Introduction
If we had the chance, we would all like to keep our bodies in top shape for as long as possible. As we age, we would certainly appreciate being able to move freely, maintain our mental sharpness, keep our senses sharp, and much more. The dream of conquering old age has existed since the beginning of human civilization; however, for most of our history it has been reserved for the realm of the divine and supernatural. Recently, with the rise of gerontology as a scientific field, there is hope for turning this pipe dream into a tangible reality. As we begin to understand the biology behind our bodies' slow but steady decline, we also gain insight into potential therapies and treatments that may slow, halt, or one day even reverse the aging process. So why wait for these anti-aging treatments to develop when we can improve our longevity now by changing certain aspects of our lifestyle? In this article, we'll introduce you to the science behind arguably the most important factor in slowing the aging process, our diet, and how we can optimize it to extend our life expectancy.
About epigenetics
Epigenetics is generally defined as the study of heritable changes in phenotype that are not related to changes in the DNA sequence and are usually due to changes in gene expression. Consider the following question: If all cells in our body carry almost exactly the same genetic information, how is it that a skin cell is so different from a liver cell or a neuron? Why can one do so many things that the other cannot? It turns out that while they all contain the same information, they use it in very different ways. Of the approximately 20,000 genes in the human genome, only a small proportion are “expressed” at any given time, i.e. h. transcribed into RNA and then translated into proteins. Therefore, it is this pattern of gene expression that determines what function each cell has, whether it replicates, and so on.
Not only does this expression pattern vary from cell type to cell type, but the same cell can also undergo changes in gene expression (i.e., epigenetic modifications) over time. The latter are generally determined by internal regulatory mechanisms as well as environmental factors, including our diet. It is these changes that contribute to the aging of our bodies over time [1]. Epigenetic changes occur primarily in the form of chemical changes, either to the DNA itself (usually in the form of DNA methylation) or to the histones, the proteins around which the DNA is wrapped (which are usually acetylated or methylated).
The role of epigenetics in aging
The mechanism underlying the aging process is quite complex and involves many elements that interact with each other. It was published in a 2013 paper in the journal Cell entitled "The Hallmarks of Aging" [2] is described in great detail, and the individual processes that contribute to aging described there are widely recognized by researchers in the field. There are now 12 such features described. Some are relatively independent of the others (e.g. the loss of proteostasis, i.e. the increase of misfolded proteins or protein aggregates in the cell), others are more interconnected (e.g. the decrease in stem cell number and the accumulation of senescent cells);
The effects of calorie restriction on aging
It turns out that when it comes to the impact of our diet on epigenetics and aging, it's not just what we eat that matters, but also how much we eat. One of the most studied diets in aging research is caloric restriction (CR). The association between CR and increased lifespan has been empirically demonstrated in a variety of animal models, and many of its health benefits have also been found in human studies [3,4]. Although the reasons for CR-induced slowing of aging are far from fully understood, they have been shown to be at least partly related to epigenetics. A variety of genes associated with age-related processes such as telomere maintenance, cellular senescence, DNA repair and genome stability are modulated by epigenetic changes following CR diets [5,6,7].
Epigenetic clocks
A highlight of these novel biomarkers is the recent emergence of epigenetic clocks as tools for measuring biological age, which are currently considered the best tool of this kind due to their strong correlation with chronological age and all-cause mortality [8]. Although there are some differences between them, all epigenetic clocks base their predictions on the DNA methylation status of a specific group of CpG dinucleotides. The main models currently used are:
- Horvath's watch, which measures 353 CpGs from DNA samples from any tissue,
- the clock from Hannum, which measures 71 CpGs from whole blood DNA samples,
- Levine's PhenoAge watch, which, in addition to DNA methylation, also takes into account clinical factors such as glucose or C-reactive protein levels or white blood cell counts, and finally,
- GrimAge, which, in addition to DNA methylation levels, also takes into account lifestyle elements such as smoking [9,10,11,12].
