The Goal of Kidney Rejuvenation

The authors of this open access paper review the aging of the kidney and consider the prospects for using factors from young blood as a means of rejuvenation. This is a fairly narrow view, as there are many other approaches that should produce rejuvenation of the aged kidney, ranging from those close to realization, such as senolytic therapies to clear senescent cells, or various approaches to stem cell therapy, to those yet to be achieved, meaning much of the rest of the SENS agenda of rejuvenation biotechnologies to repair the damage that causes aging. Nonetheless, after so many years of trying to persuade the research community to open up on the topic of addressing the mechanisms of aging as a means of therapy, it is very pleasant to see so many publications in the literature doing just that. The present open discourse is a sea change in comparison to the silence of a decade or two ago, in which few researchers were willing to speak in public about treating aging. The science was always valid and promising, it is the culture that has changed for the better.

It is well established that aging is associated with structural and functional renal changes. With the possible exception of the lung, the changes in kidney function with normal aging are the most dramatic of any human organ or organ system. The normal kidney loses about 25% of its mass during aging, with the loss involving both cortical glomeruli and tubules. Functionally, the aging kidney has a parallel decline in both glomerular and tubular function. The Baltimore longitudinal study demonstrated an average of 0.75 mL/min/year decline in glomerular filtration rate (GFR) in 254 men without hypertension or kidney disease. The GFR loss rate is tripled in subjects over 40 as compared with those under 40.

Cellular senescence describes an everlasting growth arrest of still viable and metabolically active cells. The cell-cycle regulators and tumor suppressors p16Ink4a and p19ARF are involved in cellular senescence. The expression of p16 Ink4a in the kidney has been known to increase with age and could be found in a variety of renal cell types. Renal p16Ink4a expression has been suggested as an ideal marker for renal aging and shown to foresee transplant outcome. In normal human glomerular, p16Ink4a expression is increased with age and in all resident cell types. Studies in a transgenic mouse model confirmed that ablating p16Ink4a positive senescent cells not only prolongs the lifespan, but also attenuates glomerulosclerosis in aging kidney and decreasse blood urea nitrogen levels. Furthermore, depletion of p16Ink4a resulted in reduction of renal interstitial fibrosis and nephron atrophy in mice after ischemia-reperfusion injury, indicating inhibition of senescence provides a protective effect on the development of fibrosis.

Considering the increase of the aging population, it is extremely urgent to identify a way to retard the aging process or rejuvenate the community. To test the effects of young blood on aged organ, young blood infusion or parabiosis may be used. Parabiosis is an experimental model aiming to join the circulatory system of two animals. Heterochronic parabiosis is used to connect an aged partner to a young partner, and can be used to demonstrate the effects of young blood on aged organs, and vice versa. With this model, rejuvenation in the aged heterochronic parabiont has been shown in different organs such as muscle, liver, brain, and heart.

In aged kidneys, a recent study showed that young blood environment enhances the autophagy of aged kidney through down-regulation of aging-related protein p16Ink4a and SA-β-gal, up-regulation of autophagy factors Atg5 and LC3BII, and down-regulation of autophagic degradation protein p62. Moreover, recent studies provided evidence that young systemic milieu may alleviate renal ischemia-reperfusion injury in elderly mice probably through reduction of oxidative stress, inflammation, apoptosis, and enhancement of autophagy in the injured aged kidney. Although evidence showed that young blood can attenuate renal aging and injury induced by ischemia-reperfusion injury in elderly mice, it will be important to identify and study the effects of specific blood-borne rejuvenating factors in the young blood or aging factors in the old blood in addition to put efforts into delineate the mechanisms underlying the renal cell senescence. This information will provide novel ideas to turn back the clock of the aging kidneys.

Link: https://doi.org/10.1016/j.jfma.2019.05.020

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