Obesity is now defined as a disease. According to WHO standards, obesity occurs at a BMI greater than 30. First, Veisinger reported on the relationship between severe obesity and proteinuria. In obesity, when proteinuria (possibly accompanied by microscopic hematuria) is detected, renal biopsy shows glomerular hypertrophy and focal glomerular sclerosis (FSGS)—while other diseases have been excluded—which can be considered obesity-related nephropathy. There is a connection between obesity and kidney disease. It has been estimated that 20–25% of kidney disease patients in the world are obese, and this number may be significantly increased after intermediate disease including type 2 diabetes mellitus (T2DM) and hypertension. Many epidemiological studies have shown that obesity is independently related to proteinuria, chronic kidney disease, Acute kidney injury (AKI), and End-Stage Renal Disease (ESRD) [5]. The results of a large-scale study have shown that, when the BMI increased to more than 25 kg/m, the risk of a decreased glomerular filtration rate was also increased. The specific mechanism through which obesity causes kidney damage and develops into obesity-related nephropathy has not yet been confirmed [6]. It is generally held that there are two ways by which it develops: direct and indirect, for example, some products secreted by adipocytes display nephrotoxicity. Obesity leads to an increase in intra-abdominal pressure, and the infiltration of fat into the kidney, which further leads to glomerular hypertension and activation of the renin–angiotensin–aldosterone system, thus promoting the occurrence of hypertension. On the other hand, obesity is an important risk factor for diabetes, and can indirectly cause kidney damage by promoting other disease states in MetS. These will be explained later in detail [8]. In these processes, cellular senescence also plays an important role in the disease. Obesity may speed up the induction of cell senescence while, at the same time, cellular senescence aggravates obesity. Both of these factors influence each other, and have a lot in common.

Obesity is usually due to excessive nutrient intake. It accelerates cell senescence through some internal reactions, which are part of the above-mentioned cell stress mechanism, such as telomere damage, oxidation, DNA damage, and so on, and which strongly promote cell senescence. In obesity, persistent low inflammation in adipose tissues is common, which is one of the characteristics of cell senescence. Senile preadipocytes release pro-inflammatory factors through paracrine and activate neighboring cells to a pro-inflammatory state. These senescent cells in adipose tissues may trigger the infiltration of immune cells, further aggravating inflammation. This vicious cycle leads to the accumulation of senescent cells [9]. On the other hand, cell senescence has an influence on obesity-related nephropathy. A major principle of MetS is the expansion of adipose tissues. One hypothesis is that excessive energy intake in MetS leads to the disorder of many physiological regulation systems, triggering inflammation and oxidative stress pathways [10], specifically, the expanded adipose tissue usually leads to increased free fatty acid (FFA) turnover [11,12]. In the case of insulin resistance, FFA mobilization (lipolysis) in adipose tissues is accelerated due to decreased insulin inhibition, leading to higher FFA in plasma [13,14,15]. Adipose tissue not only can store energy, but also plays an important endocrine function. It can regulate the dynamic balance of the whole body by regulating energy balance, insulin sensitivity, blood pressure, angiogenesis, and immune function. Obesity is related to the increase in adipose tissue. A large number of studies have shown that the aging of adipose tissue cells plays a positive role in insulin resistance and diabetic nephropathy [7]. Most overweight or obese people present insulin resistance [16], and, especially in obesity, a lack of physical activity and a diet leading to atherosclerosis are considered to be responsible for IR [17]. Senescent cells can secrete SASP, such as IL-6, TNF-α, and activin A, to promote insulin sensitivity. In obesity, due to the secretion of cytokines and chemokines (SASP) and the infiltration of macrophages, the inflammatory state can be observed in tissues. Tissue expansion is the main source of inflammatory cytokines. It has been shown that cell senescence partially determines the inflammation of adipose tissues [18].

A factor related to obesity and cell senescence is the tumor suppressor p53, which is the key regulator of adipogenesis. Under normal circumstances, it should be repressed before adipogenic precursor cells differentiate into insulin-reactive adipocytes. In obesity, p53 is activated and active oxygen is accumulated, interfering with normal adipogenic differentiation, potentially promoting the inflammatory reaction and insulin resistance [7].

