Age-related GSK3ß overexpression drives podocyte senescence and glomerular aging.

ABSTRACT

As life expectancy continues to increase, clinicians are challenged by age-related renal impairment that involves podocyte senescence and glomerulosclerosis. There is now compelling evidence that lithium has a potent antiaging activity that ameliorates brain aging and increases longevity in Drosophila and Caenorhabditis elegans. As the major molecular target of lithium action and a multitasking protein kinase recently implicated in a variety of renal diseases, glycogen synthase kinase 3ß (GSK3ß) is overexpressed and hyperactive with age in glomerular podocytes, correlating with functional and histological signs of kidney aging. Moreover, podocyte-specific ablation of GSK3ß substantially attenuated podocyte senescence and glomerular aging in mice. Mechanistically, key mediators of senescence signaling, such as p16INK4A and p53, contain high numbers of GSK3ß consensus motifs, physically interact with GSK3ß, and act as its putative substrates. In addition, therapeutic targeting of GSK3ß by microdose lithium later in life reduced senescence signaling and delayed kidney aging in mice. Furthermore, in psychiatric patients, lithium carbonate therapy inhibited GSK3ß activity and mitigated senescence signaling in urinary exfoliated podocytes and was associated with preservation of kidney function. Thus, GSK3ß appears to play a key role in podocyte senescence by modulating senescence signaling and may be an actionable senostatic target to delay kidney aging.