The Effect of Nutrition on Aging—A Systematic Review Focusing on Aging-Related Biomarkers

Despite the increasing life expectancy, an individual’s later years tends to be accompanied by a decrease in the quality of life. Though biological changes that occur through the natural process of aging cannot be controlled, the risk factors associated with lifestyle can. Thus, the main goal of this systematic review was to evaluate how nutrition can modulate aging. For this purpose, thirty-six studies were selected on (i) the efficiency of nutrition’s effect on aging, (ii) the evaluation of biomarkers that promote healthy aging, and (iii) how to increase longevity through nutrition, and their quality was assessed. The results showed that choosing low carbohydrate diets or diets rich in vegetables, fruits, nuts, cereals, fish, and unsaturated fats, containing antioxidants, potassium, and omega-3 decreased cardiovascular diseases and obesity risk, protected the brain from aging, reduced the risk of telomere shortening, and promoted an overall healthier life. With this study, the conclusion is that since the biological processes of aging cannot be controlled, changing one’s nutritional patterns is crucial to prevent the emergence and development of diseases, boost longevity, and, mostly, to enhance one’s quality of life and promote healthy aging.


Introduction
Aging is the gradual process of natural changes that occur throughout the human lifespan. This process begins in early adulthood; throughout the years, many mental and bodily functions begin to slowly decline, resulting in health issues, such as increased morbidity and decreased fertility [1][2][3]. Over the years, life expectancy has risen, with approximately 8% of the world population being over 65 years old, and in approximately 30 years, this number is expected to double [4]. However, this does not necessarily mean that people experience better health in their later years when compared with other generations [5,6].
In fact, despite the life expectancy increase, aging is a mechanism that has multifaceted features that are linked: molecular, cellular, physiological, and functional levels that ultimately lead to chronic diseases [7]. At the molecular level, aging is represented by genomic instability, telomere attrition (as they tend to shorten), epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication, which are believed to be decisive to determine one's lifespan [8]. These risk factors might impact the cellular level by deregulating signaling; thus, causing cellular senescence and mitochondrial dysfunction [9]. Consequently, the physiological and functional levels weaken, triggering the development of chronic inflammation, alterations in energy metabolism, such as variations in insulin sensitivity, undermining neuronal [10], and sensory functions, mainly visual, auditory, and touching (or movement) [11,12]. On a physical level, hair normally turns white, thinner, and takes longer to grow, and the skin becomes less elastic and more wrinkled, as a result of less efficient vitamin D synthesis [13]. Moreover, there are some factors that are usually associated with specific disorders that might appear: hyperglycemia, hypercholesterolemia, and hypertension [14]. Altogether, these effects give rise to numerous age-associated disorders that result from these alterations, such as sarcopenia, represented by the decline in skeletal muscle mass, and, therefore, weakening physical functioning, which is derived from chronic inflammation, hormonal changes, cell dysfunction, an unhealthy diet, lack of physical activity [15], neurodegenerative diseases, heart diseases, diabetes, and cancer [16,17].
Despite the biological changes associated with aging, there are risk factors, such as lifestyle and dietary patterns [18,19], which, if altered, can promote healthy aging, and are characterized by the development and maintenance of the functional abilities that enable one's wellbeing [20]. Healthy lifestyles promote the maintenance of cognitive abilities and boost the immune system [18,19,21,22]. Studies show that adoption of a Mediterranean diet, characterized by a decreased consumption of saturated animal fat and red meat and a higher intake of fruits and vegetables, along with maintaining a healthy weight and reducing salt intake [23][24][25][26], and lifestyle changes, such as engaging in physical and social activities and reducing smoking and alcohol consumption, can significantly modulate the inflammatory state of the body. Consequently, general health improves throughout the diverse stages of life [23,27,28]. It is also believed that these key factors may be viewed from a life-course perspective since a change of these routines can shape the rate at which human cells or organs enter in senescence, delay the onset of chronic diseases, and promote mobility, mental function, and wellbeing [23,29]. However, the main "gaps" remain as to what types of diets or what food components could actually improve healthy aging, and what biomarkers are modulated by the diet and associated with chronic diseases, in order for them to be considered more when evaluating or preventing the incidence of these diseases.
To address these gaps, the main goal of this systematic review was to perceive the quantity and quality of different diets or aspects in nutrition, how they could modulate biomarkers and prevent aging-related diseases, in order to enlighten new intervention strategies. Biomarkers that are linked to aging-associated metabolism, inflammation processes, cognitive decline, and telomere attrition were scrutinized in order to understand how these mechanisms could actually influence healthy aging. Moreover, it could provide information to future health professionals.

