How can we modulate aging through nutrition and physical exercise? An epigenetic approach

Epigenetics

Epigenetics can be defined as de novo or inherited reversible modifications of the genome, which can affect gene expression without altering the DNA sequence. Epigenetic alterations are mediated by multiple mechanisms, of which histone modifications, DNA methylation and changes in non-coding RNAs expression are the best studied [18, 27] and whose alterations with aging are schematized in Figure 1.

Figure 1. Representation of age-associated epigenetic changes. (A) Representation of a young individual chromatin: tight chromatin compactation, high levels of DNA methylation, few histone PTMs (particularly acetylation), canonical histones and balanced non-coding RNA regulation; (B) Representation of an old aged individual chromatin, we may observe a looser chromatin structure, lower levels of DNA methylation, higher levels of histones PTMs (particularly acetylation), histone variants presence, chromatin remodeling and disturbances in ncRNA regulation, what is reflected in an overall chromatin instability increase, when compared with the structure presented in A. The transition between the structures presented in A and B is represented by arrows. The arrows in red present the causes (here presented as a lifetime of risk behaviors (namely tobacco and alcohol consumption), unbalanced diet and sedentarism) whose effects are reflected by the arrows in orange/red, where darker colors represent more pronounced epigenetic alterations.

Eukaryotic DNA is organized into higher-order chromatin through nucleosomes, which are core particles composed of histone octamers. Each octamer is constituted by two of each core histone proteins (H2, H3A, H3B and H4), around which 147 base pairs of DNA are wrapped [28, 29]. The linker histone H1 is also found in proximity to this core, promoting its stability [30]. Nucleosome core particles are arranged on the DNA like “beads on a string”, with a distance of approximately 200 base pairs between “beads”. This open DNA conformation is termed “euchromatin”. Additionally, the tightly packed or closed conformation that DNA and nucleosome core particles adopt after condensation by higher-order structures was termed “heterochromatin”. Condensation of the DNA into heterochromatin makes it inaccessible and protects it from damage – a benefit that is gradually lost with old age [30, 31].

Histone modifications and heterochromatin decline

Post-translational modifications (PTMs) on histones have multiple effects on gene expression. PTMs regulate chromatin compaction by altering histone-histone or histone-DNA interactions, modulate local gene expression directly and impact the recruitment of effector proteins and transcription factors, thereby controlling gene expression indirectly [31, 32]. There are more than 20 post-translational histone modifications currently described in literature - among these are methylation, acetylation, phosphorylation, ubiquitylation and sumoylation - and their effects are interdependent, making it challenging to study how one specific alteration impacts genetic regulation [33], since it is often a combination of modifications which guides specific regulatory functions [34].

Histone modifications occur in the flexible (and easily accessible) N-terminal histone tails protruding from the nucleosome core or in other histone domains, such as the lateral histone regions or the central globular domains, directly impacting chromatin binding and associated activity [33]. Additionally, histone variants, such as H2A.W and H3.3, gradually replace some of the core histones during aging, promoting chromatin architecture changes, and adding another layer of complexity to an already intricate system [35].

In the last decade, several studies have described how histone modifications work in tandem to regulate genomic expression [36, 37]. The best studied PTMs are acetylation and methylation, which occur primarily on lysine and arginine residues in the histone tails [38, 39]. These residues are likely selected for PTM due to their positive electrostatic charges, which interact with the negatively charged nucleic acid nucleotides forming strong electrostatic bonds [38, 40]. In the case of acetylation, the addition of acetyl groups neutralizes the positive charge of arginine or lysine residues, decreasing the strength with which the modified histones interact with the DNA, resulting in euchromatin formation, increased transcription and increased genomic instability [38, 41]. Nonetheless, a study by Li and colleagues reported that the acetylation of lysine 85 of linker histone 1 resulted in heterochromatin condensation, a clear example of how the same PTM may impact genomic structure differently, depending on which residue is modified and the interactions it establishes [42]. The impact of histone methylation is similarly complex, with the stability of the genome being altered in accordance with the position of the modified residue and its interactions with other PTMs, with some methylated residues favoring genomic transcription in some contexts, while promoting repression in others [43, 44]. For example, methylation of H3K4 (lysine 4 of histone 3) represses transcription in the presence of H3K9 methylation but increases transcription when H3K9 is acetylated [45].

Histone methylation is mediated by lysine or arginine methyltransferases (KMTs and PRMTs, respectively) that add methyl groups to the target histone residues using S-adenosylmethionine (SAM) as a methyl group donor [46]. Demethylation is mediated by histone demethylases (HDMs), that remove methyl groups [41, 47]. Histone acetylation is mediated by histone acetyltransferases (HATs), which add acetyl groups from acetyl-CoA [46]. Deacetylation is mediated by histone deacetylases (HDACs) – which remove those groups [47]. HATs and HDACs have been the target of recent pharmaceutical studies, looking for therapeutic agents that can modulate gene expression in cancer [44, 48] and aging.

