With aging, there is a correlation between a decline in the body′s ability to maintain regular functioning and greater susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic agent due to its established safety record and preclinical and clinical data on its anti-aging effects. Glycosylation, one of the most common and complex co- and post-translational protein modifications, plays a crucial role in regulating protein function and has been linked to aging and various diseases. Changes in IgG glycosylation patterns have been observed with age, and these alterations may serve as valuable biomarkers for disease predisposition, diagnosis, treatment monitoring, and overall health assessment. In this study, we analyzed the IgG glycosylation patterns of individuals under treatment with metformin, testosterone, metformin plus testosterone and placebo, and investigated the longitudinal changes in glycosylation over time. We observed statistically significant differences in the IgG glycome composition between participants on testosterone therapy and placebo, with decreased agalactosylation and increased galactosylation and sialylation. However, metformin therapy did not result in statistically significant changes in glycosylation patterns. These findings contribute to our understanding of the impact of therapeutic interventions on IgG glycosylation and confirm the value of IgG glycosylation as a significant biomarker, capable of assessing biological age using the GlycanAge index and providing insight into overall health compared to chronological age.

G. L. is the founder and owner of Genos Ltd, a private research organization that specializes in high-throughput glycomic analysis and has several patents in this field. M.V., T.P., A.F.H., and F.V. are employees of Genos Ltd. Other authors declare no competing interests.

NCT02514629

This work was supported by the European Structural and Investment Funds IRI CardioMetabolic grant. Equipment and products from Waters, New England Biolabs®, Inc., and Applied Biosystems, Inc. were used for this research. J.C.F-G is supported by an intensification research program (INT21/00078, ISCIII, Spain; co-funded by the Fondo Europeo de Desarrollo Regional-FEDER). The funding organizations played no role in the design of the study, review and interpretation of the data, or final approval of the manuscript.

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The study protocol was approved by the Department of Endocrinology and Nutrition at the Virgen de la Victoria University Hospital (Malaga, Spain) review boards and the ethics committee.

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