There is a significant amount of research showing the connection between obesity and cellular senescence. For example, the research of Minminine et al. has reported that, in an obese mouse model with excessive calorie intake and T2DM, oxidative stress in adipose tissues was up-regulated, the expression of senescence markers such as p53 was increased, and SA-β-GAL and pro-inflammatory cytokines levels were increased. In addition, research has shown that p16^INK4a, p53, and p21 were significantly increased in adipose tissue from mice fed a high-calorie diet for 4 months. In another study, DNA damage and cell senescence were artificially produced in adipose tissue in mice. The result indicated that the mice were obese and presented impaired glucose tolerance [7,19]. Using pifithrin-a to inhibit p53 resulted in reversal of the above changes. Allyson et al. have shown that the reduction in senescent cells or anti-aging treatment can improve the glucose tolerance of obese mice, enhance insulin sensitivity, promote fat generation, and reduce circulating inflammatory mediators [20].

Therefore, the above evidence proves the relationship between obesity-related nephropathy and cell senescence. Adipose tissue expansion caused by excessive nutrition will increase replication, enhancing various cell stress factors of cellular senescence (e.g., telomere damage, inflammation, and oxidative stress), and inducing the occurrence of cellular senescence in adipose tissues and cells. Senescent cells change the tissue structure through SASP, leading to insulin resistance and aseptic inflammation. The secreted SASP signals lead to cell senescence of the adjacent cells, thus promoting the occurrence of obesity, which, in turn, leads to clinical symptoms such as proteinuria, secondary to obesity nephropathy. In addition, the sterile inflammatory environment and insulin resistance, which are usually associated with obesity nephropathy, also contribute to the occurrence of diabetes. It is obvious that there is a close relationship between obesity and kidney diseases. Obesity can (directly or indirectly) induce obesity-related nephropathy. At present, the specific pathogenesis is not clear, but it appears that cell senescence is an important intermediate link in these processes, and more related mechanisms need to be determined.

Diabetic nephropathy is a microvascular complication of diabetes, in which the lesions are mainly located in the glomerulus. The GFR increases early, leading to a state of high filtration. With the development of the disease, edema, proteinuria, and hypertension appear gradually, eventually leading to renal insufficiency and even uremia.

Cellular senescence also plays an important role in diabetic nephropathy. Diabetes itself can create an environment that accelerates cellular senescence; in turn, cellular senescence will promote the progress of the disease. It is well-known that age and obesity are the main risk factors of T2DM. From the above, we know that obesity itself and cellular senescence in obesity can lead to insulin resistance, which is the key mechanism of T2DM. Pancreatic B cells are insulin-secreting cells. When insulin resistance occurs, the amount of insulin needed to maintain normal blood glucose will increases. T2DM occurs when the insulin secretion function of pancreatic B cells cannot meet the insulin demand. A large number of studies have shown that cellular senescence mainly inhibits the proliferation of B cells through the p16^INK4a pathway, leading to T2DM. Taschen’s research in 2009 has shown that p16^INK4a is regulated by the BMI-1 complex. B cells are up-regulated in mice with low p16^INK4a and high BMI-1. On the contrary, the proliferation of B cells is limited. In addition, the activity of CDK4 required for B cell proliferation was also inhibited by p16^INK4a through the above-mentioned pathway [21,22]. In contrast, in 2016, Helman et al. conducted an experiment to induce the stagnation of B cell proliferation by overexpressing p16^INK4a. Their results proved that p16^INK4a can promote insulin secretion [23]. Some scholars have explained that simply increasing the single phenotype of increased p16^INK4a is insufficient to mimic cellular senescence. The stagnation of proliferation might cause B cells to compensate for insulin secretion by increasing the volume. More research is needed to validate the results of these experiments.