Aging is associated with an overall increase in histone acetylation [49]. A group of HDACs known as Sirtuins have been studied as a target for improving healthspan [50]. Sirtuins belong to a family of NAD+ dependent proteins with histone deacetylase function and their activity levels decrease with aging, in tandem with a decrease in NAD+ levels [49, 51]. Members of the Sirtuin family (SIRT), namely SIRT1, SIRT3 and SIRT6, have been shown to promote health and longevity in various model organisms, from yeast to mammals (particularly in situations of caloric restriction and high exercise). As a result, Sirtuins have been considered as potential therapeutic targets to extend healthy aging, either by increasing the availability of NAD+, essential to keeping metabolism at the required rates, or by using pharmacological compounds (such as resveratrol) that directly activate Sirtuins function [49, 52–54].

Several specific PTMs have also been associated with aging including H4K16ac, acetylation of lysine 16 of histone H4 (associated with reduced chromatin condensation), H4K20me2 and H4K20me3, di- and tri-methylation of lysine 20 of histone H4 (which increase chromatin compaction in vitro) and H3K9me3, tri-methylation of lysine 9 of histone 3 (which promotes a stronger binding between the DNA and the histone octamer - a modification that is gradually lost with aging) [29, 31, 55].

In addition to changes in acetylation and other PTMs, aging is associated with a global reduction in core histones proteins accompanied by a decline in protein synthesis [17]. The loss of histones implies a decrease in heterochromatin, an observation which led to the “heterochromatin loss model of aging”. This model suggests that there are conformational changes in heterochromatin structure with aging that result in the activation of genes that were previously silenced. These alterations, in turn, cause aging and cellular senescence along with increased genomic instability - further aggravated by chromatin relaxation, leading to age-associated changes in gene expression and increased genome damage [18, 29].

DNA methylation and aging

DNA methylation (DNAm) is observed in all eukaryotes, from plants and fungi to animals, and it is central to cell differentiation and embryonic development [56]. After replication, a methyl group is added to the fifth carbon of the cytosine base ring (5mC), most commonly in genomic locations that are rich in cytosine-guanine dinucleotides, known as CpG islands [57]. Methylation can also be observed at other nucleotide pairs (adenine-cytosine; thymine-cytosine; cytosine-cytosine), which are known as non-CpG, or CpH sites [39, 58], although it is less frequent than at CpG sites. Non-CpG methylation is particularly common in embryonic stem cells [59] and neurons [60]. DNAm is much more prevalent in heterochromatin than euchromatin [30].

DNAm is mediated by the DNA methyltransferases (DNMTs) 1 and 3, with S-adenosyl methionine (SAM) serving as donor for the methyl group, the same molecule that serves as donor for histone methyltransferases [46, 61]. The function of DNMT1 is to maintain existing methylation sites, by adding methyl groups at CpG sites that are methylated on only one DNA strand, such as after DNA replication. Conversely, DNMT3A, DNMT3B and DNMT3L promote de novo DNA methylation [57, 58, 61].

DNMTs activity is balanced by DNA demethylation, which can be either passive or active. In passive or spontaneous demethylation, the cytosine loses its methyl group during replication and is converted to thymine, which is posteriorly exchanged through repair mechanisms to an unmethylated cytosine. Active demethylation is mediated by Ten-Eleven Translocation (TET) proteins. These catalyze the demethylation process through successive oxidations, from 5mC to 5-hydroxymethyl cytosine (5hmC) and afterwards to 5-formylcytosine and 5-carboxylcytosine, which are recognized by Thymine DNA Glycosylase (TDG) and returned to their unmethylated cytosine state by the base excision repair (BER) pathway [57, 62]. There are several proteins involved in this process. Among them, are the protein GADD45A (“Growth Arrest and DNA Damage Protein 45 A”) and the members of the AID/APOBEC (Activation Induced Cytidine Deaminase (AID)/Apolipoprotein B Editing Complex (APOBEC)) protein family. GADD45A recruits TDG in situations of DNA damage [63], and recognizes promoters’ R-loop conformation, leading to TET recruitment and demethylation at CpG islands [64]. In addition, the members of the protein family AID/APOBEC are described as having a role in demethylation through deamination of 5mC cytosine [65], which generates a G-T mismatch that is posteriorly corrected by TDG [66].

