Exploring the association between common genetic deletions and aging: insights from the Canadian Longitudinal Study on Aging.

Germline deletions of UDP-glycosyltransferase (UGT) UGT2B17 and UGT2B28 genes are common in human populations, yet their association with aging remains unclear. In this exploratory study, we analyzed data from 12,934 participants, mostly Caucasian, in the Canadian Longitudinal Study on Aging (CLSA) to assess cross-sectional and prospective associations between UGT deficiencies and aging-related health outcomes, including mortality, multimorbidity, allostatic load, disease burden and polypharmacy. Sex-specific associations emerged from cross-sectional analyses: UGT2B17-deficient males were less likely to report arthritis (adjusted odds ratio (ORadj) = 0.73, 95% confidence interval (0.58-0.92), P = 0.008), UGT2B17-deficient females were less likely to report neurological problems (ORadj = 0.69 (0.51-0.91), P = 0.01), and UGT2B28-deficient females were less likely to report thyroid disorders (ORadj = 0.50 (0.29-0.82), P = 0.009). Despite these associations, multimorbidity remained prevalent across all groups and no significant associations were observed with all-cause mortality or longevity. Physiological dysregulation, assessed by the allostatic load index, was more prevalent in males. Among males aged ≥ 65, UGT2B28-deficiency was associated with reduced high dysregulation compared to UGT-proficient males (40.0% vs. 53.0%, P = 0.05), whereas UGT2B17 deficiency was associated with a higher prevalence in males (60.4% vs. 53.0%, P = 0.03). In addition, UGT2B17-deficient males had a lower prevalence of polypharmacy than UGT-proficient males (9.3% vs. 13.9%; P = 0.02). Overall, these findings indicate sex-specific associations between UGT2B17 and UGT2B28 deletions and selected healthspan-related phenotypes, suggesting that UGT-related genetic variation may modulate physiological pathways relevant to aging. Given the exploratory nature of this study and its reliance on prevalence data, the results are intended to be hypothesis-generating and will require confirmation in longer-term longitudinal studies.