Vitamin D, Cellular Senescence And Chronic Kidney Diseases: What Is Missing in The Equation?

Abstract: As life expectancy increases in many countries, the prevalence of age-related diseases also rises. Among these conditions, chronic kidney disease is predicted to become the second cause of death in some countries before the end of the century. An important problem with kidney diseases is the lack of biomarkers to detect early damage or to predict the progression to renal failure. In addition, current treatments only retard kidney disease progression, and better tools are needed. Preclinical research has shown the involvement of the activation of cellular senescence-related mechanisms in natural aging and kidney injury. Intensive research is searching for novel treatments for kidney diseases as well as for anti-aging therapies. In this sense, many experimental shreds of evidence support that treatment with vitamin D or its analogs can exert pleiotropic protective effects in kidney injury. Moreover, vitamin D deficiency has been described in patients with kidney diseases. Here, we review recent evidence about the relationship between Cistanche Glycoside and kidney diseases, explaining the underlying mechanisms of the effect of vitamin D actions, with particular attention to the modulation of cellular senescence mechanisms. 

Keywords: vitamin D; cellular senescence; biological aging; premature aging; chronic kidney diseases

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1. Introduction 

The last decades have witnessed a dramatic increase in global life expectancy. The World Health Organization (WHO) estimates that by 2030, one in six people will be aged over 60 years, and by 2050, this will rise to 22%. Unfortunately, this boost in the human lifespan is associated with a rise in age-related diseases, such as type 2 diabetes mellitus, Alzheimer’s disease, cardiovascular diseases, and chronic kidney disease (CKD). Among these diseases, CKD is one of the fastest-growing global causes of death and it is expected to become the fifth most common cause of death worldwide by 2040, being increased at the end of the century to the second position [1]. CKD is a common, progressive and irreversible disorder [2]. Lifestyle and drug interventions (e.g., SGLT2 inhibitors and ACE inhibition or angiotensin II receptor type 2 blockade) are currently the cornerstone for treatment for CKD. Still, they do not sufficiently prevent the progression of the disease. Thus, there is a high demand for better treatment options that stop CKD progression and even reverse CKD. In addition, there is a lack of treatments for acute kidney injury (AKI) that may prevent or delay the development of CKD [3–5]. Furthermore, CKD remains underdiagnosed and undertreated, and biomarkers are needed for earlier detection of kidney damage or for better prediction of progression [3–5]. Finally, CKD is characterized by premature aging in the skeletal, immune, and cardiovascular systems. Even children with kidney diseases develop atherosclerosis, showing a bidirectional aging–CKD relationship [1], suggesting that CKD can be considered as a clinical model of premature aging. 

Aging is a natural and complex process resulting in impaired physiological functions in all cells, tissues and finally organs, resulting in homeostasis loss. The hallmarks of the aging phenotype include genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, dysregulation of the nutrient sensor pathways, mitochondrial dysfunction, stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis and senescence [6,7]. These changes also happen in age-related diseases that share similar pathogenic processes, as described in CKD. Nowadays, intensive research is focused on deciphering the mechanisms of aging and finding new therapeutic strategies to treat age-related disorders and increase lifespan [8,9]. Interestingly, some of these therapeutic options can also ameliorate renal damage, as we discuss below.

The vitamin D endocrine system is an essential regulator of various physiological functions in the human body. Apart from its role in maintaining calcium balance and bone health, it has been found to possess numerous non-skeletal effects. Many immune cells, including dendritic cells, macrophages, and T and B cells, can produce vitamin D and express the vitamin D receptor, showing the interrelation of vitamin D and the immune system [10,11]. Recent preclinical studies have highlighted the beneficial effects of treatment with vitamin D or its analogs in inflammatory diseases by exerting anti-inflammatory effects, including its ability to modulate the expression of genes involved in the regulation of the immune system or pro-inflammatory factors [12,13]. The kidneys are the primary regulators of the endocrine vitamin D system, playing a key role in regulating systemic, active vitamin D levels. The tubular epithelial cells are responsible for the production of the active form of vitamin D, 1,25(OH)2VD3 or calcitriol [14–20]. In patients with CKD, there is a gradual decline in the kidney’s ability to produce 1α-hydroxylase, resulting in a decrease in the activation of vitamin D. This results in the lowering of vitamin D circulating levels, which can lead to various health complications. Vitamin D deficiency has been linked to several diseases, including cancer, Alzheimer’s disease, type 2 diabetes mellitus, cardiovascular disease, autoimmune diseases and aging [14–20].

