Germline deletions of the UDP-glycosyltransferase genes UGT2B17 and UGT2B28 — affecting androgen and steroid metabolism — show sex-differentiated associations with multiple aging phenotypes in 12,934 CLSA participants. UGT2B17-deficient males showed 27% lower odds of arthritis and 33% lower polypharmacy prevalence; UGT2B17-deficient females showed 31% lower odds of neurological problems; UGT2B28-deficient females showed 50% lower odds of thyroid disorders. Among men 65+, UGT2B28 deletion correlated with reduced high allostatic load (40% vs. 53%), while UGT2B17 deletion paradoxically associated with elevated dysregulation. No associations with all-cause mortality emerged.
UGT2B17 and UGT2B28 encode enzymes that glucuronidate androgens, estrogens, and bile acids — substrates with known inflammatory and metabolic relevance to aging. The arthritis and allostatic load findings align with UGT2B17's documented role in testosterone inactivation: males lacking this enzyme retain higher androgen bioavailability, which could plausibly suppress inflammatory arthropathy. The opposing allostatic load directions for the two paralogs hint at non-redundant physiological roles despite structural similarity.
Critical limitations warrant caution: the cross-sectional design prevents causal inference, the cohort is predominantly Caucasian limiting generalizability, and multiple comparisons across exploratory endpoints inflate false-positive risk. The null mortality finding notably constrains longevity conclusions. This is incremental rather than paradigm-shifting — but it meaningfully repositions UGT pharmacogenomics from drug metabolism into healthspan biology, opening a hypothesis-generating framework for prospective replication.