Protocol and Registration
This systematic review followed the PRISMA statement guidelines, and it was recorded in the international database of prospectively registered systematic reviews (PROSPERO)registration number CRD42021244473 [30].

Search Strategy and Inclusion Criteria
For this systematic review, searches were conducted in PubMed scientific databases on 28 February 2021.
The search was conducted by two independent researchers, and it was primarily designed to spot relevant studies on the efficacy of nutrition's effect on aging, on the evaluation of molecules that promote healthy aging, and on how to increase longevity through nutrition. The following keywords and their equivalents were used in PubMed: "(diet* OR nutri*) AND (age OR ageing OR aging OR old OR older OR elder*) AND (marker OR biomarker) " The selection criteria applied in this review were the following: (1) language: documents had to be published in English; (2) published studies from 1 January 2010 to 28 February 2021; (3) participants/population: adults/humans; (4) types of studies to include: randomized and non-randomized trials (including clusters-randomized and clustersnon-randomized), and observational studies (including case control, cross sectional, cohort, before and after, and interrupted time series). Study protocols, reviews, systematic reviews, and meta-analysis were excluded. The included studies assessed the importance of a healthy diet in order to ensure healthy aging through the study of the molecules involved. All studies that mentioned this impact were considered.
All titles retrieved from database were reviewed independently; the inclusion and exclusion criteria were applied by two independent researchers (A.M. and C.L.) and validated by a third researcher (M.E.) in cases where there was no consensus.
All studies were scored from 0 to 10, based on the sum of the scores for each parameter and it was evaluated by two independent researchers (A. M. and C. L.). Higher scores indicate higher quality research.

Data Extraction and Analysis
The articles that met the inclusion criteria were summarized in a table for: author and publication year; study design, country, setting, study population, sample size, participants' characteristics, and the main results and involved biomarkers. Two independent researchers (A.M. and C.L.) extracted data and compared their findings. In cases of disagreement, a third reviewer (M.E.) served as a referee to help reach an agreement.

Study Selection
The search strategy involved retrieving 9709 citations from PubMed-MEDLINE database, the eligible articles were carefully chosen based on the title and abstract. In the first version of this systematic review, five studies were selected. Despite these studies not appearing in the chosen string of keywords, they were present in the bibliography of the studies identified from the database. Those studies were first selected on the title, resulting in 1264 studies, and after selection based on the abstract, 163 studies were analyzed. These 163 studies were evaluated based on their full-texts, in which 31 were deemed suitable for inclusion in the current review   (Figure 1).

Quality Assessment
The quality of all of the included studies was assessed [31]. The median score for all of the studies was 6/10.