Epigenetic modifications
Commonly defined as reducing calorie intake in a diet by 20-50% without changing macronutrient composition, CR and its anti-aging effects are a topic we briefly touched on in the last article. We would like to further expand on the points made there by focusing on the three main categories of epigenetic signatures influenced by CR:
a. DNA methylation
The addition of methyl groups to nucleotides, especially to cytosine residues within CpG dinucleotides, is considered the most important and therefore best documented epigenetic marker. It is known that methylation levels decrease with age, while certain genomic regions, particularly gene promoters, become hypermethylated [13,14]. Hypermethylation of these promoter regions has in turn been linked to gene silencing [15].
A study conducted in human and mouse cell lines demonstrated that the effects of CR on transcriptomic profiles are mediated by differential expression of the SIRT1 (Sirtuin-1) gene, a histone deacetylase, which, according to this study, may also play an indirect role in DNA methylation profiles; this conclusion is also confirmed in other studies that do not specifically focus on CR [16,17,18]. Interestingly, DNA methylation changes mediated by CR appear to persist long after return to normal caloric intake; this finding is supported by evidence from both mouse models and humans prenatally exposed to starvation [19,20]. The effects of CR on biological age were examined using blood samples from participants in the CALERIE study, revealing a significant slowing of the aging process based on the DunedinPACE watch [21,22].
b. miRNAs
This type of epigenetic markers are small non-coding RNAs that modulate post-transcriptional gene expression by either repressing translation or triggering mRNA degradation [23]. Although not yet proven in humans, there is evidence that CR has significant health benefits and increases anti-aging biomarkers in mice and rhesus monkeys. This has been documented for various tissue types including skeletal muscle, vascular endothelium, brain and colon [24,25,26,27].
c. Post-translational histone modifications (PTHMs)
The final major category of epigenetic modifications consists of chemical changes to histones, the proteins around which DNA coils. These modifications typically include methylation, acetylation, ubiquitination, and phosphorylation. The resulting consequences are complex and vary depending on the histone being modified, the modified residue and the exact type of modification, but usually take the form of transcriptional activation or repression of specific genes or groups of genes [28].
In terms of slowing the aging process, the most effective type of PTHM is believed to be the deacetylation of lysine residues by a family of enzymes called sirtuins [29]. In particular, one study has shown that the sirtuin SIRT1 is involved in histone acetylation and methylation, which causes chromatin restructuring of the p16 promoter, in an in vitro simulation of CR-like conditions performed on human lung fibroblast cultures. This promoter in turn represses the expression of p16INK4a, which is known to trigger cellular senescence [30]. Similarly, regulation of hTERT, a gene involved in telomere maintenance and oncogenesis, in human WI-38 fibroblast cultures under the same simulated CR conditions was shown to be caused in part by histone modifications [31]. Other age-related histone modifiers have been documented in CR studies in yeast and mice, including NAT4 and histone deacetylase 2 [32,33].
The “Epigentic Diet”
When it comes to the quality of our diet, it's harder to separate fact from fiction, but there are a handful of compounds whose geroprotective effects are supported by published data. The so-called “epigenetic diet”[34] contains foods rich in compounds or classes of compounds that promote epigenetic maintenance of key anti-aging markers. To name just a few:
- Polyphenols are compounds naturally occurring in plants (e.g. curcumin in turmeric, resveratrol in grapes, EGCG in green tea) that are involved in fighting tumors and preventing age-related metabolic changes [35,36];
- Sulforaphanes, a compound found in cruciferous vegetables (broccoli, kale, cabbage, etc.), is associated with antioxidant and anti-inflammatory effects and the prevention of neurodegenerative diseases [37];
- spermidine, whose sources include: aged cheese, mushrooms and soy products, owe their anti-aging effects to the promotion of autophagy (i.e. the elimination of cell debris) [38].
Of course, we should also mention what we should avoid in our diet: a recent study has shown that alcohol has a potentially age-accelerating effect by shortening telomeres, which limits the number of divisions our cells can undergo [39].
Conclusion
The field of aging research is rapidly growing in importance, and numerous anti-aging treatments are already in clinical trials [40]. However, there is no telling how long these trials will last or how many of them will successfully come to market (if any). That's why, at the moment, lifestyle factors such as diet, exercise, stress, etc. are the best way to increase our chances of staying young for as long as possible, and we hope that the above guidelines provide you with a good starting point to gain more knowledge about this goal.
