The study including the Dutch Famine, which occurred during World War II, represents a historical milestone for studies involving the origin of diseases related to malnutrition in the early life. This work demonstrated that maternal malnutrition during gestation disrupts the metabolism of the descendants in the long run, resulting in hyperglycemia, a greater incidence of CVD, blood clotting disorders, as well as an increase in the capacity of response to stress and obesity.¹⁹

According to the WHO,²⁰ malnutrition refers to the deficiencies, excesses, or imbalances in the energy and/or nutrient intake. The inadequate consumption of macronutrients during the critical periods of development has been related to cardiometabolic diseases in one's offspring.²¹ Malnutrition during the intrauterine life associated with maternal food restrictions contributes to a worse performance and a premature phenotype of cardiac aging in adult offspring. Similarly, nutritional excesses in the early life, associated with maternal obesity can induce the involvement of the descendants’ cardiac function over the long term. These exposures alter one's cardiac metabolism and the microRNAs involved in each development stage of the heart and seem to play a crucial role in the unfavorable programming of CVDs.²²

Thus, diets that are restrictive in macronutrients and/or obesogenic diets, characterized by the excess of calories, sugars, and lipids, can lead to malnutrition and, if consumed by the mother during gestation and/or lactation, can be equally capable of programming the offspring for cardiometabolic diseases.²³ Maternal malnutrition (F0 generation) programs its direct descendants (F1 generation), and it is capable of programming its subsequent generations (F2, F3, for example).²⁴ Table 1 shows studies, including animal models, which evaluate the consequences, over the long term, of the excess or restriction of macronutrients during these critical periods.

The same way as macronutrients, the micronutrients are also essential to biological activity.³⁵ Their deficiencies affect many pregnant women and are considered a growing health problem that encompasses nearly 2 billion people worldwide. This condition is also known as hidden hunger, and includes deficiencies of iron, calcium, iodine, folate, and zinc, as well as other lesser-known micronutrients, such as selenium, chromium, and vanadium.^36,37

The consumption of micronutrients varies widely during gestation and among populations. Women from underdeveloped countries are more exposed to malnutrition during gestation, and the nutritional demands of this period can accentuate the deficiencies of these nutrients, with severe consequences for the health of the mother and the baby. It is currently estimated that 15-20% of these women suffer from lack of iron, 15% from lack of vitamin A, and 25% from lack of zinc.³⁵ Micronutrient supplements diminish the risk of low birth weight, small size for the gestational age, and stillbirths due to malnutrition, thus justifying this intervention during pre-natal follow-up. The positive effects of a proper maternal diet regarding micronutrients can persist into childhood, but data is scarce concerning possible benefits in the long run.³⁵ Table 2 summarizes the main findings resulting from the need for micronutrients in animal models during critical periods of development.

Breast milk is the ideal food for a newborn's nutrition. In general, human milk is 87% water, 7% lactose, 3.8% fat and 1% protein; however, its composition varies during lactation, adapting to the changes needed for the child's growth.^46,47 Supplementation with infant formula is recommended only for the cases in which exclusive breastfeeding is impossible, unsustainable, or inadequate. In most cases, cow's milk or soy milk is used as a base, complemented with ingredients produced by genetic engineering, which most closely resembles breast milk. Even though the industry's intention is to imitate human milk as closely as possible, the use of infant formulas should only be considered after having depleted all alternative possibilities of breastfeeding.^47,48

Adequate breastfeeding is essential for the survival, health, and growth of children; it preserves the mother's health and contributes to the development of human capital. Strong evidence of this can be found in studies with humans that show the existence of a proportionally inverse relationship between the duration of breastfeeding and the risk of obesity, hypertension, dyslipidemia, and type II diabetes mellitus in adulthood.⁴⁹ Based on this, since 1990, international agencies specialized in health adopted the Innocenti Declaration, recommending exclusive breastfeeding until six months of age.⁵⁰ However, the WHO analyzed the duration of breastfeeding in 108 countries and found that only 32% of the children received only breast milk in the first semester of life. One of the determining factors of early weaning seems to be the socioeconomic aspect.⁵¹ Some studies discuss that in high-income countries, the socioeconomic status seems to be positively associated with the duration of breastfeeding. Others believe that breastfeeding became less common in high-income countries during the 20^th century and that similar standards have been observed in women with a high educational level, from urban environments, and who have a higher purchasing power in middle and low-income countries.^50,51 Although breastfeeding is cited as the reason for women to leave the workplace, evidence suggests that the majority remain in their jobs and choose to use breast milk substitutes or interrupt breastfeeding.⁵⁰

Table 3 presents studies including animal models that evaluate the consequences of early weaning over the long term.

