Cellular senescence in the aging and diseased kidney

Abstract

The program of cellular senescence is involved in both the G1 and G2 phase of the cell cycle, limiting G1/S and G2/M progression respectively, and resulting in prolonged cell cycle arrest. Cellular senescence is involved in normal wound healing. However, multiple organs display increased senescent cell numbers both during natural aging and after injury, suggesting that senescent cells can have beneficial as well as detrimental effects in organismal aging and disease. Also in the kidney, senescent cells accumulate in various compartments with advancing age and renal disease. In experimental studies, forced apoptosis induction through the clearance of senescent cells leads to better preservation of kidney function during aging. Recent groundbreaking studies demonstrate that senescent cell depletion through INK-ATTAC transgene-mediated or cell-penetrating FOXO4-DRI peptide induced forced apoptosis, reduced age-associated damage and dysfunction in multiple organs, in particular the kidney, and increased performance and lifespan. Senescence is also involved in oncology and therapeutic depletion of senescent cells by senolytic drugs has been studied in experimental and human cancers. Although studies with senolytic drugs in models of kidney injury are lacking, their dose limiting side effects on other organs suggest that targeted delivery might be needed for successful application of senolytic drugs for treatment of kidney disease. In this review, we discuss (i) current understanding of the mechanisms and associated pathways of senescence, (ii) evidence of senescence occurrence and causality with organ injury, and (iii) therapeutic strategies for senescence depletion (senotherapy) including targeting, all in the context of renal aging and disease.

A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development

“…However, the increase in senescent cells with age and a chronic SASP are now known to be key drivers of many pathological hallmarks of aging, including chronic inflammation, tumorigenesis, impaired stem cell renewal, and others (Neves et al, 2015;Tominaga, 2015). Using either or both of two transgenic mouse models that allow the selective elimination of senescent cells (Baker et al, 2011;Demaria et al, 2014), or compounds that mimic the effect of these transgenes, data from several laboratories strongly support the idea that the presence of senescent cells drives multiple age-related phenotypes and pathologies, including age-related atherosclerosis , osteoarthritis (Jeon et al, 2018), cancer metastasis and cardiac dysfunction (Baar et al, 2017;Demaria et al, 2017), myeloid skewing in the bone marrow (Abdul-Aziz et al, 2018;Chang et al, 2016), kidney dysfunction (Valentijn et al, 2018), and overall decrements in healthspan .…”

The emerging role of cellular senescence in renal diseases

“…3 Cellular senescence plays a critical role in normal embryonic development in humans and animals and is involved in wound healing. 5 More importantly, cellular senescence has been verified as a fundamental cause for the development of many diseases, such as cardiovascular, liver and kidney diseases ( Figure 2). 5 More importantly, cellular senescence has been verified as a fundamental cause for the development of many diseases, such as cardiovascular, liver and kidney diseases ( Figure 2).…”

“…5 More importantly, cellular senescence has been verified as a fundamental cause for the development of many diseases, such as cardiovascular, liver and kidney diseases ( Figure 2). 5,6 Therefore, preventing cellular senescence may be a potentially important approach to inhibit the development of chronic kidney disease (CKD). 5,6 Therefore, preventing cellular senescence may be a potentially important approach to inhibit the development of chronic kidney disease (CKD).…”

“…4 However, enhanced cellular senescence is also found in multiple organs in the process of ageing or after injury, suggesting that there should be different effects of cellular senescence depending on the pathophysiological context. 5 More importantly, cellular senescence has been verified as a fundamental cause for the development of many diseases, such as cardiovascular, liver and kidney diseases ( Figure 2). 4 Additional studies confirm that the number of senescent cells increases in multiple anatomical sites in the kidney during ageing and kidney diseases.…”

“…4 Additional studies confirm that the number of senescent cells increases in multiple anatomical sites in the kidney during ageing and kidney diseases. 5,6 Therefore, preventing cellular senescence may be a potentially important approach to inhibit the development of chronic kidney disease (CKD). 7 In this review, we will focus on the mechanisms of cellular senescence and the relationship between senescence and renal diseases.…”