GSK3β Overexpression and Cellular Senescence in the Aging Kidney

Senescent cells accumulate with age, a growing imbalance between pace of creation and pace of clearance. The majority of senescent cells come into being as cells reach the Hayflick limit on replication, and survive for only a short time before succumbing to programmed cell death or immune system activity. But senescent cells can be created by injury, inflammation, and other forms of damage as well. Senescent cells secrete pro-growth, inflammatory signals. This is useful in the short term as a way to help the body clear up damage or potentially cancerous cells, but when sustained over the long term it is highly disruptive to tissue function.

A range of research in recent years strongly implicates cellular senescence in age-related kidney dysfunction. There is good evidence for removal of senescent cells to reverse kidney disease. Kidney function is so profoundly vital to health that its loss is damaging to other organs throughout the body, including heart, blood vessels, and brain. Kidney decline alone can drive a systemic fall into more ever more rapid dysfunction and rising mortality in later life, and senescent cells appear to be driving a great deal of this process. In today's open access research materials, researchers discuss the interaction between GSK3β overexpression and cellular senescence in the aging kidney. Suppressing GSK3β expression reduces markers of cellular senescence in the kidney and slows the age-related loss of kidney function. Whether this is a better approach than current attempts to build senolytic therapies that can selectively destroy senescent cells remains to be seen.

GSK3β and the aging kidney

It is well established that kidney function decreases with age. Many studies have shown this decrease in kidney function to be manifested by a decrease in kidney size as well as decreased glomerular filtration rate (GFR). Therefore, a substantial portion of the population may have GFRs in a range indicative of chronic kidney disease. As kidney disease does not become apparent until there is a remarkable loss of kidney function, there are tens of millions of individuals with some degree of chronic kidney disease. Histological studies have shown that the percentage of glomeruli showing signs typical of glomerulosclerosis increases with age. Cellular senescence has a central role in the aging process and has been studied intensively. The major molecular pathways involved in cellular senescence appear to be those regulated by p53, p16INK4A, and downstream cyclin-dependent-kinase inhibitors. Wnt signaling also likely has a role in the aging process.

GSK3 is an enzyme that has two highly conserved isoforms, GSK3α and GSK3β. As indicated by its name, GSK was originally identified as a regulator of glucose metabolism, acting downstream of insulin. GSK3β, the isoform that has received greater study, is probably best known, beyond its role in regulating glycogen synthesis, for its ability to phosphorylate β-catenin, targeting it for proteasomal degradation, thereby suppressing canonical Wnt signaling. Indeed, for many years the most commonly accepted approach to boosting canonical Wnt signaling has involved the use of GSK3β inhibitors. However, the enzymatic activity of GSK3β is able to phosphorylate serines and threonines on a wide range of proteins, such that GSK3β activity may have pleiotropic effects on cell physiology and particularly on cell senescence.

Age-related GSK3β overexpression drives podocyte senescence and glomerular aging

As a multitasking protein kinase recently implicated in a variety of renal diseases, glycogen synthase kinase 3β (GSK3β) is overexpressed and hyperactive with age in glomerular podocytes, correlating with functional and histological signs of kidney aging. Moreover, podocyte-specific ablation of GSK3β substantially attenuated podocyte senescence and glomerular aging in mice. Mechanistically, key mediators of senescence signaling, such as p16INK4A and p53, contain high numbers of GSK3β consensus motifs, physically interact with GSK3β, and act as its putative substrates.

In addition, therapeutic targeting of GSK3β by microdose lithium later in life reduced senescence signaling and delayed kidney aging in mice. Furthermore, in psychiatric patients, lithium carbonate therapy inhibited GSK3β activity and mitigated senescence signaling in urinary exfoliated podocytes and was associated with preservation of kidney function. Thus, GSK3β appears to play a key role in podocyte senescence by modulating senescence signaling and may be an actionable senostatic target to delay kidney aging.

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