We modern humans are comparatively lightly affected when it comes to kidney failure as an age-related cause of death; it ranks fairly low in the list. We are primarily killed by cardiovascular issues and cancer. In some other species, such as domestic cats, kidney failure is a leading cause of mortality, and near all older individuals are significantly impacted by the consequences of declining kidney function whether or not it is the final cause of death. Still, a comparatively low toll for humans is no great comfort to the many who suffer, especially since there is little in the way of medical technology available at present that can address the causes of kidney failure in any meaningful way. Treatments are compensatory or palliative, attempts to slow down progression only. This may start to change soon given the advent of methods to clear senescent cells from aged tissues, as senescent cells contribute to age-related fibrosis, a dysfunction of regenerative processes in which forms of scar tissue are created in place of functional tissue. Fibrosis impacts many organs, but is notably important in age-related kidney disease. Thus we might hope that removal of senescent cells will product benefits for patients - human and feline.
In past years, researchers have considered that failure of mitochondrial function might feature as a cause of age-related kidney disease. There are arguments to be made for this conclusion, but as ever it is challenging to put the many attributes and changes observed in aged tissues and organs into a definitive order of cause and effect. Aging involves changes in near every aspect of an enormously complex and still incompletely mapped set of interdependent systems. Mitochondria are the power plants of the cell, responsible for producing chemical energy stores, among many other duties. Should they fail, cells cannot function correctly. In the SENS rejuvenation research program, damage to mitochondrial DNA in a minority of cells is implicated as a significant root cause of aging. More general and widespread mitochondrial decline may also occur for other reasons, however, such as changes in the cellular signaling environment that take place in old tissues, reactions to higher levels of molecular damage and metabolic wastes of various sorts.
In the research noted below, the authors argue for kidney disease to be caused by mitochondrial decline, which is in turn caused by an age-related failure of cellular quality control processes. Mitophagy is the name given to a collection of mechanisms responsible for removing damaged and malfunctioning mitochondria before they can cause further harm. If mitophagy declines in efficiency, then cells will become stressed and malfunction as damage builds up in the population of mitochondria. Again, where this fits in the chain of cause and consequence - that starts with the molecular damage listed in the SENS vision for rejuvenation therapies - is something of an open question. Cells communicate in many ways, and that communication reflects the state of aging in a tissue. Tracing these changes back to their root causes is very challenging; research groups can spend years proving a single step in the lengthy chain. Since there is an established list of root causes, it is probably much more efficient to build repair therapies for those root causes and see what happens as a result.
Researchers have published findings that may provide a new approach to preventing kidney injury after ischemia. "We've shown that it's possible to prevent kidney damage by its preliminary 'training' with short periods of ischemia (blocking of blood supply). However, our main discovery is the fact that this mechanism is disabled in old animals and, as a result, a kidney becomes unprotected. It is an extremely important problem as the major part of clinical cases of renal failure occurs in aged patients. To afford the protection of their kidneys would be a great success for medicine."
In the current study, scientists developed assays that compared data from young and old rats. The scientists revealed that a considerable number of mitochondria in older rats had a lower transmembrane potential - inevitably leading to cell death. Since kidney cells cannot proliferate, their death becomes irreplaceable, leading to increasing symptoms of renal injury. This scenario leads to the kidneys being unable to fulfill their main function of removing products of metabolism from the organism, many of which are quite toxic. The researchers suggest that's why such "bad" mitochondria should be removed in the process of quality control. In a young kidney, quality control depends on the transmembrane potential of mitochondria. When the potential drops below the critical value for a long time, a mitochondrion gets a "black label" in the form of a special protein - PINK-1. Such a labeled mitochondrion undergoes a process of self-destruction (autophagy) and is destroyed within the cellular organelles called lysosomes. In cells of old kidneys, this process is not only broken, with low-potential damaged mitochondria not being destroyed - they actually increase in number.
"There is the following process: we block blood supply of the kidney (namely, we deprive it of oxygen and substrates), and under these conditions, the weakest mitochondria in cells lose their potential and are immediately removed by the quality control system. As a result, the 'renewal', or just 'purges', of the mitochondrion population takes place, and only the healthy ones survive. That's why in young rats and the case of severe kidney ischemia, mitochondria can cope with the damage and they survive. And what happens in old rats? We do kidney preconditioning, mitochondria lose their potential, but they aren't removed as the clean-up system operates poorly. As a result of such training, 'bad' mitochondria are only accumulated in an old cell, and in the case of kidney ischemia everything gets even worse. This project opens a prospect for renal failure treatment. Moreover, mechanisms that we discovered are quite universal, so it's obvious that they are also applicable not only to kidney ischemia but also to other renal pathologies."
In young rats, ischemic preconditioning (IPC), which consists of 4 cycles of ischemia and reperfusion alleviated kidney injury caused by 40-min ischemia. However,old rats lost their ability to protect the ischemic kidney by IPC. A similar aged phenotype was demonstrated in 6-month-old OXYS rats having signs of premature aging. In the kidney of old and OXYS rats, the levels of acetylated nuclear proteins were higher than in young rats, however, unlike in young rats, acetylation levels in old and OXYS rats were further increased after IPC.
In contrast to Wistar rats, age-matched OXYS demonstrated no increase in lysosome abundance and LC3 content in the kidney after ischemia/reperfusion. The kidney LC3 levels were also lower in OXYS, even under basal conditions, and mitochondrial PINK1 and ubiquitin levels were higher, suggesting impaired mitophagy. The kidney mitochondria from old rats contained a population with diminished membrane potential and this fraction was expanded by IPC. Apparently, oxidative changes with aging result in the appearance of malfunctioning renal mitochondria due to a low efficiency of autophagy. Elevated protein acetylation might be a hallmark of aging which is associated with a decreased autophagy, accumulation of dysfunctional mitochondria, and loss of protection against ischemia by IPC.