Summary The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide which perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized Doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred and in doing so tissue homeostasis can effectively be restored.

Kidney transplants from aged donors are more vulnerable to ischemic injury, suffer more from delayed graft function and have a lower graft survival compared to kidneys from younger donors. On a cellular level, aging results in an increase in cells that are in a permanent cell cycle arrest, termed senescence, which secrete a range of pro-inflammatory cytokines and growth factors. Consequently, these senescent cells negatively influence the local milieu by causing inflammaging, and by reducing the regenerative capacity of the kidney. Moreover, the oxidative damage that is inflicted by ischemia-reperfusion injury during transplantation can induce senescence and accelerate aging. In this review, we describe recent developments in the understanding of the biology of aging that have led to the development of a new class of therapeutic agents aimed at eliminating senescent cells. These compounds have already shown to be able to restore tissue homeostasis in old mice, improve kidney function and general health- and lifespan. Use of these anti-senescence compounds holds great promise to improve the quality of marginal donor kidneys as well as to remove senescent cells induced by ischemia-reperfusion injury. Altogether, senescent cell removal may increase the donor pool, relieving the growing organ shortage and improve long-term transplantation outcome.

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Tubular transport is a key function of the kidney to maintain electrolyte and acid-base homeostasis. Urinary extracellular vesicles (uEVs) harbor water, electrolyte, and acid-base transporters expressed at the apical plasma membrane of tubular epithelial cells. Within the uEV proteome, the correlations between kidney and uEV protein abundances are strongest for tubular transporters. Therefore, uEVs offer a non-invasive approach to probe tubular transport in health and disease. Here, we will review how kidney tubular physiology is reflected in uEVs and, conversely, how uEVs may modify tubular transport. Clinically, uEV tubular transporter profiling has been applied to rare diseases such as inherited tubulopathies, but also to more common conditions such as hypertension and kidney disease. Although uEVs hold the promise to advance the diagnosis of kidney disease to the molecular level, several biological and technical complexities still need to be addressed. The future will tell if uEV analysis will mainly be a powerful tool to study tubular physiology in humans or if it will move forward to become a diagnostic bedside test.

Background: The small blood volume of mice complicates tacrolimus pharmacokinetic studies in these animals. Here we explored dried blood spot (DBS) as a novel method to measure tacrolimus blood concentrations in mice. DBS samples were collected from three sampling sites (cheek, tail and heart) and compared with heart whole blood samples measured via LC–MS/MS. Results: Tacrolimus concentrations in the whole blood samples ranged from 2.56 to 27.64 μg/l. DBS of cheek vein blood was the most reliable sampling site, with a mean bias of 0.15 μg/l (95% CI: -4.20 to 4.50). Conclusion: The DBS cheek method can be used for serial monitoring of tacrolimus blood concentrations in mice, offering an animal-friendly method for tacrolimus pharmacokinetic studies in mice.