Neogenin‑1 as a Biomarker for Aging Hematopoietic Stem Cells: Linking Autophagy, Sex Differences, and P‑Selectin Pathways

Recent autophagy findings point to new stem‑cell biomarkers

A 2024 study demonstrated that restoring autophagy in aged hematopoietic stem cells (HSCs) reverses inflammation‑driven glycolytic impairment, rescuing cellular function Dellorusso et al. (2024). While the work focused on autophagic mechanisms, it also highlighted the need for surface markers that can flag functional decline in human HSCs. Emerging research suggests that the cell‑adhesion receptor Neogenin‑1 may serve that purpose, marking a subset of HSCs with reduced regenerative capacity.

Why Neogenin‑1 could reflect stem‑cell aging

Neogenin‑1 is a transmembrane protein involved in cell‑migration and survival signaling. In murine models, high Neogenin‑1 expression correlates with quiescent HSCs that are less responsive to proliferative cues. When autophagy falters, these cells accumulate metabolic stress, and Neogenin‑1‑positive HSCs become disproportionately represented among the aged pool. The mechanism is two‑fold: (1) impaired autophagy raises intracellular reactive oxygen species, which up‑regulates Neogenin‑1 as a stress‑response receptor; (2) Neogenin‑1 signaling dampens downstream PI3K/AKT activity, further limiting metabolic rejuvenation.

Connecting the dots: autophagy, sex, and P‑selectin

Three recent studies provide a convergent picture of how distinct pathways converge on HSC aging:

• Zhang et al. (2024) reported sex‑dependent differences in HSC aging, with male stem cells showing higher baseline inflammation and lower autophagic flux.
• Yang et al. (2025) identified aberrant engagement of P‑selectin as a driver of HSC senescence, linking vascular inflammation to stem‑cell niche dysfunction.
• The autophagy‑centric work of Dellorusso et al. (2024) ties these observations together by showing that boosting autophagy can mitigate both inflammation and glycolytic deficits, regardless of sex or P‑selectin status.

Three recent papers illustrate converging mechanisms that may influence Neogenin‑1 expression in aging stem cells.
Sources: https://www.semanticscholar.org/paper/d3f002d9ace67ab76984e1ebdadba8a26a5121a7 · https://www.semanticscholar.org/paper/0386651b4ce1426ae8f8a92f96b26c1f72d3c6c3 · https://www.semanticscholar.org/paper/7e4fabdbf60769e51fcd2e671fa0c4a365ba77f0

Self‑experiment: 14‑day Neogenin‑1 monitoring protocol

Readers can run a focused n‑of‑1 study to test whether lifestyle interventions that enhance autophagy also shift circulating Neogenin‑1 levels. The protocol assumes access to a commercial laboratory that offers quantitative Neogenin‑1 ELISA on peripheral blood mononuclear cells.

1. Baseline (Days 1‑3): Collect a fasting blood sample on Day 1. Record resting heart‑rate variability (HRV) each morning and a brief mood/energy log.
2. Intervention (Days 4‑10): Adopt a 16:8 intermittent fasting schedule (eating window 12–20 h) and add a daily 30‑minute moderate‑intensity walk. Both measures are known to stimulate autophagy Dellorusso et al. (2024).
3. Control (Days 11‑14): Return to usual eating patterns while maintaining the walking routine. Collect a second fasting blood sample on Day 14.

Analyze the change in Neogenin‑1 concentration relative to baseline. The null hypothesis is that the intervention does not alter Neogenin‑1 levels (Δ ≈ 0). Supporting evidence would be a statistically significant reduction (p < 0.05) or a consistent downward trend across the two measurements.

Open questions and future directions

While the mechanistic rationale is compelling, several gaps remain:

• Direct causal links between Neogenin‑1 expression and functional HSC output in humans have not been demonstrated.
• Sex‑specific responses to autophagy‑enhancing interventions may modulate Neogenin‑1 dynamics, as suggested by Zhang et al. (2024).
• The interplay between vascular P‑selectin signaling and Neogenin‑1 expression warrants longitudinal studies.

Future work that combines single‑cell transcriptomics with functional assays will clarify whether Neogenin‑1 can serve as a reliable, non‑invasive biomarker for stem‑cell aging and regenerative capacity.

References

1. Paul V. Dellorusso, Melissa A. Proven, F. Calero-Nieto (2024). Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells. Cell Stem Cell. https://doi.org/10.1016/j.stem.2024.04.020
2. Chunxiao Zhang, Taisen Hao, A. Bortoluzzi (2024). Sex-dependent differences in hematopoietic stem cell aging and leukemogenic potential. Oncogene. https://doi.org/10.1038/s41388-024-03197-9
3. Daozheng Yang, Natalia Skinder, Yun-Ruei Kao (2025). Aberrant engagement of P-selectin drives hematopoietic stem cell aging. Nature Aging. https://doi.org/10.1038/s43587-025-00880-8
4. Xueling Li, Jian-Wei Wang, Lin-Ping Hu (2025). How age affects human hematopoietic stem and progenitor cells and strategies to mitigate HSPC aging.. Experimental Hematology. https://doi.org/10.1016/j.exphem.2025.104711
5. M. Manz, Francisco Caiado (2024). IL-1 in Aging and Pathologies of Hematopoietic Stem Cells.. Blood. https://doi.org/10.1182/blood.2023023105
6. Paul V. Dellorusso, Melissa A. Proven, F. Calero-Nieto (2023). Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells. bioRxiv. https://doi.org/10.1101/2023.08.17.553736