it governs what it contains. “Every man can, if he so chooses, become the sculptor of his own brain.” Santiago Ramón y Cajal This thesis is dedicated to the belief that the same principle extends beyond the brain: that we can, through rigorous mathematical inquiry, become the sculptors of our understanding of disease. The finding that insulin-resistant resolution operates as a near-conservation dynamical system (tr(J) ≈ −0.0479; J22 = 0; SPM axis SINDy identification failure; t1/2 ≈ 14.47 min, vs IS ≈ 5.39 min; IS/IR dissipation ratio≈ 2.7×), with all molecular machinery present yet no structured SPM governing law to direct it, echoes Prigogine’s insight about dissipative structures: that life is not equilibrium but the sustained capacity to dissipate entropy toward order. When that capacity is lost, the system does not die. It near-freezes for the SPM axis. Restoring it will require not stronger drugs, but smarter dynamics.