Influence Of The Mediterranean Diet On Healthy Aging Part 3

5. Aging, Mediterranean Diet and Microbiome

5.1. Microbiome

The gastrointestinal tract is colonized by an array of microorganisms, including bacteria, viruses, fungi, and protozoa. These coexist symbiotically with enterocytes without being identified by the immune system as pathogens [333]. These microorganisms make up the microbiota, which consists of a total of 52 different phyla and up to 35,000 species of bacteria, mainly Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria [334].

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The intestinal microbiota has its origin in the placenta, with low levels of nonpathogenic bacteria, mostly Bacteroidetes, and Firmicutes. After birth, the intestine of the newborn and infant is rapidly colonized. Factors such as the type of delivery (vaginal or cesarean) or the type of feeding (breastfeeding or formula feeding) are determinants of the microbiota [333]. During the first three years of life, the microbiota has low diversity. After the third year, the microbiota is similar to that of the adult stage. With aging, changes occur in the morphology and function of the microbiota. Thus, after 65 years of age, the microbiota experiences a decrease in Firmicutes and Bifidobacterium, with an increase in diversity for Clostridium [28].

The changes produced throughout life could alter the diversity of the microbiota,  giving rise to metabolic and inflammatory alterations and causing the appearance of conditions such as inflammatory bowel disease or irritable bowel syndrome, among others [335]. Moreover, the microbiota has not only been linked to diseases of the gastrointestinal tract but also to other diseases such as obesity, diabetes, CVD, or cancer [336]. Since the concept of the “gut–brain axis” was created, the gut microbiota has also been linked to neurodegenerative diseases [337].

5.2. Interplay between Aging and the Microbiome 

The mechanisms by which the microbiota change with age are not fully understood. It is known that, in aging, physiological changes occur, such as alterations in dentition or decreased digestion and absorption, and modifications of lifestyle conditions, such as hospitalization or nursing homes. These modifications could be responsible, in part, for changes in diet and thus for the nutritional status of the elderly [338]. Moreover, in aging,  especially in respect of frailty, there is usually a reduction in the amount and variety of food, which leads to the appearance of malnutrition [339]. Diet seems to be one of the pillars of changes in the microbiota. The microbiota may modulate changes in aging-related to innate immunity, cognitive function, and sarcopenia, which are components of frailty syndrome [340]. Recent studies have suggested that loss of the gut microbiota is more related to age-associated frailty than to chronological age [341].

During the transition from adult to elderly, the main changes in the intestinal microbiota occur. Microbial diversity decreases compared to young adults [342]. In elderly centenarians, the microbiota consists mostly of Bacteroidetes and Firmicutes. However, in comparison with young adults, there are changes in subgroups such as Firmicutes, with an increase in Bacilli and a decrease in Clostridium. In addition, there is also an increase in Proteobacteria [343]. Intestinal dysbiosis mainly involves changes in the abundance of commensal bacteria, also including some that function as opportunistic pathogens. The importance of the dysbiosis phenomenon is that it stimulates the excretion of endotoxins, i.e.,  amyloid and microbial lipopolysaccharides, to promote intestinal wall permeability and increase the peripheral circulation of proinflammatory cytokines [344].

In the ELDERMET study, the microbiota was studied in elderly people living in a  community or living in long-stay homes in Ireland [338]. In the first group, microbiota configurations were more affected by antibiotic use than the microbiota of individuals in long-stay residences. However, this first group presented greater recovery after antibiotic use. The second group showed a loss of microbial components associated with ill health and a gain in altered microbiota associated with aging [338]. These findings on the relationship between microbiota, diet, and health status are supported by Claesson et al. [342]. They demonstrated, through an analysis of the composition of the fecal microbiota separated in 178 elderly subjects, that a change in diet associated with a transfer to a nursing home caused a change in the composition of intestinal bacteria, which correlated with nutritional status, inflammatory markers, comorbidity, and frailty [342]. Thus, the aging process and other environmental factors may alter the composition of the microbiota and contribute to the development of chronic low-grade inflammation [7].

Therefore, maintaining diversity in the microbiota appears key to maintaining health status and preventing frailty.