Specialists highlight a balanced, healthy, and varied diet as the best way to prevent chronic diseases. These recommendations are based on existing associations between the consumption of foods, such as fruits, vegetables, and whole grains, and the prevention of CNCD. In fact, epidemiological studies show an inverse association between the prevalence of these diseases and the consumption of these foods. As a result, the so-called “functional foods” emerged, which provide benefits to the health of those who eat them.⁵⁶

Brazilian law sets forth the legal definition of functional foods: “foods or ingredients that, in addition to their basic nutritional functions, when consumed as part of the usual diet, produce metabolic effects and/or physiological and/or benefits to health, which should be safe for consumption without medical prescription".⁵⁷ These foods contain components, called “bioactive compounds”, defined as “nutrients or non-nutrients normally eaten as a component of some other food, producing metabolic or physiological action in the body.”⁵⁸

Studies point out that diets rich in bioactive compounds can reduce the risk of CVD. For instance, anthocyanins present in red fruits; resveratrol, phenolic compound found in grapes; catechins, found in large quantities in green tea; phytosterols, present in vegetable oils; isoflavones, found in soy beans; Omega-3 fatty acids observed in linseed, chia, and fish; probiotics present in dairy products; prebiotics found in vegetables, fruits, and whole grain, oleaginous, and leguminous cereals; among others.^56,59–61 Evidence still suggests that intestinal dysbiosis plays an important role in the pathogenesis of these diseases, in which, bioactive compounds may act in the modulation of the microbiota in order to favor a healthy bacterial population.⁶¹

The literature proposes that these compounds can unleash epigenetic changes that have accumulated throughout life, involved in the pathogenesis of diseases related to age.⁶¹ Based on DOHaD theory, it is reasonable to assume that the early life could also constitute a temporal window to begin dietetic interventions focused on the prevention of diseases. The knowledge about the consequences of the early exposure to bioactive compounds is stiil limited. Table 4 presents experimental studies that investigated whether or not these compounds would be able to prevent both the development of cardiometabolic diseases associated with malnutrition in critical periods, as well as attenuate the injuries caused by it.

As the epigenetic changes are modulated by environmental exposure, epigenetics is considered the interface between genetics and the environment. Thus, these changes have been highlighted as molecular mechanisms that are subjacent to the process that associates malnutrition in critical periods of development and cardiometabolic programming. In addition, given the capacity of response of the epigenetic markers to food factors, one can speak of “epigenetic foods”, a type of functional food containing bioactive compounds capable of modulating the microRNA expression, DNA methylation, or histone modifications.⁷⁴

Epigenetic modifications have been observed in cardiac pathologies. Analyses of newborns mice or healthy and heart failure (HF) adult mice cardiomyocytes DNA, showed an important role in DNA methylation in the modulation of many aspects of the cardiac biology, including in the development of the disease.⁷⁵ By contrast, the role of histones in the cardiovascular biology, as well as the role of histone deacetylase (HDAC) enzymes, as therapeutic targets of heart diseases, has been well defined.⁷⁶ Treatment using an in vivo HDAC inhibitor attenuated the cardiac hypertrophy and fibrosis⁷⁷ in hearts of rodents exposed to hypertrophic stimuli. Moreover, the microRNAs can regulate multiple cell functions involved in atherosclerosis, such as oxidative stress, cholesterol metabolism, and endothelial dysfunction.⁷⁸