Influence of Different Types of Diet on Biomarkers
All of the studies aimed to evaluate the nutritional state, as described in our main goal. Besides the nutritional state, eight of the studies also considered telomere length [32,36,37,39,58,62,64,66] and five of the studies evaluated nutritional state effects in cognitive decline [33,50,52,53,65]. The main molecular outcomes and the tested biomarkers are described in Table 2.
The ketogenic diet (KD) reduced CVD risk by improving CVD biomarkers ( Figure 2) in T2D patients and decreasing inflammation [55]. It also prevented brain aging ( Figure 3) by avoiding the destabilization of brain network and network switching [52]. Network stability is represented by the ability of the brain to maintain functional communication between its regions, and when this process is affected, network switching occurs from the largescale reorganization of the network modules. Moreover, the Mediterranean diet (MedDiet) regulated the relationship between genetic risk factors and cognition [50], protecting participants with specific variants of the CR1 gene (without A minor allele of the rs3818361), the CLU gene (with T minor allele of the rs11136000), the PICALM gene (with T minor allele of the rs3851179), and both non-ApoE4 and ApoE4 carriers. Variations in this diet, such as the modified Mediterranean-ketogenic diet (MMKD), prevented cognitive decline ( Figure 3) in adults with Alzheimer's disease (AD) risk, by increasing amyloid-beta 42 (Aβ42) and decreasing tau expression [53].
The modified Alternative Healthy Eating Index (mAHEI) was used to assess diet quality in an older Chinese population, considering consumption of fruits, vegetables, soy protein, fish/meat/eggs, whole grain, fried foods, and alcohol [65]. In this study, a high diet quality combined with a varied vegetable intake was linked to a lower risk of cognitive decline (Figure 3). Daily intake of green tea catechins demonstrated beneficial effects on working memory in adults, by decreasing the commission errors in the continuous performance test (CPT), and the time response in the 4-part CPT (FPCPT) [33].
The MedDiet demonstrated beneficial effects in several key points. The role of the dietary inflammatory index (DII) used this diet in telomere shortening (Figure 3) [37]. An anti-inflammatory diet, rich in antioxidants, could reduce the rate of telomere shortening, by improving telomerase activity [62] in individuals at high risk of CVD [37,39,62,66]. In addition, diets rich in fibers, vegetables, and fruits, and poor in meat, dairy products, and PUFAs, as well as waist circumference (WC) reduction, are beneficial in improving leukocyte telomere length (Figure 3) [39,58,64]. In contrast, consumption of ultra-processed foods (UPFs) and processed meat was negatively associated with MedDiet adherence, and it was positively related with a higher risk of having shorter telomeres (Figure 3) [32,36,63]. UPF was also linked to an increased risk of CVD, ischemic heart disease (IHD)/cerebrovascular disease, and all-cause mortality (Figure 3) [63].
Cardiovascular risk factors ( Figure 2) were also attenuated in the presence of a dietary approach to stop hypertension (DASH) pattern, decreasing the levels of fibrinogen, insulin, and diastolic blood pressure (DBP) [45]. In contrast to a Western diet-like high-fat (WDHF) and a Western diet-like high-carbohydrate (WDHC), MedDiet meals promote positive effects on glycemic insulinemic, and lipemic responses (Figure 2), due to lower levels of glucose, insulin, triglycerides, and non-esterified fatty acids (NEFAs) [56]. The ketogenic-Mediterranean diet, supplemented with phytoextracts (KEMEPHY), also led to reductions in weight, BMI, WC, % fat mass, total cholesterol, LDL-C, triglycerides, and blood glucose, and increases in HDL-C [54].
A healthy Nordic diet reduced non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio, apolipoprotein B (ApoB)/ apolipoprotein A1 (ApoA1) ratio, and interleukin-1 receptor antagonist (IL-1 Ra), improving lipid profile (Figure 2), and having a beneficial effect on low-grade inflammation [59]. The Southern European Atlantic diet (SEAD), a common diet in the Iberian Peninsula, enabled reduced concentrations of C-reactive protein (CRP), triglycerides, and insulin, which could help prevent myocardial infarction [40]. Diets rich in potassium intake attenuated CVD risk ( Figure 2) since they prevented cardiomyocyte injury, through high-sensitivity cardiac troponin T (hs-cTnT) and cardiac dysfunction, through N-terminal pro-B-type natriuretic peptide (NT-proBNP) [49]. A restricted-calorie diet (RCD), allied to daily consumption of grape seed extraction (GSE), improved blood lipid profile and helped ameliorate some CVD risk factors (Figure 2), by reducing LDL-C, total cholesterol, the triglycerides visceral adiposity index, and the plasma atherogenic index. Moreover, it promoted higher levels of HDL-C and HDL-C/LDL-C ratio in obese or overweight adults [60]. A low-fat highcarbohydrate (LFHC) diet reduced weight, fat mass, fasting leptin, and adiponectin levels, when compared to a moderate-fat diet (18% protein, 36% fat, 46% carbohydrate) [57].
In older adults, a low-fat diet rich in fibers, improved periodontal disease markers, such as clinical attachment loss (CAL), bleeding on probe (BOP), probing depth (PD), and gingival crevicular fluid (GSF), as well as on the metabolic profile (body weight, hs-CRP and glycated hemoglobin) [48].
Fruit consumption, both in fruit or in juice, reduced several cardiometabolic risk factors (Figure 2), such as BMI, WC, glucose levels, and LDL-C in elders with metabolic syndrome [44]. Fruit-based anthocyanins also mitigated the negative effects of a high fat high energy (HFHE) diet, by decreasing inflammatory biomarkers, such as CRP and interleukin-6 (IL-6) [67]. Table 2. Summary of the included studies' results of outcomes related to molecular output and related biomarkers.

