Hypothesis

We propose that mitochondrial succinate accumulation acts as a central hub linking transcriptomic, metabolomic, lipidomic, and microbiome shifts that define aging archetypes. Elevated succinate drives HIF‑1α stabilization and NF‑κB activation, which in turn reshapes host gene expression, alters lipid signaling, and remodels the gut microbiome toward a pro‑inflammatory community. This cascade produces the divergent archetypes identified in multi‑omics clocks and underlies the mortality‑associated GlycA signal Phenome-Wide Multi-Omics Integration Uncovers Distinct Archetypes of Human Aging Single-Cell Multi-Omics and Advanced AI-Driven Strategies.

Mechanistic Rationale

Succinate is a TCA‑cycle intermediate that, when exported, acts on the succinate receptor SUCNR1 (GPR91) on immune and epithelial cells. SUCNR1 signaling amplifies IL‑1β and TNF‑α production, reinforcing NF‑κB activity. Chronic NF‑κB signaling enforces a senescence‑associated secretory phenotype (SASP) that remodels hepatic lipid metabolism, shifting lipidomic profiles toward oxidized phospholipids. Simultaneously, succinate released into the lumen favors growth of succinate‑utilizing pathobionts (e.g., Enterobacteriaceae), decreasing microbial diversity and increasing luminal LPS, which further fuels systemic inflammation. These multi‑layer changes manifest as distinct archetypes in unsupervised multi‑omics embeddings, with GlycA emerging as a downstream read‑out of IL‑6‑driven acute‑phase response Single-Cell Multi-Omics and Advanced AI-Driven Strategies.

Testable Predictions

1. In human iPSC‑derived hepatic organoids, pharmacological inhibition of SUCNR1 will reduce HIF‑1α target gene expression and lower secreted GlycA‑equivalent proteins under oxidative stress.
2. Fecal succinate concentrations will positively correlate with the relative abundance of Enterobacteriaceae and inversely with microbiome diversity across the 52,874‑feature cohort.
3. Individuals classified into the "inflammatory" archetype by the multi‑omics clock will exhibit higher plasma succinate levels than those in the "metabolic" archetype, independent of age Phenome-Wide Multi-Omics Integration Uncovers Distinct Archetypes of Human Aging.
4. Oral administration of a succinate‑scavenging probiotic (e.g., engineered E. coli Nissle expressing succinate dehydrogenase) will shift participants from the inflammatory to the metabolic archetype within 12 weeks, accompanied by reduced GlycA and improved bone density insulin‑resistance scores.

Experimental Design

• Cohort: Recruit 200 adults aged 60‑80 with baseline multi‑omics profiling (transcriptome, metabolome, lipidome, 16S rRNA). Measure plasma succinate via targeted LC‑MS.
• Stratification: Assign archetype using the published LightGBM multi‑omics model Phenome-Wide Multi-Omics Integration Uncovers Distinct Archetypes of Human Aging.
• Intervention: Randomized, double‑blind, placebo‑controlled trial of the succinate‑scavenging probiotic vs. placebo for 12 weeks.
• Outcomes: Primary – change in archetype probability score; secondary – plasma succinate, GlycA, bone density, HOMA‑IR, microbiome alpha diversity.
• Analysis: Mixed‑effects models adjusting for baseline covariates; mediation analysis to test whether succinate reduction mediates archetype shift and clinical improvements.

Potential Implications

If validated, succinate‑centered signaling would explain why diverse omics layers converge on shared archetypes and offer a druggable node to re‑program aging trajectories beyond p‑value‑driven clock validation.