Fight Aging!

Loss of specialized cells is a feature of aging, exhibited in tissues throughout the body. There are many examples of cell types that could in principle be replaced once lost, but in practice are not replaced. The underlying reasons for this selective lack of regenerative capacity are incompletely understood. Examples of highly specialized cell types that do not regenerate include sensory hair cells in the inner ear and the podocyte cells of the kidney that are the subject of today's research materials. Interestingly, some of the cell types that regenerate poorly or not at all in mammals are in fact restored when lost in other species. While comparative biology allows for an exploration of these differences, cells are enormously complex and expanding the understanding of any specific topic in cellular biology remains a slow and difficult undertaking.

Researchers in the field of regenerative medicine are very interested in finding ways to encourage regeneration of cells and tissues that would not normally occur in our species. As yet, progress towards meaningful enhancement of human regeneration remains in its infancy, however. Despite some limited advances, the research community is not yet capable enough when it comes to controlling the behavior of cells to reliably achieve enhanced regeneration. A future in which transplanted cell and native cell behaviors can be shifted in desired ways to allow replacement of lost cells is entirely plausible, but we are not there yet.

Structural Adaptations in Aging Podocytes

The kidneys are vital organs that sustain life by filtering the blood and producing urine. This filtration process takes place in specialized structures called glomeruli, where podocytes play a crucial role by forming the filtration barrier on the glomerular surface. Mature podocytes cannot regenerate once lost, which means that the podocytes generated during fetal development must be used throughout life. It is well known that the number of podocytes decreases with age; however, lost podocytes are not replaced by newly generated cells, and continued podocyte depletion ultimately leads to loss of glomerular function. Therefore, the remaining podocytes are thought to adapt in order to preserve glomerular function despite a reduction in cell number; however, how podocytes adapt to this loss has long remained unclear.

In this study, the research team employed array tomography (AT), a technique that enables whole-cell observation of podocytes with their complex three-dimensional architecture, to elucidate age-related structural changes in podocytes in rats. As podocytes are lost, podocyte density on the glomerular surface decreases, while the volume of remaining aged podocytes increases markedly. The volume of aged podocytes was found to be approximately 4.6-fold greater, indicating compensatory hypertrophy in response to podocyte loss. In addition, areas lost through fragmentation were repaired by coverage from surrounding podocytes, during which atypical self-cellular junctions were frequently formed. These autocellular junctions are entirely absent in normal glomeruli and are considered to represent structural "footprints" of injury repair in aging glomeruli. Furthermore, although aging cells generally exhibit a decline in intracellular degradation capacity for unnecessary cellular components, podocytes were found to compensate for this functional decline by exporting such materials into the extracellular space rather than degrading them intracellularly.

Structural Plasticity of Aged Podocytes Revealed by Volume Electron Microscopy

Aged podocytes exhibited eight characteristic structural alterations: hypertrophy, pseudocystic changes, irregularity of foot processes, fragmentation, pruning of foot processes, autocellular interdigitation, release of lysoendosomal and multivesicular body contents, and an increase in lysosomal volume. Among these, hypertrophy was particularly notable - it resulted in an approximately 4.6-fold increase in podocyte volume and a 3.0-fold increase in total surface area, enabling adequate coverage of the enlarging glomerular surface. Furthermore, in areas where portions of podocytes seemed to be lost because of fragmentation, adjacent podocytes formed de novo autocellular junctions/interdigitation, thereby preventing exposure of the basement membrane. In addition, aged podocytes showed clustering of lysoendosomes and multivesicular bodies, with evidence of their exocytotic release into the urinary space. This process may compensate for the reduced intracellular degradation capacity associated with aging.