5.3. Mediterranean Diet and Microbiome: Health Status and Disease

Diet has a major impact on the biology of the gut microbiota [345]. Some nutrients have effects on the structure, function, and secretion of metabolites of the gut microbiota that can modulate immune functions and multiple metabolic and inflammatory pathways [346,347]. Emerging evidence is showing that adherence to the MedDiet promotes beneficial effects on the microbiota, favoring microbial diversity mainly in the colon, and it is associated with a reduction in Clostridium and an increase in Bacteroidetes and Firmicutes [28] (Figure 3).

5.3.1. Mediterranean Diet, Microbiome and CVD, Obesity, and Diabetes

Variations in the microbiota have been linked to the development of diseases. The microbiota can be modified through diet. Polyphenols from the MedDiet play a  key role in the microbiota. These compounds can reach the gut microbiota and modify the bacterial population and its metabolism. In this respect, it has been reported that the administration of polyphenols in rats, specifically resveratrol and curcumin, was associated with alterations in the Bacteroidetes and Clostridium groups of bacteria, thus providing metabolic benefits in glycemic control [348]. Additionally, the high content and bioavailability of fiber in the MedDiet (two times higher than in a Western diet)  have beneficial effects on the cardiovascular system of older adults. These benefits could be due, in part, to changes in the microbiota. Fiber appears to have a positive impact on the composition of the gut microbiota, increasing the number of beneficial bacteria,  inhibiting the growth of pathogens, and reducing atherogenic serum cholesterol in the microbiome. It also prevents glucose intolerance by reducing postprandial hyperglycemia through the formation of a viscous layer around the small intestine, which slows down the chyme transition [7]. This, in turn, increases the thickness of the aqueous layer through which solutes must pass to reach the enterocyte membrane, leading to a decrease in glucose in the enterocyte blood and resulting in a decreased absorption of glucose, lipids,  and amino acids [7]. High fiber intake has been found to promote modifications of the gut microbiota with an increase in Bacteroidetes (in particular, Bacteroides acidifies),  which produce high levels of short-chain fatty acids, including acetate, butyrate, and propionate [349]. Some of the beneficial effects of these metabolites are thought to be mediated by binding to specific G-protein-coupled receptors expressed on enteroendocrine and immune cells [349]. Conversely, poor adherence to the MedDiet was associated with an increase in l-Ruminococcus and Streptococcus bacteria and an increased concentration of trimethylamine N-oxide (TMAO) in urine. Compared to the Western diet, MedDiet has significantly lower contents of choline and L-carnitine (present in egg, cheese, and red meat), and the production of TMAO by the microbiota is lower [350]. This could reduce the risk of CVD, independent of the presence of cardiovascular factors. Zhu et al. concluded that an elevated level of TMAO could also be involved in the pathogenesis of obesity and type 2 diabetes mellitus, as it induces vascular inflammation and a prothrombotic effect by increasing platelet hypersensitivity to multiple agonists [351]. Indeed, the review by Cornejo-Pareja et al. concludes that the increase in fat mass in obese patients is not only due to more efficient energy uptake but that the microbiota is involved in changes in endotoxemia, intestinal permeability, insulin resistance, the hormonal environment, the expression of lipogenesis regulatory genes, interaction with bile acids and changes in the proportion of brown adipose tissue [352].

5.3.2. Mediterranean Diet, Microbiome, and Cancer

Numerous epidemiological studies have supported the importance of lifestyle factors and exposure to known or suspected carcinogens in the development of cancer. It is estimated that 30–35% of cancer risk factors are associated with diet, physical activity, and/or energy imbalance [353], and 15–20% of cancers are caused by infectious agents [354]. The microbiota that inhabits our body can be considered an environmental factor to which we are continuously exposed throughout life. However, the underlying mechanisms by which the MedDiet decreases the risk of cancer are not entirely clear [355]. In the diet–microbiota interaction, it has been observed that many dietary and digestive components are metabolized by bacteria in the gastrointestinal tract, leading to tumor suppressor metabolites and putative oncometabolite [356,357]. As an example, the excessive consumption of red meat, present in the Western diet, is a risk factor for CRC and other cancers by several mechanisms, including some that are dependent on intestinal bacteria. Elevated levels of protein intake can lead to an increase in certain types of bacteria, including Bacteroides and Firmicutes. These ferment amino acids into N-nitroso compounds,  which induce DNA alkylation and mutations in the host [357]. Proteobacteria that encode nitroreductases and nitrate reductases are also related to this process, which is strongly associated with inflammation [358].

