1. The Epigenetic Code Above DNA Regulates Aging
Aging in organisms begins at the level of individual cells. In addition to the well-known direct relationship between telomere shortening and increasing age, changes related to epigenetic modifications are also inextricably linked to aging.
What is epigenetics? "Epi" means "external" or "beyond," and "genetic" refers to inheritance, which stand for phenomenon a genetic character changes without DNA base sequence changes.
Most of us come into the world without genetic disease. However, as can be seen from the image below, during our growth process, positive or negative lifestyle habits can variously effect our bodies.
Epigenetics plays an important role in this process, sensing stimuli from the environment (in the biological sense, the environment includes but is not limited to dietary nutrition, exercise, air and water quality, etc.) and transmitting signals into the body to produce effects.
In general, epigenetics includes regulatory processes such as DNA methylation, histone modification, chromatin remodeling, and non-coding RNA interference. These processes accumulate lifespan, leading to human diseases, tumor development, and aging through signal transduction. In this context, many proteins get involved in the regulatory events, including modification enzymes which write or eraser various modification on protein or DNA, transcription factor which initiate the DNA expression. SIRT protein family is one of these key proteins participating in cellular metabolism and regulating many cellular function.
2. The Top Trend in Anti-Aging: Sirtuins
How dose Sirt protein play an important role in epigenetic regulation? Next, I will mainly explain it from two aspects: DNA methylation and chromatin modification.
DNA methylation is the most extensively studied mechanism for regulating gene expression and maintaining genome stability. In many regions of the genome, dinucleotides composed of cytosine and guanine (CpG) appear at high density, forming CpG islands.
The cytosine (C) at this site is easily modified by DNA methyltransferases (DNMTs) to form 5mC (Mitchell et al., 2016). Generally speaking, DNA methylation in gene promoters is negatively correlated with gene expression, while methylation in gene bodies weakens transcription (as shown in the image below).
Promoter-associated sites with relatively low overall methylation levels tend to gain methylation with increasing age, while sites with higher DNA methylation levels lose methylation over time (Jones et al., 2015).
Overall, DNA methylation levels decrease along with increasing age, and DNA hypomethylation may imply genome instability and telomere damage generated by aging.
As can be seen from the image below, during human aging, DNA methylation (red dot part) increases in the promoter region, while DNA methylation partially disappears in the gene body.
Epigenetic changes during the aging process are influenced by various environmental factors. For example, literature shows that certain dietary compounds can regulate DNA methylation, and changes in DNA methylation are associated with aging.
It is currently known that a healthy lifestyle and calorie restriction can prolong the human lifespan. Studies have shown that when calories are restricted, the expression of SIRT1 increases in some tissues, and changes in DNA methylation have been detected in overweight populations (Ions et al., 2013).
In addition, the gradual loss of DNA methylation with increasing age may be related to decreased activity of DNA methyltransferases (DNMTs).
While SIRT1 can upregulate DNMT1 enzyme activity, which contribute to the DNA methylation process. DNMT1 is deacetylated by SIRT1, thereby increasing its DNA methyltransferase activity and transcriptional repression function (Peng et al., 2011).
DNMT like a vehicle transporting methyl groups to DNA, and SIRT1 is the key to ignite the process. It promotes the generation of DNA methylation.
Therefore, the higher the expression level of SIRT1, the stronger the activity of DNMTs, and the more likely the DNA methylation pattern is to proceed normally, and the more stable the genome may be. Various indications suggest that SIRT1 may prolong lifespan by maintaining the integrity of the epigenome and appropriate DNA methylation patterns.
3. Sirtuins - Switches of Gene Expression
Histone post-translational modification (PTM) is an epigenetic mechanism that controls lifespan in various organisms by regulating transcriptional activation or inactivation, chromosome packaging, and DNA damage repair. The most well-known histone covalent PTMs include acetylation, methylation, phosphorylation, etc., with acetylation being the most prevalent.
Histone acetylation leads to a more open chromatin structure and is associated with transcriptionally active regions. Histone deacetylation results in inaccessible chromatin, leading to gene silencing (Feser and Tyler, 2011).
