PGC-1α as a Target to Treat Age-Related Kidney Disease

The research reviewed here is a great example of the presently dominant paradigm in efforts to treat age-related disease. Scientists analyze the disease state, find regulator proteins that are differently expressed in normal and diseased tissue, and look for ways to force expression in diseased tissue to look more like that of normal tissue. There is no consideration of trying to fix the underlying molecular damage that caused this change. It is a little like pressing the accelerator harder in a car with a failing engine. This strategy is why most efforts to treat age-related disease in the past have either failed or produce only minor benefits. Without fixing the underlying damage, it will continue to cause all of the downstream consequences that lead inexorably to failure of tissue function and death.

Aging is a progressive disruption of the homeostasis of physiological systems with age. It results in structural destruction, organ dysfunction, and increased susceptibility to injuries and diseases. The kidney is one of the most susceptible organs to aging. Aging-associated complications can lead to kidney dysfunction, including a decreased glomerular filtration rate, tubular dysfunction, and glomerulosclerosis. Furthermore, kidney aging has important implications for aging-associated comorbidities, especially cardiovascular diseases.

While the molecular mechanism underlying kidney aging remains unclear, chronic kidney disease (CKD) shares many phenotypic similarities with aging, including cellular senescence, fibrosis, vascular rarefaction, loss of glomeruli, and tubular dysfunction. The pathogenic mechanisms involved in CKD may thus provide insight into the molecular pathways leading to kidney aging. They might also provide potential targets against kidney aging.

Recent efforts to overcome aging have shifted from the identification of risk factors to the determination of endogenous protective factors that might neutralize the adverse effects of aging. Among the various endogenous protective factors reported are AMP-activated protein kinase (AMPK), fibroblast growth factor 21 (FGF21), insulin, and vascular endothelial growth factor (VEGF).

Recent studies have shown that aging-related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose metabolism and lipid metabolism. PGC-1α is abundant in tissues, including kidney proximal tubular epithelial cells, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC-1α by genetic or pharmacological intervention prevents telomere shortening and aging-related changes in the skeletal muscle, heart, and brain. The activation of PGC-1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC-1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

Link: https://doi.org/10.1111/acel.12994

Comments

True, but we can slow aging in the meantime while the bigger puzzle is solved. Plus, we learn something along the way. This is good for those of us (me) that are likely to miss the LEV cutoff.

PGC1-a can be activated with Valsartan.

"Both drugs reduced the expression of AT1R and increased myocardial levels of the longevity genes Sirt1 and PGC-1α along with increased Akt and eNOS phosphorylation."

"Aliskiren and Valsartan reduce myocardial AT1 receptor expression and limit myocardial infarct size in diabetic mice."
https://www.ncbi.nlm.nih.gov/pubmed/21987107

Posted by: Lee at July 23rd, 2019 6:10 AM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.