Here, we review recent evidence on the relationship between vitamin D, CKD and aging. In addition, the emerging evidence on the pleiotropic effects of treatment with vitamin D or its analogs in CKD is also reviewed, describing the underlying mechanisms elicited by vitamin D, with special attention to the modulation of the cellular senescence mechanisms.

2. Cellular Senescence in Biological Aging and Age-Related Disorders

During the natural biological process of aging, both extrinsic and intrinsic agents can cause accumulative damage in the cells, leading to the activation of cellular senescence-related mechanisms [21]. Cellular senescence is a process where cells decrease their proliferative capacity and are no longer able to divide, in association with unique characteristics, such as flattened and enlarged morphology, increased expression of cell cycle inhibitors, and elevated senescence-associated β-galactosidase activity [22]. Notably, the excessive accumulation of senescent cells in different organs and biological systems leads to a functional decline [6,7]. The senescence phenotype is characterized by an aberrant secretome known as the senescence-associated secretory phenotype (SASP). The components of the SASP include pro-inflammatory cytokines, profibrotic factors and extracellular vesicles [23–25]. These factors released by senescent cells can act on the surrounding cells inducing secondary senescence [22], therefore contributing to the amplification and progression of the damage. Further research in this area offers a chance to design new therapeutic approaches, including inhibitors of the cell cycle or SASP components, as well as eliminating senescent cells. 

During biological and premature aging, senescence-related mechanisms activate in all types of cells of the entire organism. These implicate significant consequences for the immune system, inducing two major events. First, there is a low-grade inflammation, known as inflammation [26], and second, there is a decrease in innate and adaptative functions, called immunosenescence [27,28]. This highlights the relevance of the deepening understanding of the relationship between immune cells and aging. Nevertheless, senescence is necessary for correctly maintaining tissues, organs and physiological processes, such as embryogenesis, development, and wound healing [22,29,30]. Moreover, molecular and cellular senescence-related mechanisms can be also activated in response to injury and are involved both in maladaptive responses and endogenous repair mechanisms, as described in kidney injury [2]. The complexity of these mechanisms emphasizes the importance of future research in this area. 

Senescence: The Molecular View 

Cellular senescence is a hallmark of aging. This process can be triggered by different types of damage, including oncogene activation, the DNA damage response (DDR) pathway [31], telomere shortening, mitochondrial injury, viral or bacterial infection, reactive oxygen species (ROS) production, nutrient imbalance, and mechanical stress [22,32]. Senescent cells are characterized by a permanent cell cycle arrest in the G1 or G2 phases, mediated by the activation of the tumor suppressor protein p53, the inhibitors of the cyclin-dependent kinases CDKN2A/p16 and CDKN1A/p21, as well as the retinoblastoma-1 (RB1) family proteins [21]. Cellular senescence activation provokes several intracellular metabolic and functional changes, including mitochondria dysfunction and redox disbalance together with transcriptional reprogramming, leading to a phenotype change. As commented before, one key feature of senescent cells is a specific secretome, the SASP. Many components of the SASP are regulated by the transcription factors NF-κB and C/EBP (CCAT/Enhancer Binding Protein) [33–35], suggesting that targeting the activation of these transcription factors could be used as anti-aging strategies. The SASP comprises a core of growth factors, cytokines, and chemokines, but its composition depends on the cell type and the trigger stimulus. Although senescence transcriptome signatures have been identified [36], a recent study based on proteomics showed a lack of correlation between transcriptome and proteome [37]. Nevertheless, the authors identified a top core SASP, constituted by GDF15, STC1, SERPINs and MMP1, proteins that can be used as aging plasma markers [36]. Future studies are needed to identify further and define senescent markers, which can differ depending on the tissue and pathological condition.

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