Sirtuins are 7 NAD+ dependent deacylase genes which have been found to regulate different of the hallmarks of aging by interacting with all the major conserved longevity pathways, such as AMP-activated protein kinase (AMPK), insulin/IGF-1 signaling (IIS), target of rapamycin (TOR), and forkhead box O (FOXO). Of these, FOXO transcription factor is the most fascinating target of Sirtuin. These genes can be divided into nuclear (SIRT1, SIRT6, and SIRT7), mitochondrial (SIRT3, SIRT4, and SIRT5) and cytosolic (SIRT2) forms, and some sirtuins are found in more than one compartment. Additionally, Sirtuins are believed to be the major reason why calorie restriction (CR) and exercise improve health (Bordone et al., 2007; Guarente, 2005; Rogina and Helfand, 2004).
SIRT1 protects cells against oxidative stress, regulates glucose/lipid metabolism, and promotes DNA stability by binding to and deacetylating several substrates, acting as a transcription factor and cofactor. Because of these protective roles against several age-related pathologies, SIRT1 is thought as one of the candidate molecules for promoting healthy aging. This gene is also a target for histone and non-histone proteins and is able to regulate signaling pathways such as DNA repair and apoptosis.
Regarding previous studies, one performed with SIRT1 knockout mice showed a significantly shorter lifespan compared with wild-type mice. Another study done in 2014 revealed that SIRT1 activation shows promise for the treatment of aging and age-related diseases. (Sinclair, et.al)
Regarding previous studies, one performed with SIRT1 knockout mice showed a significantly shorter lifespan compared with wild-type mice. Another study done in 2014 revealed that SIRT1 activation shows promise for the treatment of aging and age-related diseases such as cancer, Alzheimer’s disease and Type 2 Diabetes. (Sinclair, et.al)
Of important note, SIRT1 has received most attention because of its ability to deacetylate key histone residues including H3-K9, H4-K16, H1-K26 and multiple non-histone protein targets including p53, FOXO1/3, PGC-1alpha and nuclear factor (Sinclair, et.al).
SIRT2 is primarily a cytoplasmic protein that can transiently shuttle into the nucleus in a cell cycle-dependent manner (North et al., 2003; North and Verdin, 2007a). Its protein levels vary accordingly to the cell cycle phase, increasing during mitosis. SIRT2 prolongevity effect of Sirtuin is tissue-specific and in yeast, it promotes longevity by suppressing the formation of toxic extrachromosomal rDNA circles (Sinclair and Guarente, 1997).
Moreover, overexpression of SIRT2 or treatment of mice with the NAD+ precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo, with a greater effect in male mice. In this study, researchers speculated that SIRT2 could directly modulate BubR1 abundance by deacetylating specific lysine residues on BubR1. (North, et al., 2014)
One more study suggests that extra copies of the SIR2 gene extended lifespan by 50%, whereas SIR2 deletion reduced longevity (Kaeberlein et al., 1999). Also, when SIRT2 is overexpressed it delays cell cycle progression. Thus, SIRT2 activators could be used as a novel therapeutic approach to obesity and in a more general way to metabolic syndrome. Dramatically, obesity is associated with a decrease in life expectancy (Haslam and James, 2005).
This importance of SIR2 in aging was recently corroborated by an unbiased genome-wide associated study (GWAS) that identified the SIR2 locus as the most significant regulator of replicative lifespan (Stumpferl et al., 2012).
SIRT6 functions in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation. It is often called the "longevity gene" because of its important role in organizing proteins and recruiting enzymes that repair broken DNA by stimulating HRR. Additionally, mice without the gene age prematurely, while mice with extra copies live up to 16% longer (only in males). Researchers have found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes are more potent. SIRT6 also rescues the decline in base excision repair of aged human fibroblasts. (Zhu, et al., 2015)
Worth mentioning, when the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. It was concluded that five amino acids determine the differential activities of mouse and beaver SIRT6 and that a stronger SIRT6 leads to a longer lifespan. (Xiao, et al., 2019)
Using an analogy suggested by David A. Sinclair PhD, the genome can be thought of as hardware whereas the epigenome would be the software. The epigenome consists of chemical compounds that have been added to the DNA, as a way to regulate gene expression. While these "tags" are not part of the DNA sequence itself, they can remain when a cell divides and in some cases, they can even be inherited.
A common way to refer to this process is the addition of "tags", which are methyl groups (CH3), to the genome. When this happens, genes can be silenced. In other words, DNA methylation won't allow a protein to be produced, which can lead to genetic disorders.
In human DNA, methyl groups most often attach at 'CpG sites' (places where a cytosine precedes a guanine in the DNA). A typical human genome contains more than 28 million such sites. But the microarray technology used to detect methylation samples finds only a fraction of them: older machines pin down just 27,000 sites and newer ones around 485,000. (Gibbs, 2014)