In addition, in the process of the digestion of saturated fat associated with red meat consumption, approximately 5% of the primary bile acids escape from the enterohepatic circulation and reach the colon, where they are converted by bacteria into secondary bile acids. Primary cholic acid is converted to secondary deoxycholic acid by certain bacteria, including Clostridium cinders. Secondary deoxycholic acid functions as a tumor promoter by disrupting cell membranes to release arachidonic acid, which is converted by cyclooxygenase-2 and lipooxygenase into prostaglandins and ROS that trigger inflammation and DNA damage [359]. By contrast, the dietary fiber present in the MedDiet is fermented by certain types of colonic bacteria, such as Clostridium groups IV and XIVa,  into short-chain fatty acids. Butyrate, which is one of the most abundant short-chain fatty acids, is the main source of energy for colonocytes and is involved in the prevention of CRC. It has been observed that butyrate probably exerts its tumor-suppressive properties through multiple mechanisms. Butyrate epigenetically regulates the expression of genes that are involved in apoptosis and cell proliferation apoptosis [116]. It also acts as a ligand for certain G-protein-coupled receptors due to its involvement in tumor suppression [360]. Both mechanisms are believed to be important for butyrate’s ability to induce regulatory T  cells. In addition, butyrate helps maintain the epithelial barrier function, which is important for preventing inflammation. Other components of the MedDiet that are related to cancer prevention are polyphenols. Ellagitannins are polyphenols found in nuts and berries. When they reach the intestine, they are modified by the microbiota and transformed into different compounds. Urolithin is one of the most studied products, and it has been shown that it can be absorbed by the enterohepatic circulation and transported by the blood and thus distributed to different tissues. It has anticarcinogenic effects through the inhibition of the Wnt signaling pathway, which could have a protective effect against CRC [361].

Thus, our diet dictates whether the microbiota produces metabolites that exacerbate or enhance tumor progression [362].

5.3.3. Mediterranean Diet, Microbiome and Neurological Diseases

Regarding neurodegenerative diseases, better cognitive functions and a lower risk of dementia have been associated with higher adherence to the MedDiet. The PREDIMED  study demonstrated a modest beneficial effect of adherence to the MedDiet for 4–6 years on cognitive functions in cognitively healthy adults at high risk of CVD, especially in the domains of global cognition, memory, and executive function [363,364]. By contrast, no benefit on cognitive function was reported after 1 year of the MedDiet in older adults in the NU-AGE trial. However, participants with higher adherence to the MedDiet demonstrated better global cognition and episodic memory compared with those that have low adherence [365]. These benefits appear to be related to certain components of MedDiet (omega-3 fatty acids, antioxidants, and polyphenols) as they may inhibit neuroinflammation associated with AD and other degenerative diseases [366].

Changes in the microbiota could also be involved in the pathogenesis of these diseases by initiating and perpetuating neuroinflammatory processes. In this respect, a study demonstrated the existence of the brain microbiota in cerebral blood vessels through micrographs of the human brain [367]. These bacteria and gut-derived toxins appear to compromise the integrity of the blood–brain barrier and could contribute to early neuroinflammatory changes by stimulating microglia and hindering amyloid clearance [368,369]. In addition,  microbial amyloid and circulating oligosaccharides activate innate resistance receptors, such as the Toll-like receptor and the receptor for advanced glycation end products, to increase proinflammatory signaling and to promote chronic neuroinflammation and progressive neurodegeneration, especially in sensitive brain regions such as the hippocampus [368,370]. Moreover, the microbiota has also been linked to other disorders, such as epilepsy. One study in epileptic patients found that antibiotic treatment reduced seizure frequency by 10% [371].

