Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation.

Abstract

Because spermatogonial stem cells (SSCs) are immortal by serial transplantation, SSC aging in intact testes is considered to be caused by a deteriorated microenvironment. Here, we report a cell-intrinsic mode of SSC aging by glycolysis activation. Using cultured SSCs, we found that aged SSCs proliferated more actively than young SSCs and showed enhanced glycolytic activity. Moreover, they remained euploid and exhibited stable androgenetic imprinting patterns with robust SSC activity despite having shortened telomeres. Aged SSCs showed increased <i>Wnt7b</i> expression, which was associated with decreased Polycomb complex 2 activity. Our results suggest that aberrant <i>Wnt7b</i> expression activated c-<i>jun</i> N-terminal kinase (JNK), which down-regulated mitochondria numbers by suppressing <i>Ppargc1a</i> Down-regulation of <i>Ppargc1a</i> probably decreased reactive oxygen species and enhanced glycolysis. Analyses of the <i>Klotho</i>-deficient aging mouse model and 2-y-old aged rats confirmed JNK hyperactivation and increased glycolysis. Therefore, not only microenvironment but also intrinsic activation of JNK-mediated glycolysis contributes to SSC aging.