In young stages of life, eukaryotic DNA is hypermethylated in repetitive elements of the genome, in intergenic regions and in gene bodies. Hypermethylation promotes genomic stability and limits transcription of these regions of the genome. With aging, there is global hypomethylation of previously methylated regions, leaving these more available to transcription factors and other effectors and consequently promoting transcription of these genomic sites [59]. This hypomethylation is associated with a decrease in DNMT1 expression [67], which likely contributes to impaired maintenance of DNAm patterns associated with aging.

There is also, contradictorily, some evidence of age-associated DNA hypermethylation in genomic regions that in young individuals’ DNA are usually unmethylated. Methylation of these regions is associated with genomic compactation, restricting gene transcription, which may also lead to genomic instability, if genes that should be transcribed find themselves restricted by this event [29, 56, 68].

DNAm alterations are widely described in cancer studies. Hypermethylation of tumor suppressor genes and hypomethylation of oncogenes are both associated with genomic imbalance and dysregulated proliferation of cancer cells [69]. A similar phenomenon is hypothesized to occur in aging, with age-associated genes as the target - in this case, hypomethylation at the promoters of genes regulating senescence may translate into increased expression of these genes and accelerated aging.

Recently, DNAm has been used as a biomarker to measure aging by analyzing methylation status across a large set of CpG sites [70]. This led to the creation of epigenetic clocks (e.g. Horvath’s, Hannum’s, PhenoAge and GrimAge [71, 72], which were designed to predict chronological age based on epigenetic criteria. Subsequently, epigenetic clocks have been used as a proxy for biological age and have been extensively studied for their ability to predict healthspan, disease risk and mortality [73, 74] Epigenetic clocks are reliable predictors of chronological age, but their utility in predicting mortality and healthspan is less clear. Further studies are required to determine whether specific CpG sites can be used to predict healthy longevity [75–78].

Modulation of aging by non-coding RNAs

Non-coding RNAs (ncRNA) contribute for the control of gene expression as they have key regulatory functions in both physiological and biological processes [79]. As measurable molecules, circulating ncRNAs and particularly microRNAs (miRNAs), are considered promising biomarkers for the study of aging and age-associated processes, as they have been linked to aging (and age-related pathways), cellular senescence and age-associated conditions [80–83].

MiRNAs, the most studied of the ncRNAs, are short molecules of 18 to 25 nucleotides that regulate gene expression by binding to the 3′ untranslated region (3′UTR) of their target genes blocking protein translation or inducing mRNA degradation [84]. There are more than 2800 miRNAs encoded in the human genome, and it is estimated that at least 60% of all human genes are regulated by miRNAs [80, 85, 86]. MiRNAs may also impact other epigenetic events by regulating their associated enzymes. For instance, members of miR-29 family, modulate the expression of DMNTs and TET enzymes in both healthy and pathological conditions, namely brain maturation and cancer [84, 87], leading to the reduction of DNA hypermethylation in tumor suppressor genes [87, 88].

LncRNAs or “long non-coding RNAs” are a diverse class of ncRNAs longer than 200 nucleotides. They can bind to DNA, RNA or proteins and are involved in the post-transcriptional and post-translational regulation of gene expression. It has also been suggested that lncRNAs may interfere with chromatin structure modulation and/or transcription [79, 89].

Both of these ncRNAs have been implicated in senescence and inflammation-related pathways (such as the p23/p21 and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB)), in the development of neurological disorders (such as Huntington’s and Alzheimer’s disease) [90] and other age associated conditions, such as fibrosis [79], cardiovascular disease [89, 91] and osteoporosis [92]. Thus, ncRNAs are increasingly being targeted for anti-aging therapies [93].

ncRNAs influencing aging include miR-28e3p and miR-126, whose levels are reduced in diabetes mellitus type 2 [94], and miR-146a, that inhibits NF-κB pro-inflammatory activity and shows reduced expression levels associated with aging [6]. Another ncRNA, miR-21, was demonstrated to modulate inflammation and the NF-κB pathway and shows altered levels in cardiovascular diseases and osteoporosis [92, 95]. Another ncRNA that has been linked to aging is nc886 (or pre-miR-886), which was shown to impact senescence by reducing the expression of senescence biomarkers, such as p16^INK4A and Cyclin Kinase Inhibitor p21 (p21^Waf1/Cip1), and decreasing reactive oxygen species (ROS) levels in fibroblast cell models. This molecule is under investigation as a potential target for anti-aging therapy [96].

In short, the aging process leads to alterations in non-coding RNA levels, which in turn modify the expression levels of age-related genes and increases age-related genomic instability.

