Visceral Adipose Tissue Influence on Health Problem Development and Its Relationship with Serum Biochemical Parameters in Middle-Aged and Older Adults: A Literature Review

Background The amount of visceral adipose tissue (VAT) tends to increase with age and is associated with several health problems, such as cardiometabolic diseases, increased infections, and overall mortality. Objectives This review provides a general assessment of how visceral adiposity correlates with the development of health problems and changes in serum biochemical parameters in middle-aged and older adults. Methods We searched specific terms in the Virtual Health Library (VHL) databases for VAT articles published in the English language between 2009 and 2019 related to older adults. Results The search found twenty-three publications in this period, of which nine were excluded. The publications had a population aged between 42 and 83 years and correlated the VAT area ratio with several comorbidities (such as pancreatitis, depression, cancer, and coronary heart disease) and serum biochemical parameters. Conclusion Further research on the association between visceral obesity and the emergence of health problems and the relationship between VAT and changes in serum biochemical parameters in older individuals should deepen the understanding of this connection and develop preventive actions.


Introduction
Obesity has been one of the rising comorbidities globally, reaching pandemic proportions to become the foremost cause of preventable death. is condition is associated with a decreased life expectancy of about 5 to 20 years, depending on the severity and other associated comorbidities [1]. According to the World Health Organization (WHO), an individual is classified as obese if their body mass index (BMI) is greater than or equal to 30 kg/m 2 . Individuals with a BMI between 25 and 29.9 kg/m 2 are classified as overweight and may already present health risks from excess fat [2]. e population's life expectancy has increased in recent years compared with the past decade, and although obesity in young people is a risk factor for morbidity and mortality, the effect of obesity in older adults is much more complicated [3]. Studies show that when analyzing the link between age and body fat distribution, overweight and obesity increase with age up to about 70 years, and afterward, it tends to decrease [4,5]. Aging is associated with body fat distribution changes mainly due to visceral adipose tissue (VAT) accumulation, known as visceral obesity [6].
Visceral obesity is characterized as increased adipose tissue (fat) around the intra-abdominal organs and can also be called abdominal or central obesity [7]. Quantitative and qualitative VAT analysis can be determined by gold standard diagnostic techniques such as dual-energy X-ray absorptiometry (DXA, formerly DEXA), computed tomography, magnetic resonance, ultrasonography, or a combination of techniques. Anthropometric standards such as waist circumference and waist-to-hip ratio, for example, can also assess the presence of central obesity, but not its quantity and quality [7,8].
Excessive deposition of VAT influences the pro-inflammatory response regulation, and with aging, adipocytes tend to have a higher pro-inflammatory level due to adipokines' action [9]. us, an elevated VAT area contributes to a greater risk of metabolic and hemodynamic disorders, favoring the appearance of diseases, such as arterial hypertension, diabetes, atherogenic cardiovascular disease, coronary disease, and kidney problems [10], and changes in serum biochemical parameters [11,12].
In addition to obesity, another relevant factor for older adults' health is the decline in skeletal muscle mass associated with functional deterioration, known as sarcopenia.
is condition leads to higher rates of disability and frailty and has been associated with more extended hospital stays, increased infections and postoperative complications, increased chemotherapy toxicity, and worse recurrence-free survival and overall survival [13]. In the context of progressive population aging, the association of obesity, particularly VAT, with loss of lean mass leads to sarcopenic obesity, which is independently associated with increased mortality, cardiovascular complications, and cancer progression [14]. e VATaccumulation and the relative muscle mass loss analysis can become, in old age, an essential component in determining the health risk associated with obesity [14]. e number of studies on visceral obesity epidemiology in middle-aged and older adults, mainly in developing countries, is still limited. e available studies reveal an increase in this condition's prevalence in older individuals and that visceral adiposity should be considered a severe health epidemic worldwide, which reaffirms the need to expand knowledge about central obesity in this population group. In this context, this review aims to assess the correlation between visceral adiposity and the development of health problems and possible changes in serum biochemical parameters in middle-aged and older adults.

Search Strategy.
We performed a bibliographic search through the Virtual Health Library (VHL) database. is bibliographic database includes publications found in LI-LACS, MEDLINE, and other information bases, such as open educational resources, websites, and scientific events. e search took place in January 2020, researching publications that show information on visceral adipose tissue (VAT) area analysis in older adults. e search terms used were as follows: "visceral adipose tissue area" and "elderly." A hierarchical approach was employed to assess the studies' relevance based on their title, summary, and full report. e Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist was used to analyze and report the search results [15].

