Multi-modal atlas of lifestyle interventions reveals malleability of ageing-linked molecular features

Extending human healthspan requires understanding how lifestyle interventions impact molecular systems across tissues and time. Here, we present the TirolGESUND Lifestyle Atlas (ClinicalTrials.gov: NCT05678426), a longitudinal, multi-modal resource profiling 156 healthy women (aged 30-60 years) undergoing 6-month intermittent fasting (n=114) or smoking cessation (n=42) interventions. Participants were sampled up to four times across seven tissues and fluids, generating >3,450 biospecimens with harmonised DNA methylation, metabolomics, microbiome, and immune profiling, alongside skin histology, barrier measurements, and rich clinical metadata. We demonstrate the utility of this dataset through: (i) multi-omics-wide association studies linking traits to molecular features; (ii) integrative factor modelling revealing coordinated cross-tissue signatures; (iii) epigenetic-biomarker cross-omic associations, and (iv) CpG-level variance decomposition mapping stable, individual-specific, tissue-restricted, and intervention-responsive methylation patterns. We further show that ageing-linked features are selectively malleable: highly compliant intermittent fasting participants exhibited attenuated or even age-opposing molecular trajectories within six months. The atlas enables unprecedented within-cohort comparisons across omic layers and tissues, supporting discovery of context-dependent biomarkers, cross-system coordination, and intervention responsiveness. Data are available via an interactive portal, with sensitive data under controlled access (https://eutops.github.io/lifestyle-atlas/). This resource provides a foundation for exploring biomarker association and multi-tissue epigenetics, enabling hypothesis generation and benchmarking for systems biology and human healthspan research. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/673115v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@fec2d9org.highwire.dtl.DTLVardef@1aa5d13org.highwire.dtl.DTLVardef@1c4a6f2org.highwire.dtl.DTLVardef@1ac62fb_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMulti-tissue multi-modal profiling of two clinically-relevant lifestyle interventions in 156 women aged 30-60 C_LIO_LIIntermittent fasting modifies ageing-linked molecular features in an age-opposing direction C_LIO_LICross-tissue epigenetic biomarker mapping links immunity, metabolism, and microbiome C_LIO_LITissue-specific epigenetic plasticity maps reveal candidate meQTLs, C_LIO_LIData sharing and interactive portal enable broad reuse for hypothesis generation and exploration C_LI