Rejuvenation of white adipose tissue in a longitudinal heterochronic transplantation model

Moldakozhayev, A.; Tyshkovskiy, A.; Nigro, P.; de Magalhaes, C. G.; Ying, K.; Eames, A. W.; Poganik, J. R.; Tskhay, A.; Zhang, B.; Tikhonov, S.; Anekal, P. V.; Carbone, N. P.; Hirshman, M. F.; Goodyear, L. J.; Van Raamsdonk, J. M.; Gladyshev, V. N.

doi:10.64898/2025.12.28.696721

bioRxiv · 10.64898/2025.12.28.696721

Rejuvenation of white adipose tissue in a longitudinal heterochronic transplantation model

Moldakozhayev, A.·Tyshkovskiy, A.·Nigro, P.·de Magalhaes, C. G.·Ying, K.·Eames, A. W.·Poganik, J. R.·Tskhay, A.·Zhang, B.·Tikhonov, S.·Anekal, P. V.·Carbone, N. P.·Hirshman, M. F.·Goodyear, L. J.·Van Raamsdonk, J. M.·Gladyshev, V. N.

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Abstract

Exposure to a younger system can induce organismal rejuvenation, yet whether all tissues can be rejuvenated and by what mechanisms remains understudied. We performed heterochronic and isochronic transplantation of subcutaneous white adipose tissue (WAT) between young and old mice and longitudinally tracked changes in biological age. Transplantation accelerated tissue aging, and the molecular age of grafts shifted toward that of the host. Most importantly, old WAT was rejuvenated in a young body. Epigenetic and transcriptomic clocks revealed a reduction of predicted age, accompanied by coordinated activation of canonical and previously unrecognized thermogenic pathways. Molecular rejuvenation was further supported by architectural changes toward a youthful state, including reduced lipid droplet size and decreased cellular heterogeneity. Mitochondrial abundance and morphology remained unchanged, while collagen deposition increased. These results demonstrate that WAT biological age is partially reversible and identify molecular and cellular features underlying its rejuvenation

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Moldakozhayev, A., Tyshkovskiy, A., Nigro, P., de Magalhaes, C. G., Ying, K., Eames, A. W., Poganik, J. R., Tskhay, A., Zhang, B., Tikhonov, S., Anekal, P. V., Carbone, N. P., Hirshman, M. F., Goodyear, L. J., Van Raamsdonk, J. M., Gladyshev, V. N.. 2025-12-29. Rejuvenation of white adipose tissue in a longitudinal heterochronic transplantation model. https://doi.org/10.64898/2025.12.28.696721

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