Study Selection.
e filters used were related to full-text open access, database, language, and year of publication. e literature search was unrestricted regarding the species and study type, and two reviewers (V. M. and I. S.) independently evaluated the identified articles. e inclusion criteria were as follows: (1) the study should address the VAT area in older adults, regardless of the diagnostic methodology employed; (2) the study should correlate VAT with comorbidities or serum biochemical tests; (3) the study must be published in the MEDLINE database; (4) the study must be in English; and (5) the study must have been published in the past ten years (2009 to 2019). We excluded studies if they had the following: (1) opinion or review; (2) only address muscle mass; (3) related the drug or supplement effect on VAT; (4) intended for validation of a novel VAT area estimator; and (5) studies to determine VAT by analyzing imaging tests, programs, and software protocols.

Data Extraction and Analysis.
All identified articles were screened independently by two authors (V. M. and I. S.) based on title and abstract for inclusion or exclusion, and all those that met the inclusion criteria had their full text also independently assessed by V. M. and I. S. Any discrepancies in the inclusion and exclusion criteria assessment were discussed until a consensus was reached.
V. M. and I. S. independently reviewed eligible articles and extracted relevant data. e gathered information included authors' names, study title, objective, year of publication, the country where the study took place, sample size, population's age group, study type, analyzed comorbidity, laboratory tests associated with VAT, research's results, and statistical values.

Results
e keyword search identified 23 articles from MEDLINE. After subjecting the articles to title and abstract review, we excluded three articles for not meeting inclusion criteria: software programs and protocols for imaging examination studies, respectively [16,17], and one focused on muscle mass analysis [18]. After the title and abstract review, we selected 20 articles for full-text review. Of these, two were excluded for focusing on drugs or supplement effect on visceral adipose tissue (VAT) [19,20], two for not addressing VAT association with health problems or biochemical tests [21,22], an article that limited their comparison between the VAT estimated by bioelectrical impedance analysis (BIA) and computed tomography (CT) [8], and one intended to validate a novel VAT area estimator in Japanese people [23]. e research did not result in duplicate articles or different studies on the same group of participants. is search selected fourteen articles published between 2009 and 2019 that met inclusion criteria and were deemed eligible to be included within this systematic review. Figure 1 presents a flowchart with the results of the literature search process.
Of the selected articles, four were published in Japan, two in Korea, two in the Netherlands and the United States, followed by Brazil, China, Iran, and Turkey, and distributed in seven cross-sectional studies, four cohort studies, one retrospective case-control study, and one observationalretrospective study at a single center. e publications had a sample population with ages ranging from 42 to 83 years with older adults' predominance (Table 1).

VAT Area and Its Correlation with Health Problems and
Biochemical Parameters. Of the 14 articles analyzed, seven presented an association between VAT and disease manifestations such as ischemic colitis [24], nonalcoholic fatty hepatitis [25], acute pancreatitis [26], depression [27], and coronary artery disease [28].
ree studies related visceral adiposity to procedures' outcomes, such as cecal insertion in colorectal cancer screening, retropubic prostatectomy, and renal function after nephrectomy in living donors [29][30][31]. VAT correlation with muscle mass was addressed by three studies: two related to cancer-related sarcopenia [32,33] and one related to sarcopenic obesity [34].
As for serum biochemical tests, only three studies showed a direct association between VAT patterns and serum levels of uric acid, amylase, and lipid profile [11,12,35].

Discussion
Our literature review presented visceral adipose tissue (VAT) association with several health problem manifestations-such as colitis, cancer, pancreatitis, depression, and coronary and liver diseases-in middle-aged and older adults.
Studies indicate that VAT closely correlates with nonalcoholic fatty liver disease (NAFLD) and risk factors for coronary artery disease such as dyslipidemia, diabetes, and metabolic syndrome [36,37]. In his study, Kim et al. [25] observed that individuals with NAFLD have a high risk of coronary atherosclerosis, regardless of traditional cardiovascular risk factors, such as visceral adiposity. VAT attenuated, but did not eliminate, the relation between NAFLD and artery calcification, suggesting that NAFLD's presence may be an independent risk factor for coronary artery disease.
NAFLD association with atherosclerosis may be related to the hepatic pro-inflammatory process that stimulates reactive oxygen species to induce cytokine production (such as tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6)) that, together with increased hepatic C-reactive protein levels, add more atherogenic stimuli to the body [38]. Furthermore, low adiponectin serum levels, which are inversely related to NAFLD severity, play a vital role in the pathogenesis between NAFLD and subclinical coronary atherosclerosis [37] since it regulates the inflammatory response by inhibiting macrophages and cytokine production, impacting the diseases' manifestation and severity [9].
Visceral adiposity correlates with an increased likelihood of having coronary artery disease, and if the disease is already present, it will be more diffuse compared with patients without visceral adiposity [39,40]. Ohashi et al. [28] also reported the VAT area's association with coronary artery calcium (CAC)'s presence and extension, regardless of body mass index (BMI). Increased VAT area likewise correlated significantly with noncalcified coronary plaques' presence and extent, contributing to atherosclerosis's acceleration, regardless of the traditional cardiovascular risk factors, such as hypertension, hypercholesterolemia (high cholesterol