DN itself can also accelerate kidney aging. In DN, the accumulation of advanced glycation end-products (AGEs) may induce podocyte injury, glomerular mesangial cell apoptosis, and TGF-β expression, thus leading to renal insufficiency and accelerated aging [4]. AGEs stimulate the activation of AGEs receptors, which leads to oxidative stress and cell dysfunction, and stimulates the occurrence of cellular senescence. High glucose levels promote macrophage infiltration into the kidney, mitochondrial dysfunction, and activation of NOX1-PKC signaling, which leads to an increase in reactive oxygen species (ROS) and the aging of renal tubular epithelial cells and endothelial cells [7,9]. Hyperglycemia can also induce endoplasmic reticulum (ER) stress, leading to the senescence of renal tubular epithelial cells. Mesangial cells provide structural support for the glomerular capillary ring and regulate the ultrafiltration surface for glomerular filtration, which is directly affected by hyperglycemia. In cultured glomerular mesangial cells, a high extra-cellular glucose concentration promotes extracellular matrix (ECM) accumulation, cell cycle arrest, cell hypertrophy, and the induction of senescence [10]. Furthermore, studies have shown that, in a high-glucose environment, NOX activity and ROS production in mouse podocytes are increased, and cell apoptosis may occur [11]. Kidney cell senescence occurs, and, as a result, kidney-related clinical symptoms appear in DN. In addition, the clinical symptoms of DN include hypertension, as a result of renin–angiotensin–aldosterone system (RAAS) dysfunction. Abnormal activation of RAAS may lead to cellular senescence, as it can cause oxidative stress and/or the down-regulation of anti-aging proteins (e.g., Klotho and SIRT). Oxidative stress (OS) is also a key factor [12,13] that can lead to DN and increase senescence, and it plays an important role in MetS. In MetS, oxidative stress is characterized by the up-regulation of ROS, which are mainly derived from NADPH oxidase (NOX) 1,2,4. Due to metabolic factors, NOX leads to excessive ROS production in glomerular podocytes, endothelial cells, and mesangial cells, which may lead to the occurrence of cellular senescence and, eventually, can cause kidney lesions. In patients with DN, an increase in OS leads to a series of cellular events (e.g., DNA damage, endoplasmic reticulum stress), which will cause cellular senescence, as described above.

In summary, cellular senescence plays an important role in the pathogenesis of DN, which may be mediated by the inhibition of islet B cell proliferation through the p16^INK4a pathway. However, the determination of the specific mechanism still requires further study. In DN, there are many factors that can cause cell stress, thus accelerating the occurrence of cellular senescence.

Hypertension-related nephropathy is one of the main complications of hypertension. Hypertension can cause systemic arteriosclerosis, and the kidney is seriously affected by nephron anatomy, which will lead to decreased GFR. Long-term hypertension can also cause dysfunction of glomerular capillary endothelial cells and injury of glomerular visceral epithelial cells, resulting in an increase in basement membrane permeability and proteinuria. The local and systemic inflammatory environment promoted by cell senescence promotes the development of cardiovascular disease. It is well-known that age is a major risk factor for hypertension and the occurrence of cellular senescence can be observed in almost all hypertensive patients or vascular tissues of experimental models. Cellular senescence is a common phenotype in hypertension. In hypertension, the decline of SASP and vascular function often occurs before actual aging. If cellular senescence is out of control, the relative age of blood vessels may increase, thus promoting the occurrence and development of hypertension. In pathological cardiovascular tissues, many studies have demonstrated an increase in aging markers, including p16 [22] and SA-β-GAL. Senescent cells may promote the progression of hypertension by mediating inflammation and oxidative stress; however, the specific mechanism needs to be verified through further studies. Some studies in the opposite direction can help us to speculate on the relationship between them. According to these studies, the removal of senescent cells can delay aging and restore organ function to some extent [24,25], including the vascular system and kidney [26]. Evidence has been presented that targeted aging therapies, such as drugs involving DNA damage repair mechanisms, cell cycle checkpoint kinases, and tumor suppressor factors, can reduce pathophysiology [27,28].

The article “Novel Contributors and Mechanisms of Cellular Aging in Hypertension-Associated Premature Vascular Aging” has integrated and reported a series of studies on aging in experimental models of hypertension into a table. Endothelial progenitor cells (EPCs) contribute to neovascularization [14,15,16,17], and the dysfunction of EPC is closely related to the development of hypertension. Studies have shown that, in hypertension, the function of EPCs is damaged [18], and some hypertension drugs can correct the functional damage of EPCs [19]. There are some studies on the mechanism leading to the dysfunction of EPCs in hypertension; however, the exact mechanism remains unclear. Haendeler et al. assessed the effect of antioxidant therapy, and their results showed that aging marker levels were decreased, proving the correlation between the accumulation of ROS and cellular senescence in endothelial cells [20]. Studies have proved that oxidized low-density lipoprotein and angII induce the cell senescence of EPCs through oxidative stress [21,22]. In addition, vascular oxidative stress has also been experimentally confirmed to induce hypertension [29,30,31]. Clinical studies have shown that the production of ROS is increased in patients with hypertension [24,32]. From this research, it appears EPCs are more likely to undergo cell senescence through oxidative stress; however, whether there exist other pathways requires further research to reveal. The overall conclusion is that there exists a pressure-dependent relationship between the increases in cellular senescence and hypertension.

