Nucleoside supplementation for telomere defense

Overview

Telomere shortening is a fundamental driver of aging and tissue decline, contributing to conditions such as aplastic anemia and other degenerative disorders. This research proposes thymidine supplementation as a novel nutritional intervention to maintain telomere homeostasis in human stem cells. The approach is grounded in the first genome-wide CRISPR screen for telomere length regulators in humans, which identified thymidine nucleotide metabolism as a critical pathway governing telomere length. By leveraging a naturally occurring nucleoside with Generally Recognized as Safe (GRAS) potential, this strategy aims to restore tissue regenerative capacity without the risks associated with direct genetic manipulation of telomerase.

Technical specifications

• Mechanism: Thymidine supplementation supports telomere elongation in telomerase-positive cells by enhancing nucleotide metabolism pathways critical for telomere maintenance.
• Validated effects: Thymidine supplementation in cell culture media for up to three weeks significantly increased telomere length in two conventional human cell lines (293T and K562) and five induced pluripotent stem cell lines, including four from patients with hypomorphic genetic disorders impairing telomerase (P<0.01).
• Cell-type specificity: Effects observed in TERT-positive cells, including primary fibroblasts with ectopic TERT expression, but not in TERT-negative cells, reducing risk of cellular immortalization.
• Safety profile: Oral thymidine has previously been administered to patients with a rare mitochondrial disorder and was well-tolerated.
• Planned validation: Testing in CD34+ hematopoietic stem and progenitor cells (HSPCs) using in vitro differentiation assays and a novel human HSPC xenotransplantation assay to evaluate engraftment and differentiation following oral thymidine administration.

Technology readiness level

The technology is currently at an early-to-mid stage of development. The discovery and initial validation have been completed and published, demonstrating reproducible telomere elongation effects across multiple cell lines including patient-derived iPSCs. Unpublished data extends these findings to primary fibroblasts. The proposed next phase involves validation in disease-relevant human hematopoietic stem and progenitor cells through both in vitro assays and in vivo xenotransplantation models. This validation phase is expected to take approximately one year and requires partnership support for personnel and experimental resources. Upon successful validation, the pathway toward advancing thymidine as a nutritional intervention for telomere defense would involve guidance from partners experienced in supplement development and commercialization.