Molecular mechanisms of renal aging

Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The underlying molecular mechanisms could be the target of therapeutic strategies in the future. Here, we summarize recent insight into cellular and molecular processes that have been shown to contribute to the renal aging phenotype.The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons. Mechanistically, this has been linked to different processes, such as podocyte hypertrophy, glomerulosclerosis, tubular atrophy, and gradual microvascular rarefaction. Renal functional recovery after an episode of acute kidney injury is significantly worse in elderly patients. This decreased regenerative potential, which is a hallmark of the aging process, may be caused by cellular senescence. Accumulation of senescent cells could explain insufficient repair and functional loss, a view that has been strengthened by recent studies showing that removal of senescent cells results in attenuation of renal aging. Other potential mechanisms are alterations in autophagy as an important component of a disturbed renal stress response and functional differences in the inflammatory system. Promising therapeutic measures to counteract these age-related problems include mimetics of caloric restriction, pharmacologic renin-angiotensin-aldosterone system inhibition, and novel strategies of senotherapy with the goal of reducing the number of senescent cells to decrease aging-related disease in the kidney. Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The underlying molecular mechanisms could be the target of therapeutic strategies in the future. Here, we summarize recent insight into cellular and molecular processes that have been shown to contribute to the renal aging phenotype.The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons. Mechanistically, this has been linked to different processes, such as podocyte hypertrophy, glomerulosclerosis, tubular atrophy, and gradual microvascular rarefaction. Renal functional recovery after an episode of acute kidney injury is significantly worse in elderly patients. This decreased regenerative potential, which is a hallmark of the aging process, may be caused by cellular senescence. Accumulation of senescent cells could explain insufficient repair and functional loss, a view that has been strengthened by recent studies showing that removal of senescent cells results in attenuation of renal aging. Other potential mechanisms are alterations in autophagy as an important component of a disturbed renal stress response and functional differences in the inflammatory system. Promising therapeutic measures to counteract these age-related problems include mimetics of caloric restriction, pharmacologic renin-angiotensin-aldosterone system inhibition, and novel strategies of senotherapy with the goal of reducing the number of senescent cells to decrease aging-related disease in the kidney. While life expectancy in developed countries has constantly increased in the last century, incidence rates of acute kidney injury and chronic kidney disease have also grown and will continue to grow in proportion to the expanding geriatric population. Although the aging process per se does not cause renal disease, the kidney undergoes distinct physiologic changes during the lifespan, predisposing to renal pathology. Renal volume and the number of functioning nephrons decrease progressively, and the glomerular filtration rate declines with advancing age. In parallel, the kidney develops reduced capacities for adaptation to stress and for structural repair. Combined with the cumulative impact of age-associated risk factors, these features lead to renal disease in the elderly. From a cellular and molecular point of view, considerable advances in identifying some of the mechanisms involved have been made. A comprehensive view of these findings may provide insight into novel therapeutic possibilities. In this review, we discuss specific cellular and molecular processes that show promise for elucidating the complex biologic events that lead to normal and pathologic renal aging. The aging process per se is characterized by a progressive decline in intrinsic physiologic function of all organs.1Flatt T. A new definition of aging?.Front Genet. 2012; 3: 148Crossref PubMed Scopus (17) Google Scholar The kidney is one of the best organs to study this decline because age-associated functional changes are easily detectable by standard clinical measures. The glomerular filtration rate drops by approximately 5%–10% per decade after the age of 35 years.2Glassock R.J. Rule A.D. The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli.Kidney Int. 2012; 82: 270-277Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Glassock R.J. Rule A.D. Aging and the kidneys: anatomy, physiology and consequences for defining chronic kidney disease.Nephron. 2016; 134: 25-29Crossref PubMed Scopus (6) Google Scholar The structural correlate for this decline is a loss of functioning nephrons. It was recently observed that kidneys from healthy donors aged 70 to 75 years had 48% fewer intact nephrons than kidneys from donors aged 18 to 29 years.4Denic A. Lieske J.C. Chakkera H.A. et al.The substantial loss of nephrons in healthy human kidneys with aging.J Am Soc Nephrol. 2017; 28: 313-320Crossref PubMed Scopus (26) Google Scholar An estimated 6000–6500 nephrons are lost per year after the age of 30.4Denic A. Lieske J.C. Chakkera H.A. et al.The substantial loss of nephrons in healthy human kidneys with aging.J Am Soc Nephrol. 2017; 28: 313-320Crossref PubMed Scopus (26) Google Scholar, 5Hoy W.E. Douglas-Denton R.N. 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Zhang Z. et al.Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney.Kidney Int. 2016; 89: 1281-1292Abstract Full Text Full Text PDF PubMed Google Scholar, 28Kang D.H. Anderson S. Kim Y.G. et al.Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease.Am J Kidney Dis. 2001; 37: 601-611Abstract Full Text Full Text PDF PubMed Google Scholar, 29Ma L.J. Nakamura S. Whitsitt J.S. et al.Regression of sclerosis in aging by an angiotensin inhibition-induced decrease in PAI-1.Kidney Int. 2000; 58: 2425-2436Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The disequilibrium of these and other factors might well cause a functional disruption in capillaries, leading to chronic hypoperfusion, ischemia, and nephron loss (Figure 1). A recent pilot study, in which elegant 3-dimensional microimaging in human kidneys was used, indicated that small arterial changes might be crucial primary contributors to the development of glomerulosclerosis in old kidneys.30Uesugi N. Shimazu Y. Kikuchi K. et al.Age-related renal microvascular changes: evaluation by three-dimensional digital imaging of the human renal microcirculation using virtual microscopy.Int J Mol Sci. 2016; 17Crossref PubMed Scopus (0) Google Scholar It has also been demonstrated that the number of pericapillary pericytes decreases in the kidney with age.31Stefanska A. Eng D. Kaverina N. et al.Interstitial pericytes decrease in aged mouse kidneys.Aging (Albany NY). 2015; 7: 370-382Crossref PubMed Scopus (22) Google Scholar Because pericytes are crucial for peritubular vessel function and capillary survival, this might also contribute to microvasculature deterioration and should be further explored in renal aging studies.31Stefanska A. Eng D. 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