Analyses of DNA methylation in the entire genome of siblings of the same sex in the cohort of the Dutch Famine study revealed a pattern of differentially methylated regions, associated with malnutrition.⁷⁹ Experimental studies that analyzed offsprings of mothers submitted to protein restrictions during gestation observed a reduction in the supply of methyl groups stemming from glycine, hypomethylation of the hepatic receptor of the glucocorticoids, altered histone methylation, and an increase in the DNA methylation in hepatocytes.²¹ Consistent with these findings, the mother's energy restriction during gestation led to DNA hypomethylation in the hepatic tissue of the offspring, resulting in an increase in the gene expression involved in the oxidation of fatty acids and the reduction of genes involved in the lipid synthesis.²¹ By contrast, the excessive consumption of carbohydrates by the mother during gestation changes the DNA methylation, leading to changes in the gene expression responsible for adipogenesis in the white adipose tissue, in turn programming obesity in the offspring.²¹ Finally, Strakovsky et al.⁸⁰ showed that, upon modifying the histone acetylation, a maternal hyperlipidic diet contributed to changing the expression of antioxidant enzymes in newborns.

Many micronutrients are essential for a wide range of metabolic processes, including methylation and transamination reactions.⁸¹ These processes involve many enzymes with methyltransferase activity, in addition to co-factors, such as choline, methionine, zinc, and vitamins B6, B12, and B9, acting as methyl donors. B9 is a donor of one-carbon for DNA methylation and synthesis; its role is crucial during the early post-natal development, when rapid growth and cell proliferation take place. The B12 deficiency can result in global hypomethylation, since, together with the B9, it is involved in methionine synthesis and S-adenosil methionine, necessary donors for the maintenance of DNA methylation patterns.^81,82 Due to its role in DNA methylation, zinc can exert a key influence upon the epigenome. Its deficiency during the intrauterine and post-natal life can contribute to change the methylation processes, which can lead to the development of chronic diseases and increase cardiovascular risks.⁸²

There is evidence that sustains the notion that breast milk influences the DNA methylation and that this food contains microRNAs involved in the regulation of the gene expression at the post-transcriptional level. This study raised the hypothesis that the microbioma mediates the effects of this compound in this process, given that breastfeeding can modulate the composition of the intestinal microbiota and that this influences the DNA methylation.⁸³ One study, which compared rats submitted to early weaning, who were fed a formula rich in carbohydrates, and rats fed only with breast milk, showed lower levels of mRNA of the Nyp gene (which codifies the Y neuropeptide – orexigenic peptide) and of histone acetylation, as well as higher levels of mRNA of the Pomc gene (anorexigenic peptide) in the rats that received breast milk, possibly associated with high levels of histone acetylation in this group. Both of the genes are involved in many physiological processes, mainly energy homeostasis.⁸³

As regards the bioactive compounds, in vitro and in vivo studies have demonstrated that these perform their protector effects in the chronic diseases by means of different mechanisms involving nutrigenomics. Anthocyanins have been associated with histone modifications, DNA methylation, and microRNA expression. Other bioactive compounds, such as isoflavones, curcumin, and resveratrol can regulate the activity of HDAC enzymes and histone acetyltransferase (HAT) and, consequently, modulate the histone acetylation. The benefits to one's health are attributed to these epigenetic mechanisms.^15,61

DNA methylation has also been associated with the catechins present in green tea. The epigallocatechin-3-gallate (EGCG) can inhibit the DNMT enzyme (DNA methyltransferase) through indirect mechanisms or through the reduction of its expression, in addition to modulating epigenetic processes at the level of histone modifications. Moreover, studies have also suggested that butyrate, a short chain fatty acid formed in the colon through prebiotic fermentation by bacteria, seems to inhibit the HDAC activity, corroborating with a possible interaction between the epigenome and the microbioma.^15,61

The development of public policies that favor the adequate nutrition of mothers in gestational and breastfeeding periods, as well as exclusive breastfeeding up to six months of age, seem to constitute important strategies to reduce the incidence of cardiometabolic diseases in the population, diminishing direct and indirect expenses in health care.

Although it is challenging to obtain consistent findings in clinical studies with bioactive compounds, the introduction of functional foods in one's diet can constitute an additional strategy to mitigate the deleterious effects observed in the long run, resulting from malnutrition in early life. Epigenetic mechanisms, which can be gender dependent, represent the key to developmental plasticity and are involved in both programming and reprogramming of the cardiovascular system.