Hypothesis

We propose that progressive deterioration of the nuclear lamina drives a loss of nuclear architecture that disrupts chromatin organization, transcription coupling, and signaling cascades, thereby acting as a upstream integrative driver of multiple hallmarks of aging.

Mechanistic Rationale

The nuclear lamina, composed of A‑type and B‑type lamins, anchors chromatin to the nuclear periphery and organizes topologically associating domains (TADs). Age‑related lamin A/C truncation (progerin) and oxidative damage weaken this scaffold, leading to:

• Heterochromatin relaxation and ectopic gene expression (epigenetic alterations) {2}
• Impaired DNA repair factor localization, increasing genomic instability {4}
• Altered mitochondrial‑nuclear communication via altered NAD+ metabolism, fostering mitochondrial dysfunction {5}
• Disrupted mechanotransduction that sensitizes cells to senescence‑associated secretory phenotype (SASP) {6} Thus lamina decay creates a coordinated collapse of nuclear‑cytosolic networks, manifesting as the observed hallmarks.

Testable Predictions

1. Restoring lamina integrity in aged mice will simultaneously improve epigenetic fidelity, reduce DNA damage markers, enhance mitochondrial respiration, and lower SASP.
2. Conversely, inducing lamina damage in young animals will precipitate premature onset of multiple hallmarks.
3. The degree of lamina defect (measured by lamin A/C oligomerization and nuclear shape index) will correlate negatively with tissue‑specific network integration scores derived from multi‑omics correlation matrices.

Potential Experiments

• Generate a knock‑in mouse expressing a cleavage‑resistant lamin A/C under a ubiquitous promoter; assess lifespan, frailty index, and hallmarks at 24 months.
• Use CRISPR‑based dCas9‑lamin A/C recruitment to reposition heterochromatin at the periphery in aged human fibroblasts; measure ATAC‑seq, γH2AX foci, OCR, and IL‑6 secretion.
• Apply longitudinal live‑cell imaging of nuclear shape in C. elegans expressing fluorescent lamin; correlate shape entropy with aging biomarkers.

Implications

If validated, the nuclear lamina would represent a structural node whose progressive loss coordinates the aging network, offering a single upstream target for interventions that could reset multiple hallmarks simultaneously.

Key References [1] https://pmc.ncbi.nlm.nih.gov/articles/PMC12094518/ [2] https://www.nad.com/news/harvard-professor-david-sinclairs-information-theory-of-aging [3] https://www.nad.com/news/anti-aging-breakthrough-dr-david-sinclair-predicts-age-reversing-pill-by-2035 [4] https://pmc.ncbi.nlm.nih.gov/articles/PMC9009120/ [5] https://pmc.ncbi.nlm.nih.gov/articles/PMC7726203/ [6] https://pmc.ncbi.nlm.nih.gov/articles/PMC10824251/ [7] https://sciexplor.com/articles/Geromedicine.2025.0007