Identification
Records identified through database (virtual health library) searches (n = 23)

Screening
Records remaining after title and abstract screening (n = 20) Full-text articles assessed for eligibility (n = 20) Eligibility

Studies included into final literature review (n=14) Included
Full-text articles excluded, with reason (n = 6): Related to drugs or supplements effect on VAT [19,20] Not related, VAT association with comorbidities or biochemical tests [21,22] Comparison between imaging exams [8] Validation of a novel VAT area estimator [23] Excluded studies (n = 3): Software programs [16] Protocols for imaging exams [17] Muscle mass analysis [18]     Journal of Aging Research levels in the bloodstream), and diabetes or other body composition parameters, such as the subcutaneous adipose tissue (SAT) area, BMI, and waist circumference (WC) [28]. Such findings may explain the excessive cardiovascular risk in patients with visceral adiposity. Coronary artery calcification correlated with cardiac events' risk, indicating coronary atherosclerosis presence and extension [41]. In addition to pro-inflammatory cytokine action and increased plasminogen activator-1 levels, the presence of insulin resistance (a common condition in visceral obesity) promoted by free fatty acids increases atherosclerotic plaque's atherogenesis and instability, further increasing the tissue's inflammatory process [42]. Such findings may explain the excessive cardiovascular risk in patients with visceral adiposity and improve risk stratification, helping to identify viscerally obese patients at high risk of cardiovascular events and apply lifestyle modification strategies and pharmacological interventions [28].

