Immune Ageing Clocks: A Methods-Oriented Review of Tasks, Modalities, Models, and Recalibration

Area of Science:

• Immunology
• Biomarker Discovery
• Computational Biology

Background:

• Population ageing and immune-mediated diseases necessitate reliable biomarkers for immunosenescence.
• Existing immune ageing clocks face challenges due to varied methodologies and evaluation criteria, hindering clinical application.

Purpose of the Study:

• To review immune data modalities for building clinically usable immunosenescence biomarkers.
• To propose a standardized workflow and a task-modality-model taxonomy for developing and validating immune ageing clocks.
• To identify key limitations and future directions for advancing immune ageing clock research.

Main Methods:

• Comprehensive review of major immune data modalities (immunophenotyping, transcriptomics, proteomics, epigenomics, etc.).
• Outline of an end-to-end workflow encompassing cohort design, assay standardization, data preprocessing, feature engineering, model development, validation, and recalibration.
• Proposal of a taxonomy categorizing clocks into chronological age, outcome-anchored risk, and cell lineage/state clocks.

Main Results:

• Identified common limitations across studies, including batch effects, compositional confounding, endpoint mismatch, insufficient external validation, and lack of mechanistic grounding.
• Highlighted the potential of bulk blood transcriptomics as a versatile modality supporting different clock tasks.
• Emphasized the need for improved standardization and validation protocols.

Conclusions:

• Standardization of assays, data processing, and evaluation is crucial for comparable and translatable immune ageing clocks.
• Future research should focus on multimodal data integration, longitudinal studies, tissue-specific models, and pathway-grounded clocks for intervention linkage.
• Developing robust immune ageing biomarkers is essential for addressing age-related health challenges.