Authors (Year) Main Results Biomarkers and Outcomes
Alonso-Pedrero, Lucia at al., 2020 [32] Higher consumption of UPF (>3 servings/d) presented higher risk of having shorter telomeres in an elderly Spanish population.
Participants with >3 servings/day of UPF consumption: higher short telomere risk (p = 0.032), higher family history of CVD (p = 0.045), and diabetes and dyslipidemia prevalence (p = 0.014); higher consumption of fats, SFAs, sodium, sugar-sweetened beverages (SSBs), fast food, and processed meat (p < 0. MedDiet and low-fat diet in patients with T1D and MetS could help with weight loss, with no significant changes in anthropometric and metabolic parameters between regimens. BMI, WC, weight, and triglycerides: decreased overtime with both diets (p < 0.05).
Fretts, Amanda M. et al., 2016 [36] Processed meat, but not unprocessed red meat consumption, was linked to a shorter LTL.
García-Calzón, Sonia at al., 2015 [37] Diet, through proinflammatory or anti-inflammatory pathways, could be a fundamental predictor of telomere length. MedDiet + CoQ promotes urine metabolites excretion, reducing oxidative stress. Metabolites excreted after SFA diet are linked to increased oxidative stress.

Gu, Yian et al., 2015 [39]
Among whites, greater adherence to a MedDiet was significantly connected with longer LTL. In addition, eating a diet rich in vegetables and poor in meat, dairy, or cereal might contribute to longer LTL.
Higher SEAD adherence: lower plasma CRP, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), urine albumin, and SBP (p-trend < 0.001), triglycerides (p-trend = 0.012), urine albumin/creatinine ratio (p-trend < 0.034).  In comparison to the harmful activity of an SFA diet, which initiates the p53-dependent DNA repair mechanism, the MedDiet diet and MedDiet + CoQ10 have beneficial effects on DNA damage. Becerra-Tomás, Nerea et al., 2021 [44] In older adults with MetS, increased total fruit consumption is linked with lower WC, plasma glucose and LDL-C levels, as well as higher SBP and DBP. Total and natural fruit juice consumption was associated with reduced WC and glucose levels.
Jalilpiran, Yahya et al., 2020 [45] Inverse correlation between the DASH and MedDiet patterns and several cardiovascular risk factors.
Kanerva, Noora et al., 2014 [46] Lower hs-CRP levels are due to the Baltic Sea diet.
BSDS: inverse association with hs-CRP (p < 0.01), contributed mainly by high intake of Nordic fruits and cereals, low intake of red and processed meat, and moderate intake of alcohol (p < 0.05).

Authors (Year) Main Results Biomarkers and Outcomes
Khalatbari-Soltani, Saman et al., 2020 [47] Adherence to the MedDiet decreased hepatic steatosis risk based on the FLI, in addition to the existing evidence of reducing CVD risk. When different parameters for determining the NAFLD score were used, no connection was found.
Adherence to MedDiet: lower risk of hepatic steatosis based on FLI (p-trend < 0.006), after adjustment for BMI (p-trend = 0.031) and after adjustment of BMI and WC (p-trend = 0.034).

