Pathway
Notch Signalling
Last updated 2026-07-02· Last reviewed 2026-07-02· 1 min read
Reviewed by the Ultimate Longevity Bible editorial team. Educational reference — not medical advice. See disclaimer.
What it is
Notch signalling proceeds through direct contact: Delta or Jagged ligands on the signal-sending cell engage Notch receptors on the signal-receiving cell. Ligand engagement triggers cleavage of the Notch intracellular domain (NICD), which translocates to the nucleus and activates transcription of target genes (HES, HEY, MYC, cyclin D1).
Why it matters for longevity
- Stem cells: Notch balances self-renewal vs differentiation in intestinal, haematopoietic, muscle satellite, and neural stem-cell pools. Age-related niche changes weaken Notch inputs.
- Vasculature: Notch (
DLL4,Notch1) regulates tip-vs-stalk cell selection in angiogenesis; dysregulation contributes to age-related microvascular rarefaction. - Immune aging: T-cell development depends on Notch signalling in the thymus; thymic involution is partly a Notch-tone issue.
Interventions
Small-molecule gamma-secretase modulators can boost or dampen Notch; their therapeutic use has been dominated by oncology and Alzheimer's trials rather than longevity.
- Calcium Signalling Dysregulation — Pathway.
- Mesenchymal Stem Cell (MSC) Therapy — Intervention.
- TB-500 (Thymosin Beta-4) — Intervention.
Related entries
Stem-cell exhaustion, Wnt, Altered intercellular communication.