#1

https://www.pnas.org/doi/10.1073/pnas.2501584122

Gpt5: Here’s a tight read of the PNAS paper you linked.

Summary

Question. Is extracellular ACBP/DBI a causal driver of pathological aging across organs?

Approach. The authors combine human observational data with mouse intervention studies:

  1. Humans: measured circulating ACBP in (near-)centenarians and related it to health status (eGFR) and SASP cytokines.

  2. Mice: neutralized ACBP with a monoclonal antibody (mAb) in multiple “accelerated-aging” contexts (progeroid strain; cisplatin CKD; HFD+CCl₄ liver injury; natural and doxorubicin-exacerbated cardiac aging). Single-nucleus RNA-seq was used in hearts ±doxorubicin ±anti-ACBP.

Main findings.
• Humans: Plasma ACBP is elevated in (near-)centenarians and tracks with poorer renal function and higher SASP cytokines.
• Mice (interventions): Anti-ACBP mAb improved healthspan in a progeroid mouse line; protected kidney function and histology in cisplatin-induced CKD; limited hepatocyte senescence in HFD+CCl₄ injury; reduced natural and doxorubicin-accelerated cardiomyocyte senescence. Cardiac snRNA-seq suggested anti-ACBP reverses doxorubicin-induced transcriptional dysregulation in autophagy, FAO, mitochondrial homeostasis, and OXPHOS programs. Collectively, authors argue ACBP broadly promotes age-related pathology.

What’s novel

System-level causality across organs. Prior work showed ACBP neutralization protects liver and is autophagy-permissive; here, the authors extend causal protection to kidney, liver, and heart in multiple aging/toxicity models, positioning ACBP as a pan-organ driver rather than a tissue-specific factor.

Human aging link at the extreme end of lifespan. The centenarian analysis ties higher ACBP to worse physiologic status (eGFR) and SASP cytokines—integrating the human correlative signal with murine interventions.

Cardiac single-nucleus transcriptomics. snRNA-seq after doxorubicin shows anti-ACBP shifts cardiomyocyte programs (autophagy/mitochondria/FAO), giving a mechanistic transcriptomic anchor to the functional readouts.

Critique

Strengths

Convergence across models. Multiple independent disease/aging models all improve with ACBP neutralization—good triangulation for causality.

Mechanistic plausibility. Results cohere with earlier evidence that extracellular ACBP represses autophagy and that its neutralization is protective in injury models.

Multi-omic cardiac readout. snRNA-seq provides mechanistic texture (autophagy/mitochondria/FAO signatures) beyond histology.

Limitations / open questions

Human data are correlational. In centenarians, higher ACBP tracks with worse eGFR and SASP, but directionality is unclear; reduced kidney function could elevate circulating ACBP via decreased clearance. Cohort size, adjustment for confounders, and longitudinal change are critical to interpret causality.

From transcripts to flux. Autophagy/mitochondrial programs are inferred largely from transcriptional shifts; direct flux measurements (e.g., LC3 turnover with lysosomal blockade, mitophagy reporters, FAO flux) would strengthen mechanistic claims in heart and kidney.

Target biology and safety. Intracellular ACBP is essential for acyl-CoA handling; although antibodies should mainly mop up extracellular ACBP, long-term blockade may have unforeseen metabolic/neuro effects (DBI/GABA-A interactions). Chronic dosing, PK/PD, immunogenicity, and CNS safety need careful profiling. (General ACBP biology; prior neutralization study supports feasibility but long-term safety is unknown.)

Generalizability of models. Progeroid strains and toxin-injury models do not fully recapitulate human aging trajectories; efficacy in naturally aged wild-type mice across sexes and diverse genetic backgrounds would be more compelling.

Competing interests. Several authors hold related patents and consultancies; this underscores the need for independent replication.

Bottom line

This paper materially advances the ACBP/DBI story from “interesting autophagy brake” to a multiorgan, intervention-grade target for aging-related pathology, with supportive human correlation at extreme ages. The causal case is strong in mice, but translation will hinge on (i) longitudinal human data, (ii) hard functional flux readouts, and (iii) rigorous safety/PK for chronic extracellular ACBP neutralization.

If you want, I can sketch a one-page study map (models, endpoints, proposed mechanism) or pull figures from the PMC version for a slide.

1 Like
#2

I was initially interested in this because I wondered if it bound acetyl-CoA, but it doesn’t. It only binds quite long acyl-CoAs (acyl is a category of group).

What it does do, however, is act as an anti rapamycin in a sense of activating mTOR.

Along with IL-10 it is a factor that causes aging in older blood.

#3

Great follow-up — let’s look at what is known to increase ACBP (Acyl-CoA Binding Protein / DBI) levels, especially in the extracellular / circulating pool that is relevant for autophagy and aging.

  1. Aging

Circulating ACBP rises progressively with age in humans and mice.

In (near-)centenarians, higher plasma ACBP correlates with frailty, kidney dysfunction (↓eGFR), and SASP cytokines.

Suggests ACBP is part of the “pro-aging secretome.”

  1. Cellular stress & damage

Stress, injury, or cell death can cause non-classical release of ACBP (it lacks a signal peptide for standard secretion).

Triggers include:

Nutrient stress / starvation

Cytotoxic injury (e.g., doxorubicin in cardiomyocytes, cisplatin in kidneys, CCl₄ in hepatocytes)

Cell senescence, which is associated with ACBP release as part of the SASP.

  1. Metabolic disease

Obesity and metabolic syndrome are associated with higher circulating ACBP in humans.

Animal models (high-fat diet) also show increased ACBP release, especially from adipose and liver tissue.

  1. Inflammation & SASP cytokines

ACBP correlates with inflammatory cytokines (IL-6, IL-1β, TNFα) in human plasma.

Senescent cells seem to both release ACBP and stimulate its systemic rise.

  1. Cancer contexts

Some tumor cells secrete ACBP.

Intracellular ACBP can also be upregulated in proliferating cancer cells to handle lipid metabolism, indirectly raising release into circulation.

Key Takeaway

ACBP levels increase with age, stress, injury, metabolic disease, and senescence. In other words, it behaves like a “danger/aging signal”: when tissues are stressed or damaged, ACBP is released extracellularly, and systemic levels climb.

:balance_scale: So in simple terms:

Youth, health, low stress → low extracellular ACBP

Aging, stress, obesity, senescence, toxicity → high extracellular ACBP