The Immune Cell Atlas of "Longevity Molecular Tag": Identification of Principal Immune Cell Subsets and Their Underlying Molecular Regulatory Mechanisms.

Scissor+ cells positively associated with longevity phenotypes predominantly comprise NK cells, CD8+ T cells, and γδ T cells with enhanced cytotoxic and immunomodulatory functions.

• The Scissor algorithm was applied to integrate single-cell RNA sequencing data spanning the entire lifespan of East Asian populations with bulk transcriptomic data from a centenarian cohort in Guangxi.
• Scissor+ cells were characterized by enhanced cytotoxic and immunomodulatory functions.
• These cell types represent the primary components of the 'Longevity Molecular Tag' immune cell atlas on the positive association side.

Scissor- cells negatively associated with longevity phenotypes mainly include CD4+ T cells, B cells, and dendritic cells (DCs), linked to inflammatory signaling pathways and Th17/Th1 differentiation.

• Scissor- cells were linked to inflammatory signaling pathways and Th17/Th1 differentiation.
• These cell types represent the primary components of the 'Longevity Molecular Tag' immune cell atlas on the negative association side.
• The association suggests these cell subsets may contribute to immunosenescence rather than healthy aging.

Trajectory analysis elucidated the differentiation pathways of NK cells, CD8+ T cells, CD4+ T cells, and B cells in the context of longevity.

• Trajectory analysis was performed on NK cells, CD8+ T cells, CD4+ T cells, and B cells.
• The analysis revealed distinct differentiation pathways associated with longevity phenotypes.
• This methodology provided insight into how immune cell lineages evolve across the lifespan in centenarians.

Differentially expressed genes in longevity-associated immune cells were enriched in NF-κB signaling, T cell receptor signaling, and NK cell cytotoxicity pathways.

• Pathway enrichment analysis was conducted on differentially expressed genes between Scissor+ and Scissor- cell populations.
• Key enriched pathways included NF-κB signaling, T cell receptor signaling, and NK cell cytotoxicity.
• These pathways collectively reflect the balance between inflammatory regulation and cytotoxic immune competence in centenarians.

Co-localization analysis identified five eQTL-colocalized events associated with longevity, involving genes rs3793537-GLIPR2/CD72/TLN1 and rs8019902-TRDV2/TRDC.

• Five eQTL-colocalization events were identified through co-localization analysis.
• The events involved two genetic loci: rs3793537, colocalized with GLIPR2, CD72, and TLN1; and rs8019902, colocalized with TRDV2 and TRDC.
• TRDV2 and TRDC are genes related to γδ T cell receptor components, consistent with the finding that γδ T cells are positively associated with longevity.
• These colocalization events provide genetic evidence linking specific immune regulatory genes to longevity phenotypes.

Centenarians demonstrate a distinctive immune 'compensatory adaptation' mechanism that contributes to the maintenance of immune homeostasis.

• The study used centenarians as a natural model of 'healthy aging' in an East Asian population from Guangxi.
• Single-cell RNA sequencing data spanning the entire lifespan was integrated with bulk transcriptomic data from the centenarian cohort.
• The compensatory adaptation involves remodeling cytotoxic immune lineages and finely tuning inflammatory responses.
• This mechanism is proposed to promote health span and longevity by maintaining immune equilibrium.