A nucleolar‑mitochondrial axis driven by fibrillarin decline coordinates systemic aging hallmarks and striatal D1/D2 loss

Hypothesis

Age‑dependent reduction of the nucleolar protein fibrillarin (FBL) initiates a coordinated decline in mitochondrial‑nuclear signaling, proteostasis, and epigenetic stability, producing the observed constellation of aging hallmarks and specifically driving dopaminergic D1/D2 receptor loss in the basal ganglia.

Mechanistic Rationale

FBL is essential for rRNA processing and ribosome biogenesis, linking nucleolar output to mitochondrial translation via the mitochondrial ribosomal proteins that are nucleolus‑derived[1]. In aging, nucleolar stress reduces FBL levels, diminishing cytosolic and mitochondrial ribosome synthesis, which lowers oxidative phosphorylation capacity and elevates ROS[2]. ROS activates mTORC1, suppressing autophagy and exacerbating proteostatic stress[3]. Concurrently, nucleolar stress triggers release of nucleolar‑associated chromatin domains, promoting heterochromatin loss and DNA damage accumulation[4]. These cascades reproduce the transcriptional signatures of downregulated mitochondrial genes, protein synthesis machinery, and growth factor signaling seen across species[1]. Importantly, striatal neurons are highly dependent on robust mitochondrial ATP production for dopamine synthesis and vesicular release; a nucleolar‑mitochondrial deficit therefore preferentially impairs D1/D2 receptor trafficking and stability, reproducing the 5–10% per decade loss documented in aging[3].

Predictions & Experimental Design

1. Correlative prediction – In mouse and human tissues, FBL expression will negatively correlate with age‑related mitochondrial gene downregulation, p‑S6K (mTOR activity) increase, and striatal D1/D2 density across the lifespan.
   • Test: Quantify FBL, mitochondrial transcripts (e.g., Mt‑Co1), p‑S6K, and D1/D2 binding via autoradiography in cohorts from 3 to 24 months.
2. Causal prediction – Neuron‑specific overexpression of FBL in the dorsal striatum of aged mice will rescue mitochondrial gene expression, reduce mTORC1 hyperactivation, restore proteostatic markers (e.g., LC3‑II/p62 ratio), and halt or reverse D1/D2 loss.
   • Test: Use AAV‑Syn‑FBL vectors in 18‑month‑old mice; assess outcomes after 8 weeks via qPCR, western blot, and [^11C]raclopride PET.
3. Falsifiable prediction – If FBL overexpression fails to improve any of the three downstream readouts (mitochondrial transcription, mTOR activity, D1/D2 density) despite confirmed nucleolar localization, the hypothesis is falsified.

Potential Confounds & Controls

• Off‑target viral effects will be controlled with AAV‑Syn‑GFP.
• Systemic metabolic changes will be monitored via body composition and glucose tolerance to ensure observed rescue is not secondary to altered caloric intake.
• Epigenetic readouts (e.g., H3K9me3 ChIP‑seq) will be added to verify that nucleolar stress‑driven chromatin changes are indeed modulated by FBL levels.

By positioning fibrillarin as a linchpin that couples nucleolar output to mitochondrial function, mTOR‑driven proteostasis, and epigenetic integrity, this hypothesis offers a single, experimentally tractable node whose manipulation could synchronously ameliorate multiple aging hallmarks and the circuit‑specific dopaminergic decline that underlies motor aging.