Kondo, Keiko et al., 2014 [48]
Treatment with a high-fiber, low-fat diet for 8 weeks effectively improved periodontal disease markers and metabolic profiles, at least in part, by mechanisms effects other than caloric restriction. Higher EDI was associated with lower risk of being overweight or obese, as well as having LDL-C levels. However, in elderly men, there was no significant association between EDI and other CVD risk factors.
Mujica-Parodi, Lilianne R. et al., 2020 [52] Destabilization of brain networks may be an early sign of hypometabolism, which is linked to dementia. Dietary interventions that result in ketone utilization increase available energy and, as a result, may have the potential to protect the aging brain.

Biomarkers and Outcomes
Neth, Bryan J. et al., 2020 [53] MMKD may help prevent cognitive decline in adults at risk of Alzheimer's disease (AD) risk, by improving cerebral spinal fluid (CSF) AD biomarker profile, peripheral lipid and glucose metabolism, cerebral perfusion and cerebral ketone body uptake.
Paoli, Antonio et al., 2011 [54] The KEMEPHY diet resulted in weight and WC loss, as well as improvements in cardiovascular risk markers.
Bhanpuri, Nasir H. et al., 2018 [55] After a year, CCI improved the majority of biomarkers of CVD risk in T2D patients. The increase in LDL-C seems to be restricted to the large LDL subfraction. LDL particle size increased, while total LDL-P and ApoB remain unchanged, and inflammation and BP decreased.
Tiainen, A-MK. et al., 2012 [58] Fat intake is inversely associated with LTL whereas vegetable intakes were positively associated with LTL.

Biomarkers and Outcomes
Yousefi, Reyhaneh et al., 2020 [60] When combined with a calorie-restricted diet, daily consumption of 300 mg GSE improved LDL-C, HDL-C, visceral adiposity index (VAI), and atherogenic index of plasma (AIP) and helps to ameliorate some CVD risk factors in obese or overweight individuals.

Yubero-Serrano, Elena M. et al., 2012 [61]
The anti-inflammatory effect of a MedDiet rich in olive oil and exogenous CoQ supplementation has an additive effect in aged men and women, regulating the inflammatory response and ER stress, indicating that a MedDiet + CoQ is helpful for healthy aging. Lower telomere shortening and higher Peripheral blood mononuclear cells (PBMCs) TA may play a role in lifespan and, more importantly, health span in populations consuming traditional MedDiet.
Bonaccio, Marialaura et al., 2021 [63] Higher levels of UPF were linked to increased risk of CVD and all-cause mortality, partly due to its high dietary content of sugar.
Intake of UPF: lower adherence to the MedDiet and intake of fiber (p < 0.001); higher energy intake, fat, sugar, dietary cholesterol, and Na + (p < 0.001); increased risks of CVD mortality LTL, which is a putative biomarker of chronic disease risk, is associated with body composition and dietary factors.

Biomarkers and Outcomes
Chou, Yi-Chun et al., 2019 [65] In older adults, a high-quality diet containing a variety of vegetables was linked to a lower incidence of cognitive decline.
High diet quality with high vegetable diversity: lower risk of global cognitive decline (p-trend = 0.03) and of decline of attention domain (p-trend = 0.049); lower risk of global cognitive decline (p-trend = 0.03) in elders.
Crous-Bou, Marta et al., 2014 [66] Longer telomeres were associated with greater adherence to the MedDiet. These results further support the benefits of adhering to this diet in terms of promoting health and longevity.
MedDiet score: proportional with TL (p = 0.016); higher in women with lower BMI (p = 0.01), who smoked less, had higher intake of total energy, were more physically active; higher with vegetables, fruits, grains, fish, nuts, and total fat intake, as well as lower meat intake (p < 0.001); TL: longer in younger women (p < 0.001); shorter in women who smoked more (p = 0.02); LTL: longer with AHEI (p = 0.02).
do Rosario, Vinicius A. et al., 2020 [67] In overweight older individuals, fruit-based anthocyanins attenuated the potential negative postprandial effects of a HFHE challenge on vascular and microvascular function, as well as inflammation biomarkers.
A Nordic alternative to the MedDiet, the Baltic Sea Diet, was evaluated regarding inflammation markers (Figure 3), and a reduction of high-sensitivity C-reactive protein (hs-CRP) was noted [46]. Consumption of a MedDiet supplemented with virgin olive oil (MedDiet + VOO) demonstrated protective effects on the bones (Figure 3), by increasing serum osteocalcin [34].