In metabolic syndrome patients, hypertension is usually accompanied by insulin resistance. Under physiological conditions, insulin may regulate GFR by expanding local renal vessels. In patients with MetS, this effect will be weakened, or may even disappear. Therefore, insulin resistance can accelerate renal sclerosis in hypertension [33]. Moreover, hyperinsulinemia caused by insulin resistance can stimulate the secretion of endothelin-1, affect the function of endothelial cells, reduce the release of NO, and cause vasoconstriction. As mentioned above, cell aging promotes insulin resistance, which may indirectly accelerate the development of hypertension.

Hyperuricemia is a common disease, mainly caused by abnormal metabolism of serum uric acid. Its pathological manifestations are mostly metabolic diseases, such as gout, hypertension, diabetes, and hypertriglyceridemia, often accompanied by metabolic syndrome. High uric acid may promote the occurrence of the above-mentioned diseases by inducing cellular senescence in various tissues. For example, the induction of endothelial cellular senescence leads to cardiovascular disease and induces the senescence of islet B cells, leading to diabetes, and so on. About two-thirds of the uric acid produced in the human body is excreted by the kidney, such that hyperuricemia is related to kidney diseases in many cases.

In observational studies, it has been shown that hyperuricemia can predict the occurrence and development of kidney disease. In animal studies, researchers have found that hyperuricemia may lead to lesions in the afferent arterioles, increased glomerular pressure, glomerular hypertrophy, and hypertension [35,36,37]. This may be related to the pro-inflammatory effects of hyperuricemia described above [38,39,40]. At the same time, hyperuricemia leads to afferent arteriopathy and tubulointerstitial fibrosis through its influence on RAAS [35].

However, the role of hyperuricemia in kidney disease is still unclear, and multiple mechanisms may be involved. The main mechanisms may be as follows: 1. The oxidation of uric acid leads to the production of reactive oxygen species (ROS) in kidney tissues, which can cause the accumulation of cellular senescence and the occurrence of lesions [41,42]; 2. uric acid blocks the release of NO, as well as inhibiting vascular expansion and the proliferation of endothelial cells [35,43,44]; and 3. uric acid can activate nuclear transcription factors, inflammatory mediators such as cyclooxygenase-2 (COX2) and tumor necrosis factor α (TNF-a) and stimulate the angiotensin–aldosterone system (RAAS) to induce smooth muscle cell proliferation, leading to endothelial cell dysfunction [42,43,44,45]. Points 2 and 3 above contribute to hypertension, which may indirectly cause hypertension-related kidney disease. In these mechanisms, many intermediate products also trigger cellular senescence, which may appear in the form of cell senescence by inducing the senescence of renal parenchyma cells and renal vascular endothelial cells. Eventually, the accumulation of senescent cells reaches a threshold, leading to pathological changes.

Uric acid is one of the most important antioxidants in the blood circulation, which can protect cells from exogenous oxidants [46,47]; however, the results of most clinical studies have shown that an elevated uric acid level is closely related to endothelial dysfunction [22,28], manifested as the decreased utilization of endothelial NO, which is a key factor in renal lesions and cardiovascular diseases [33,48]. Uric acid has a pro-inflammatory effect on endothelial cells [49,50,51,52].

In summary, although uric acid is considered to have an important antioxidant effect, in the hyperuricemia environment, uric acid may exert the opposite effect—that is, causing oxidative stress, blocking the release of NO, and activating RAAS, among other effects. Additionally, there may exist other unknown mechanisms, which, in turn, cause the cellular senescence of various cells. Eventually, the accumulation of cell aging exceeds a threshold, after which various pathological changes occur.