Nearly 60% of the variation in gut microbiota is attributable to diet [372]; therefore,  modulation of the gut microbiota through diet could be an effective approach for reducing the inflammation associated with neurological diseases. Preliminary data have shown positive associations between the MedDiet and increased numbers of beneficial species of the microbiota, e.g., Bacteroidetes, and their short-chain fatty acid metabolites, which have anti-inflammatory effects [373,374]. However, only a few studies have evaluated dietary patterns and gut microbiota, most of them being observational, which prevents establishing causality [375,376]. Further research is therefore needed to understand the complex relationships between gut microbiota and cognitive health and whether diet-induced effects are mediated by alterations in gut microbiota.

All of this is important because increasing evidence suggests that the reprogramming of gut microbial functions through long-term adherence to healthier diets can influence physiological responses to nutrients and other features of host biology that are critical to promoting health and longevity [377]. Thus, the modification of the microbiota through MedDiet could benefit the evolution and prognosis of these diseases. 

6. Methods

Interventional studies involving animals or humans, and other studies that require ethical approval, must list the authority that provided approval and the corresponding ethical approval code. A comprehensive search of the literature published in PubMed from November 2022 was conducted to identify articles relating to MedDiet, microbiota, aging,  and frailty. Search strategies were based on the following search terms: MedDiet, polyphenols, omega-3 PUFAs, healthy aging, hallmarks of aging, telomere length, microbiota,  oxidative stress, mitochondrial function, inflammation, cellular senescence, anti-senescence compounds, frailty, and sarcopenia. A selection of articles published in English providing original human research, observational prospective and retrospective studies, randomized controlled trials, reviews, and meta-analyses were included.

In addition, we considered case series, single-case reports, editorials, research or original articles, letters to the editor, comments (on an article or from the editor), responses (to a  comment, letter, or article), corrections, short reports, short communications, perspectives,  opinions, and discussions. Priority was given to the largest studies and the strongest available evidence and the most recent studies.

7. Conclusions 

There is an increasingly aging global population. However, the way to achieve healthy aging has not yet been fully elucidated. The loss of function and frailty syndrome associated with aging increases the vulnerability of the elderly and their propensity to disease. There are different molecular pathways or hallmarks involved in aging that bring us closer to understanding the deterioration associated with the senescence process, such as genomic instability, telomere attrition, epigenetic effects, proteostasis, nutrient-sensing pathways,  mitochondrial dysfunction, cellular senescence, stem cell depletion, and altered intercellular communication. Likewise, microbiota disturbances seem to play a relevant role in frailty in the elderly.

It has been shown that MedDiet promotes healthy aging, increasing the life expectancy of the population. This review has shown that MedDiet positively influences the molecular pathways that determine age. Consequently, MedDiet has been associated with a lower risk of age-related diseases, mainly CVD, neurodegenerative, and oncological diseases. Therefore, further evidence of the beneficial effects of this dietary pattern on human health and longevity has been provided. However, most studies do not evaluate the impact of the Mediterranean diet pattern as a whole on the hallmarks of aging but rather its components, especially certain bioactive components. Certainly, some clinical trials are exploring the role of the Mediterranean diet (mostly PREDIMED substudies), but they focus on specific dietary supplementation with nuts or EVOO. Therefore, it would be useful to evaluate the pattern as a whole without special emphasis on these more studied components. In addition, more quality studies on MedDiet and the prevention of frailty and disease in aging are needed, as many studies are observational, and causality cannot be determined.

Overall, more research is needed to provide a better understanding of the mechanism of action of MedDiet on aging. However, at present, MedDiet could be recommended as a baseline anti-aging therapy to prevent frailty and maintain functionality until the later stages of life, as the benefits of MedDiet on human health present robust evidence.

Author Contributions: Study design: M.C.A.-L. and V.C.-B., study conduct: M.C.A.-L. and V.C.-B.,  data collection: M.C.A.-L. and V.C.-B., data interpretation: M.C.A.-L., V.C.-B., B.G.-F., C.G.-F. and M.M.-T., drafting of the manuscript: M.C.A.-L. and V.C.-B., reviewing the manuscript and approving the final version of manuscript: All authors have read and agreed to the published version of the manuscript.

Funding: Victoria Contreras-Bolívar was funded by a postdoctoral fellowship from the Junta de Andalucia (RH-0141-2020) and C.G.-F. was funded by a postdoctoral fellowship from the Instituto de Salud Carlos III (CD20/00022).

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