Journal of Aging Research
Low adiponectin levels and increased lipotoxicity present in individuals with visceral obesity may also explain the relationship between VAT and acute pancreatitis manifestation [9]. Natu et al. [26] noted that the VAT area was significantly larger in individuals with severe pancreatitis than in those with mild or moderate disease. ose with an increased VAT area had a higher incidence of persistent systemic inflammatory response syndrome, acute necrotic collections, and multisystem organ failure. With each 25 cm 2 increase in the VAT area, the probability of a severe episode rose by 20%. ese findings suggest that an increase in the VAT area is a strong predictor of severe pancreatitis, necrosis, systemic inflammatory response syndrome, and multisystem organ failure.
VAT accumulation is also associated with outpatient ischemic colitis development. According to Aoki et al. [24], even when BMI was considered simultaneously, colitis remained associated with abdominal obesity, suggesting that the primary mechanisms for developing ischemic colitis are atherosclerosis and inflammation potentiated by VAT accumulation. As previously discussed, VAT tends to stimulate the release of cytokines (such as IL-6 and TNF-a) and hormones that can lead to systemic inflammation, thereby increasing coagulation and adhesion molecules, contributing to atherosclerosis formation [43]. Visceral obesity also correlates with metabolic syndrome-characterized by hypertension, diabetes mellitus, and dyslipidemia, all risk factors that also contribute to atherosclerosis-and increases plasminogen activator inhibitor-1 levels, making abdominal visceral fat a potential risk factor for mesenteric artery thrombosis [44].
Another association found in this systematic review was between depression and VAT accumulation. Depressive symptoms correlated with intra-abdominal fat and women's proportion of visceral and total adipose tissue area after controlling for confounding factors, such as BMI, hypertension, and diabetes. In men, diabetes mellitus presence and high BMI significantly correlated with depressive symptoms. According to the study, for every 1 cm 2 of VAT area in women, the risk of individual inclusion in the clinically depressed group increases by 1.006 times, whereas for a 1% increase in the visceral and total adipose tissue area ratio, the risk of being clinically depressed increases 1.028 times [27]. Some hypotheses might explain the connection between VAT and depressive symptoms, such as the hormone cortisol action [45], the hypothalamic-pituitary-adrenal axis deregulation [46], the inflammatory process originating from adipose tissue [47], and insulin resistance, common in individuals with high VAT [48]. High triglyceride levels, low HDL-c (low-density lipoprotein) levels, high blood pressure, and high glucose levels can also contribute in some way to the association of VAT with depression [49].
Another three articles analyzed correlated VAT with the outcome of invasive procedures such as nephrectomy, radical retropubic prostatectomy, and cecal insertion. When analyzing individuals that underwent colonoscopy for colorectal cancer detection/monitoring, Nagata et al. [30] observed that VAT's relative distribution might also have different effects on the risk of more prolonged cecal insertion time. However, the excessive SAT accumulation has demonstrated a better predictive factor for easier colonoscope passage, even in patients with average weight. A possible explanation is that a larger SAT area may provide resistance and help prevent sigmoid looping [50].
Obesity also significantly affects the performance of radical retropubic prostatectomy, which may be associated with the severity of post-prostatectomy incontinence and favorable surgical margin rates [51]. In this context, Ongun et al. [31] observed that an elevated VAT area might impact the trifecta failure in individuals undergoing radical retropubic prostatectomy, as well as the presence of positive surgical margins, higher prostate-specific antigen (PSA) levels, lower prostate volume, and narrower prostate width in older individuals. ese findings suggest that the pelvic and VAT biometric measurements may help preoperative planning and prostatectomy management.
Obesity can be an independent risk factor for developing chronic kidney disease (CKD) and hypertension [52]. According to Hori et al. [29], the preoperative VAT distribution and nutritional status may predict postoperative renal function in living donors more than the BMI. Moreover, donors with preoperative hypertension tend to have a VAT area ≥80 cm 2 , hinting at obesity being a risk factor for hypertension. Hence, living donors' preoperative management regarding visceral obesity, hypertension, and nutritional status may lead to better results and help maintain renal function after donor nephrectomy.
Among the studies analyzed, three articles showed an association between muscle mass and visceral adiposity. e primary approach was toward sarcopenia, a clinical condition resulting from the involuntary loss of skeletal muscle with or without losing body fat from a disease [53]. Sarcopenia is a common condition in individuals over 70 and patients with advanced cancer, contributing to death in almost all cancer patients by enhancing their sensitivity to chemotherapy toxicity and increasing the risk of developing postoperative complications [54,55].
Visceral obesity and sarcopenia are relatively common in individuals diagnosed with colorectal cancer [56]. Although there is evidence that obesity is associated with worse health-Journal of Aging Research related quality-of-life outcomes in colorectal cancer survivors, van Roekel et al. [33] found no significant association between visceral obesity and sarcopenia with long-term health-related quality of life in survivors of colorectal cancer in stages I to III. In contrast, Malietzis et al. [57] observed an association of these body parameters with worse clinical results and short-term survival. ese results suggest that interventions targeting patients with colorectal cancer with unhealthy body composition at the time of diagnosis may be favorable for improving clinical outcomes and short-term survival but may not be essential for improving the quality of life related to long-term health [58]. e amount of visceral adipose tissue also appears to impact patients with pancreatic cancer, although sarcopenia also correlated with poor results in several other types of cancer [59]. Low attenuation of muscle radiation was associated with reduced survival after pancreatic surgery. In contrast, elevated VAT was associated with the risk of infections at the surgical site in patients with pancreatic head cancer, showing the importance of preoperative body composition analysis to reduce risks [32]. e increased risk of infection may be related to wound healing and tissue oxygenation problems, common in individuals with visceral obesity in which arterial function and angiogenesis tend to be impaired [60]. e association of obesity with sarcopenia, called sarcopenic obesity, was the only independent risk factor for 30day mortality in critically ill patients with intra-abdominal sepsis, indicating the need for sarcopenic obesity assessment as part of the risk analysis in patients critically ill with intraabdominal sepsis [34].
