Senolytic Treatment Reverses Age-Related Loss of Kidney Regeneration in Mice

Senescent cells accumulate with age and cause a great deal of harm in the aged body. Their numbers are not thought to be very high in most tissues, perhaps a few percent of all cells by late life, but senescent cells secrete a potent mix of signals that has a widespread disruptive effect. This signaling spurs chronic inflammation and causes malfunctioning of the normal processes of tissue regeneration and maintenance, amongst other issues. In organs like the kidney, this results in a lack of resilience to injury, increased fibrosis, and eventually chronic kidney disease. Researchers have shown that senolytic treatment to destroy senescent cells is beneficial in animal models of chronic kidney disease, and a human trial is ongoing, with encouraging early results. Here, researchers show that senolytic treatment can also restore some degree of lost regenerative capacity in aged kidneys.

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy.

We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor β1, induced fibrosis, and inhibited tubular proliferative capacity after injury.

Treatment of aged and irradiated mice with the senolytic drug ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.