Age-, sex- and proximal-distal-resolved multi-omics identifies regulators of intestinal aging in non-human primates.

ABSTRACT:

The incidence of intestinal diseases increases with age, but the regulators of gut aging and the molecules linking gut aging and diseases remain largely unknown. By profiling the transcriptome, proteome, phosphoproteome and metabolome of 104 Macaca fascicularis large intestinal tissues, we unveiled asynchronous aging within the proximal and distal colon. The levels of many gene products, phosphosites and metabolites changed with age in a location- and sex-dependent manner, and many of these changes occurred at distinct rates or even in opposite directions at different locations. Assessment of 60 age-related molecules (genes, phosphosites, metabolites) across C. elegans, mice, and cell lines identified 32 crucial regulators of gut atrophy and barrier integrity. Notably, we found that tryptophan metabolism via the kynurenine and serotonin (5-HT) pathways was more active in the proximal and distal colon, respectively. In a mouse colitis model, reducing 5-HT production with a Tph1 inhibitor alleviated distal but not proximal colitis, while adding 5-HT aggravated distal symptoms, indicating that distal colitis is more sensitive to 5-HT fluctuations. Moreover, we identified 24 proteins, particularly HPX, that potentially link gut aging to colorectal cancer (CRC). High levels of HPX in CRC predicted poor prognosis in patients older than 50 yr but not in younger patients, suggesting that an age-linked HPX increase in the gut may contribute to CRC progression. Collectively, this work reveals the heterogeneity of large intestinal aging in non-human primates and offers promising targets for preventing gut aging and diseases.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

SUBMITTER: he siyu 

PROVIDER: MTBLS7612 | MetaboLights | 2023-12-14

REPOSITORIES: MetaboLights