Conclusion and future perspectives

Aging is a complex and natural process in every living organism’s life cycle and it manifests in many ways, including epigenetics. In this article we explore aging and its associated epigenetic changes as well as how these changes may be delayed or reversed through nutrition, caloric restriction and sustained physical activity, as schematized in Figure 2. In this Figure we may observe a looser chromatin structure in the component B than in the component A, as well as lower levels of DNA methylation and increased histone PTMs, but nonetheless these values are closer to the component A than to the component B presented in Figure 1, where lifestyle strategies to promote a healthy aging are not considered, and consequentially imply an overall increase of chromatin instability.

Figure 2. Representation of age-associated epigenetic changes after following a healthy lifestyle. (A) Representation of a young individual chromatin, with tight chromatin compactation, high levels of DNA methylation, decreased histone PTMs (particularly acetylation), canonical histones and balanced non-coding RNA regulation; (B) Representation of a healthy old aged individual chromatin, we may observe a looser chromatin structure and lower levels of DNA methylation than in A, and higher levels of histones PTMs (acetylation) than in A. There are also different histone variants presence (in exchange of the canonical histones) and an increase of ncRNA imbalance, which is reflected in an overall increase of chromatin instability. The alterations between the structures presented in A and B are represented by arrows. The arrows in green present the causes (here presented as a mindful lifestyle - achieved through a healthy diet, caloric restriction and physical activity) whose effects are reflected by the arrows in yellow/orange, with the lighter colors representing less marked epigenetic alterations.

It is important to note, however, that epigenetic events are dynamic and interdependent. Moreover, the relationship between age-associated epigenetic changes and healthspan is not always well-established and one epigenetic modification may lead to folding or unfolding of the chromatin structure depending on other nearby modifications. Future epigenomic studies must adopt a genome-wide perspective, rather than a targeted approach, and should adopt a three-dimensional perspective to give deeper insight into their impact on chromatin structure. Furthermore, it would be relevant to develop strategies that could enable the differentiation of standard and healthy older aging from age-associated pathologies themselves.

The aging global population is placing ever-growing demands on social and health infrastructure. Strategies to promote health aging are important to maximize quality of life for the elderly and minimize pressure on health care systems. The simplest “treatments” are lifestyle changes including healthy eating and regular physical exercise. Pharmacological or biological treatments are also in development, and may, in the future, help reduce the risks associated with unhealthy behaviors, such as smoking and drug abuse. Understanding the relationship between biological aging and healthspan is critical to assessing the value of these interventions and identifying new therapies that can promote healthy aging.

Author Contributions

Ana Teresa Rajado - planned the article, performed the literature search and wrote the manuscript. Nádia Silva, Filipa Esteves, David Brito, the ALFA Score Consortium, Alexandra Binnie, Inês Araújo, Clévio Nóbrega and José Bragança - provided intellectual input and manuscript writing and revision. Pedro Castelo-Branco - planned the article, provided scientific guidance and critical revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

The research by the authors is developed at Algarve Biomedical Center. We acknowledge the Algarve Biomedical Center for the structural support.

Conflicts of Interest

The authors declare no conflicts of interest related to this study.

Funding

This work was supported by the Algarve Regional Operational Programme (CRESC – Algarve), Reference: ALG-01-0145-FEDER-072586.

Editorial Note

The list of ALFA Score Consortium members:

Raquel P. Andrade^1,2,3,5, Joana Apolónio^1,2,3, Sofia M. Calado^1,2,3, Maria Leonor Faleiro^1,2,3,4, Carlos Matos^1,2,3, Nuno Marques^1,2,3, Ana Marreiros^1,2,3, Hipólito Nzwalo^1,2,3, Sandra Pais^1,2,3, Isabel Palmeirim^1,2,3,5, Vânia Palma Roberto^1,2,3,6, Sónia Simão^1,2,3, Natércia Joaquim⁷, Rui Miranda⁷, António Pêgas⁸ and Ana Sardo⁹

¹Algarve Biomedical Center, Research Institute (ABC-RI), University of Algarve, Campus Gambelas, Bld.2, 8005-139 Faro, Portugal

²Algarve Biomedical Center (ABC), University of Algarve, Campus Gambelas, Bld.2, 8005-139 Faro, Portugal

³Faculty of Medicine and Biomedical Sciences (FMCB), University 28 of Algarve, Gambelas Campus, Bld. 2, 8005-139 Faro, Portugal

⁴Faculty of Science and Technology (FCT), University of Algarve, Gambelas Campus, Bld.8, Faro Portugal

⁵Champalimaud Research Program, Champalimaud Centre for the Unknown, Lisbon, Portugal

⁶ABC Collaborative Laboratory, Association for Integrated Aging and Rejuvenation Solutions (ABC CoLAB), 8100-735 Loulé, Portugal

⁷USF Balsa, Tavira

⁸USF Ossónoba, Faro

⁹USF Mirante, Olhão

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