Zenodo · May 28, 2026
The Telomere-rDNA Co-regulation model describes inter-individual variation rather than a universal aging clock: a multi-tissue computational test in human transcriptomes
By Miles E
We present a systematic computational test of the Telomere-rDNA Co-regulation model for Cell Senescence (TRCS), which asserts that progressive loss of telomere and rDNA function drives aging through a unified p53 activation pathway. Using GTEx v8 RNA-seq data from 17,382 samples across 54 tissues and qPCR-measured mtDNA copy numbers from 5,176 matched donor-tissue pairs, we tested whether rDNA and telomere functional decline predict p53 pathway activation through the specific mechanism TRCS proposes: reduced p53 degradation rather than transcriptional induction. By constructing scores for three known transcriptional p53 activators (AMPK signaling, DNA damage response, ribosomal stress) and regressing p53 target activation on all three, we isolated a residual activator-independent p53 signal. rDNA functional activity and telomere integrity predicted this residual in most of the tissues, spanning all major tissue categories including proliferating tissues, consistent with stability-driven p53 accumulation. Strikingly, the residual showed no systematic age trend in any tissue, indicating that TRCS describes inter-individual variation in rDNA and telomere silencing burden rather than a universal aging clock. In anterior cingulate cortex (BA24), the telomere coefficient on the activator-independent residual showed convergent evidence across three independent analyses for tissue-specific telomere–mitochondria–p53 signaling in this region. Mitochondrial dysfunction signals (OxPhos score, MiDAS signature, mtDNA copy number) were stronger and more universal predictors of p53 activation than TRCS proxies in direct comparison, but operated in parallel rather than series with TRCS, supporting a multi-pathway model in which rDNA silencing burden, telomere integrity, and mitochondrial dysfunction each contribute independent variance to p53 activation.