Discussion
This systematic review was accomplished to, first, demonstrate how different diets or different aspects in nutrition impact aging-related diseases, and second, to pinpoint putative molecular markers that change with diet and nutrition along aging. The results of the studies analyzed in this systematic review show that avoiding unhealthy habits, mainly concerning diets, may improve life quality and promote healthy aging (Figures 2 and 3).
The diets studied in this systematic review presented diverse similarities. KD is a low-carbohydrate diet, whereas MedDiet is based on low consumption of saturated animal fat and red meat, and a high intake of fruits, vegetables, fish, olive oil, nuts, and vitamins [68]. The DASH diet pattern is very similar to MedDiet, since it is rich in the same products and poor in SFAs, added sugars, sodium, and refined carbohydrates [69]. The KEMEPHY diet maintains the use of vegetables and olive oil just like the MedDiet [70], but presents elevated ketone bodies in the blood or urine [71]. The SEAD is represented by high intakes of fresh fish, red meat, and pork products, legumes and vegetables, vegetable soup, potatoes, dairy products, whole-grain bread, and wine [40]. The Baltic Sea diet is described as a variant of the MedDiet with healthy Nordic foods [72]. The healthy Nordic diet is based on the consumption of whole-grain products, abundant intake of berries, fruits, and vegetables, rapeseed oil, three fish meals per week, low-fat dairy products, and a reduction of sugar-sweetened products [59]. The MMKD is a very low-carbohydrate diet that is modeled on a MedDiet, emphasizing protein sources low in saturated fat (fish, lean meats), healthy fats, fruit and vegetable consumption, whole grains, and a glass of wine per day [53].
The adoption of a KD reduced CVD risk, by improving CVD biomarkers (Figure 3) in T2D patients, and decreased inflammation [55,[73][74][75]. Since inflammation has a role in every facet of CVD pathogenesis [76] and hs-CRP and WBC count are well-established markers of inflammation and risk factors for CVD [77,78], the decrease of these markers in the CCI indicated that inflammation was diminished after 1 year of intervention. KD also protected brain aging (Figure 2) by avoiding the destabilization of the brain network, which is what happens when glucose is used as fuel [52]. These stabilizing effects of nutritional ketosis were replicated when exogenous ketones were administrated, suggesting that they were specifically due to glucose metabolism rather than ketone body metabolism [52]. Furthermore, it supports the hypothesis that there are some beneficial neural effects associated with the hypocaloric state; intermittent fasting and severe caloric restriction may result from the use of ketone bodies by the brain [79].
The MedDiet modulated the impact of genetic risk factors on cognition (Figure 3) [50]. The variants studied have been associated as risk factors for AD [80][81][82] and cognitive decline, mainly with poor memory performance in population-based studies [83,84]. The MedDiet has already been revealed as protective in cognitive functioning [85], cognitive decline [86], and the development of mild cognitive impairment and dementia [87,88]. Daily intake of green tea catechins also demonstrated beneficial effects on the working memories in adults [33,89,90]. The MMKD prevented cognitive decline (Figure 3) in adults with Alzheimer's disease (AD) risk, by increasing Aβ42 and decreasing tau expression [53]. Moreover, a high diet quality that prioritizes foods that are the base of the KD and MedDiet, allied to a diverse vegetable intake, was linked to a decrease of cognitive decline risk [65]. This was supported by previous studies that demonstrated that dietary interventions had a huge impact on cognitive deterioration [91]. Additionally, this protective effect may be due to individual characteristics of foods. Antioxidants and phenolic compounds can minimize oxidative damage and inflammation, and boost neuronal antioxidant defenses [92,93].
The MedDiet was used to assess the role of DII in telomere shortening, proving that an anti-inflammatory diet or one rich in antioxidants could reduce the rate of telomere shortening in individuals at a high risk of CVD [37]. Studies that evaluated adherence to the MedDiet achieved the same conclusions [39,62,66,[94][95][96][97].