In the image below, the pink balls are nucleosomes, and the blue threads are the DNA wrapped around them. The orange horns on the pink balls are acetylated histones, which are more likely to recruit RNA polymerase (green), who is responsible for transcription, to activate downstream gene expression.
Conversely, in the right image, after the acetylation are removed by deacetylases, the DNA in this region is no longer visited by RNA polymerase, and the genes dose not keep expressing.
It is generally believed that as age increases, chromatin tends to form euchromatin (that is, a more relaxed chromatin structure due to higher acetylation levels) and more active transcription events occur (Tsurumi and Li, 2012).
Anyway, according to the views of some researchers, new heterochromatinization in certain regions of aging cells may also increase.
In some organisms, the increase in histone acetylation is caused by decreased sirtuin activity (Chandra et al., 2012).
Sirtuin-mediated deacetylation of specific lysine residues in histones can lead to gene silencing and mediate DNA repair regulation. SIRT1, SIRT2, and SIRT6 are the most studied proteins in this process (Jing and Lin, 2015; Kanfi et al., 2012).
Inhibition of SIRT1 in mammalian cells leads to hyperacetylation of H3K56 and promotes genomic instability, resulting in an increase in the cellular senescence process.
SIRT2 knockout in Drosophila leads to a significant increase in H3K56ac levels, confirming that Sir2 can deacetylate H3K56 (Das et al., 2009). Deacetylation of H4K16ac is crucial for the formation of condensed chromatin, and SIRT2 is the main contributor during the re-establishment of condensed chromatin in the cell cycle (Vaquero et al., 2006).
In yeast and Caenorhabditis elegans, Sir2 can deacetylate the lysine residues of H4K16 and H3K9, thereby establishing a more repressive chromatin conformation of histones H3 and H4, which is associated with lifespan extension (Jing and Lin, 2015).
In summary, Sirt2's deacetylation function on histones is positively correlated with longevity.
SIRT6 is a nuclear protein that can deacetylate H3K9 and H3K56. Its deacetylation function can regulate and protect telomeric chromatin in human cells (Michishita et al., 2008).
Moreover, SIRT6 deficiency leads to telomere dysfunction, chromosome fusion, and premature cellular senescence. Studies have shown that when it is overexpressed, the lifespan of male mice can be extended by 16% (Kanfi et al., 2012).
In addition, there are reports on other SIRT proteins. For example, SIRT7 is also an NAD+-dependent histone deacetylase. During the senescence process of human mesenchymal stem cells (MSCs), the expression level of SIRT7 decreases, and the lack of SIRT7 accelerates aging (Bi et al., 2020).
Overall, the epigenetic mechanisms involving SIRT activity and their impact on histone modifications in aging still need to be fully elucidated. However, longevity research to date suggest that there is a close association between histone acetylation and aging.
Thus, from the scientific evidence listed above, it can be seen that the expression of Sirtuins is negatively correlated with aging, and many epigenetic modifications may be driven by sirtuins. Sirtuin-mediated gene silencing and DNA repair regulation are achieved through the deacetylation of specific lysine residues in histones.
Sirtuin deacetylation of histone H4K16, H3K9, and H3K56 helps establish a more repressive chromatin conformation, which is associated with lifespan extension.
We already known that DNA methylation levels decrease with age, which may lead to age-related genomic instability and loss of telomere integrity. The above studies confirmed that the expression of SIRT1 also decreases in aging organisms, so we can consider that DNA methylation events may be related to the expression level of SIRT1.
Therefore, we can draw the conclusion that sirtuins, especially SIRT1, can enhance the DNA methylation process, and the DNA methylation process is crucial for maintaining genome stability and longevity.
All in all, epigenetics is closely correlated with aging and the SIRT protein family builds a bridge between them by amplifying the signal transmission of epigenetics and producing effects on the aging process.
Of course, apart from Sirtuins, there are many other ways in which epigenetics influences the aging process, which I will not elaborate on one by one.
In addition, maintaining a good lifestyle, healthy eating habits, and a pleasant mood are very important for longevity. After all, epigenetics is watching!