Sarcopenia and visceral obesity are considered multifactorial syndromes with various causes and interconnected feedback mechanisms acting in synergy [61]. Sarcopenia induces a decline in the basal metabolic rate and, consequently, reduces energy expenditure, leading to visceral obesity [62]. e increase in VAT secretes more pro-inflammatory cytokines and induces chronic inflammation, contributing to sarcopenia's development and progression [63].
As for biochemical parameters, body composition and adipose tissue distribution are critical conditions in assessing the link between obesity and adverse metabolic outcomes [12]. VAT is highly lipolytic and performs direct drainage to the liver, promoting an excessive flow of nonesterified fatty acids [64]. is phenomenon triggers changes such as verylow-density lipoprotein (VLDL-c) overproduction and, indirectly, low-density lipoprotein (LDL-c) overproduction, and a decrease in high-density lipoprotein (HDL-c) levels that might result in hypertriglyceridemia (high triglyceride levels in the bloodstream), hypercholesterolemia (high cholesterol levels in the bloodstream), and atherogenesis (fatty plaque formation in the arteries) [65]. VAT strongly correlates with the tests' results for triglycerides, VLDL-c, and uric acid in older adults, indicating a direct association between them [11]. In contrast, VAT has a low correlation with total cholesterol and LDL-c and an inverse correlation with HDL-c in both sexes. Compared with younger women, older women showed an increase in all biochemical parameters (glycemia, triglycerides, total cholesterol, LDL-c, VLDL-c, and uric acid), except HDL-c [11].
On the other hand, Sadeghi et al. [12] observed that in patients without coronary heart disease (CD), VAT had a better correlation with dyslipidemia, while in individuals with CD, waist circumference and waist-to-height ratio were better correlated with dyslipidemia. In individuals without CD, apolipoprotein A (apo A) had the highest levels, and VAT positively correlated with LDL-c, triglycerides, and apo B and inversely correlated with HDL-c. After adjusting the correlation between adiposity and lipid profile measures, individuals without CD showed an association of VAT with total cholesterol, LDL-c, triglycerides, and apo B and were inversely associated with HDL-c, regardless of the age of sex.
Triglycerides represent 99.0% of circulating fat and are substrates for the VLDL-c formation. erefore, elevation in its concentrations is almost always accompanied by hypercholesterolemia. Reduced HDL-c serum levels, present in approximately 10.0% of the population, might be unable to eliminate excess cholesterol from the vascular walls, as it presents antiatherogenic and antioxidant effects. Notwithstanding, studies suggest evaluating cholesterol as an index and not in isolation; e.g., the total cholesterol/HDL-c ratio is considered a potent predictor for coronary heart disease due to a probable high atherogenic effect [11,66].
Concerning uric acid, evidence points to it as a risk factor for hypertension, dyslipidemia, and glucose metabolism disorder, and it also may have a causal role in cardiovascular disease pathogenesis. However, its correlation with VAT has not yet been fully elucidated [67].
Recent studies have reported an association between amylase and obesity owning to the salivary amylase gene expression ability to predict obesity in humans [68]. Curiously, Dias and [35] observed that serum amylase is more strongly associated with VAT than SAT and BMI. Low amylase serum levels have also correlated with an increase in diabetes and metabolic syndrome cases [69]. A possible explanation for this is that saturated fatty acids stimulate pancreatic amylase release in a dose-dependent manner. However, excess circulating free fatty acids can inhibit serum amylase secretion stimulation due to a feedback loop in pancreatic cells [70]. Another explanation is the influence of insulin resistance since stimulation of amylase's secretion and synthesis occurs in response to insulin binding to its receptor in pancreatic acinar cells. If there is a resistance, such as a connection not occurring, it may reduce amylase secretion [71]. Excessive free fatty acids levels can also impair insulin receptor activity due to the accumulation of these fatty acids' metabolic by-products [70]. e findings, in general, confirm the importance of investigating VAT the strong correlation with serum biochemical parameters. However, biochemical tests are risk indicators for diseases but are not diagnostic and should be associated with complementary information such as medication use, comorbidities, lifestyle, and other factors associated with metabolic changes [11].
is review's main strength is that, to our knowledge, this is the first review that addresses the association of VAT with health problems and biochemical tests in an older adult population. Notwithstanding, there are some limitations to our study. For instance, our inclusion/exclusion criteria limited the articles reviewed as it excluded articles without open access, outside the scientific publication community, and published in other languages, which could change the results and generate some publication bias. Another limitation was the impossibility of conducting a meta-analysis due to the immense heterogeneity in the research projects and objectives among the selected studies.

Conclusions
Knowledge of age-related changes in body composition and fat distribution is essential to understand the association between obesity, morbidity, and mortality in a population's age group. Increased visceral adipose tissue (VAT) area is considered a risk factor for cancer onset and cardiometabolic and biochemical changes. A better understanding of how visceral obesity correlates with health problem development can contribute to the emergence of promising intervention strategies. In this context, visceral obesity must be treated as a public health problem, highlighting the need for further studies, especially for the older adult population, to provide healthy aging.
Data Availability e article's data supporting this review are from previously reported studies and datasets, which have been cited. e processed data are available in Virtual Health Library (https://bvsalud.org/).