Higher consumptions of vegetables [58] and diets rich in fibers [39,64] were also positively associated with leukocyte telomere length, as well as lower WC, whereas SFAs were negatively linked [58]. Thus, an anti-inflammatory diet can avoid telomere shortening and, consequently, reduce the impact of aging and cancer development [98]. In contrast, consumption of UPF and processed meat was linked to an increased risk of having shorter telomeres [32,36]. UPFs are industrial formulations of food-derived substances (oils, fats, sugars, starch, protein isolates) that include flavorings, colorings, emulsifiers, and other cosmetic additives [32]. UPFs have been linked with several diseases, such as hypertension [99], obesity [100], MetS [100], T2D [101], and cancer [101]. Higher total intakes of salt, saturated fat, and sugar, as well as inadequate intakes of fiber and minerals, could explain the association between UPF consumption and the risk of developing short telomeres. [102].
The MedDiet [35,47,56], or its components [44,67], RCD, allied to daily consumption of GSE [60], DASH patterns [45], LFHC diet [57], the Baltic Sea diet [46], the Nordic diet [59], SEAD [40], the KEMEPHY diet [54], or the use of EDI scores to assess MedDiet adherence [51], promoted decreased inflammatory markers and improved cardiometabolic risk factors (Figure 2), including components that belong to MetS. MetS is one of the most significant risk factors associated with CVD [103,104] and it is defined as having at least three of the following characteristics: (i) central obesity, (ii) increased serum triglyceride levels, (iii) low HDL levels in the blood, (iv) cholesterol levels, (v) hypertension, and (vi) higher fasting blood glucose levels [104]. Since these diets are very similar, this might explain the similar results. In several studies, researchers note that the MedDiet is able to prevent CVD [24,26,68,105]; this effect is due to the combination of different foods that have anti-inflammatory properties. The DASH diet pattern was already established as a potential treatment for hypertension [106], to reduce both fasting and postprandial insulin concentrations [107], and CRP levels [108,109]. The KEMEPHY diet, by inducing a physiological ketosis through elevated ketone bodies present in blood or urine [71], stimulates positive changes in cardiovascular risk factors and body composition [110].
SEAD, just like the MedDiet, is rich in folate and vitamin C from vegetables, as well as omega-3 fatty acids from fish; these compounds have already been connected with reduced insulin [111,112] and low hs-CRP [113]. This inflammatory marker was also reduced in this diet, suggesting that it may reduce CVD risk (Figure 2). The Baltic Sea diet also promotes the reduction of CRP concentrations (Figure 2), due to the presence of Nordic fruits and berries and cereals [46]. They contain antioxidant components, such as polyphenols, minerals, vitamins, and dietary fibers, which diminish these levels and the release of E-selectin [114,115]. This molecule is produced and released into circulation during endothelial injury, and its reduction improves endothelial function [115]. The healthy Nordic diet decreases IL-1 Ra [59], which is one of the most sensitive inflammatory markers, in obesity and MetS. It has been associated with high intakes of SFAs and lower consumption of berries, fruits, and whole-grain products [116][117][118]. Moreover, higher levels of IL-1 Ra have been revealed to predict T2D and the progression of MetS to T2D [116]. In addition, this healthy Nordic diet promotes the reduction of non-HDL-C and LDL-C, which are designated to have an important impact on CVD morbidity and mortality [119,120]. CVD risk is also attenuated by high intakes of potassium ( Figure 2) due to its nonlinear association with CVD biomarkers (Figure 2) [49,121,122], which is supported by previous studies [123][124][125], thus endorsing the World Health Organization (WHO) recommendation that adults increase their potassium intake [126]. In contrast, CVD, IHD/cerebrovascular disease, and all-cause mortality was linked to UPF consumption [63,[127][128][129].
The MedDiet, allied to a supplementation of CoQ, was shown to protect DNA from oxidative damage (Figure 3) by reducing the activation of p53 [41] and, consequently, the expression of genes involved in p53-dependent DNA repair were downregulated [42]. Previous studies demonstrated that DNA damage plays an important role in the pathogenesis of atherosclerosis (buildup of fats, cholesterol, and other substances in and on the artery walls), as well as other aging-related diseases [130]. As for diets rich in PUFAs-CoQ supplements have been shown to mitigate oxidative and lipid peroxidation chain reaction damage [131,132], regenerate other antioxidants, such as α-tocopherol and ascorbate [133][134][135], and reduce CVD risk and inflammation [131]. The fatty acid content of cellular membranes and fluids is linked to oxidative stress, so it was expected that MedDiet + CoQ helped prevent this event [136][137][138]. Furthermore, recent research has shown that changes in the expression of p53 and the p53-regulated DNA damage response genes, such as gadd45a and mdm2, can be used as genotoxic and carcinogenic stress markers [139,140]. This diet also has an additional influence on the inflammatory response and ER stress [61], since it reduces the p65, IKK-b, and IL-1b gene expression.
A low-fat diet rich in fibers has demonstrated protective effects on periodontal disease (Figure 3), by reducing its biomarkers in older adults [48]. This disease has already been associated with obesity [109,141]. Other studies reported on how weight reduction promotes a decrease in system inflammation, as well as a loss of adipose tissue [142], and since hs-CRP was decreased in this study, obesity and periodontal disease may be connected by inflammation [142].
In contrast, previous studies [143][144][145][146][147][148][149] have demonstrated that unhealthy habits, such as westernized diets (high intakes of red meat, processed foods, "fast-foods", high-fat dairy products, snacks, and sugary soft drinks, and low intakes of fruits, vegetables, vitamins, and minerals), lack of physical activity, alcohol consumption, or smoking can potentiate the risk of development of diabetes, obesity, cardiovascular diseases, and cancer. Thus, even in the absence of traditional CVD risk factors (smoking, T2D, high BP, and elevated levels of cholesterol), weight-loss strategies should always be recommended in order to keep a healthy body weight to decrease CVD and other comorbidities risk.
Despite the insights provided in this systematic review, there is still much information that needs further research. Designing proper diets and addressing new strategies to combine them with different types of physical activity should be further explored. Moreover, extending this type of research to the cancer field may help in the discovery of new biomarkers that can promote an early diagnosis and treatment or novel approaches to prevention.
This systematic review has several strengths, specifically, the extensive and systematic research of articles on the stated theme and information concerning the different effects of multiple diets. This study sought to compact different diets and food components that help decrease the prevalence and severity of several diseases, such as cardiovascular diseases, obesity risk, brain diseases, and even, delay the progression of cancer, through the reduction of telomere shortening. These results are of major importance to the development of new interventions in nutrition targeting aging-related biomarkers. However, this systematic review also presents some limitations. One of the limitations is the use of only one database (PubMed), which may have resulted in a failure to consider other potentially relevant articles on other databases. Another limitation was the difficulty to organize and structure the types of diets and biomarkers, since they present different effects. Finally, some of the biomarkers analyzed in this systematic review are not always valid for certain health outcomes, since they can be considered subrogated variables.

Conclusions
In conclusion, this systematic review demonstrated the necessity for individuals to improve their diets, to reduce the emergence and development of several comorbidities and promote healthy aging. Diets rich in vegetables, fruits, nuts, cereals, fibers, fish, unsaturated fats, containing antioxidants, vitamins, potassium, omega-3-and reducing red meat and UPF intake-could prevent obesity, CVD, and inflammation, and promote favorable glycemic, insulinemic, and lipidemic responses. Moreover, the MedDiet and KD, or a combination of these diets (MMKD), and increasing consumption of vegetables and green tea catechins, could improve one's working memory and decrease destabilization of the brain network and the attention domain, preventing cognitive decline. Finally, the MedDiet, supplemented with CoQ or VOO, or a low-fat diet, also rich in antioxidants, could help to decrease the prevalence of atherothrombosis, hepatic steatosis, diabetes, and telomere attrition, as well as prevent oxidative and DNA damage. These diets can enhance one's quality of life and increase life expectancy. Moreover, a putative panel of molecular markers (see Figures 2 and 3) would follow the impact of diet/nutrition alterations during aging.