Almost everyone is talking about Sirtuins; the diet craze, ‘Sirtfood Diet’ is ample proof of this. This explosion of interest is mostly triggered by the role of Sirtuins proteins in protecting the body from inflammation and various kinds of diseases, regulate metabolism (thus helping to lose weight) and increasing health and lifespan. So, what exactly are Sirtuins?
The silent information regulator 2(SIR2), also called Sirtuins, are NAD+ dependent proteins. They are found in every living organism. Researchers have been particularly fascinated with these proteins as they appear to play a direct role in regulating life span. Studies show that in mammals Sirtuins regulate biological responses to metabolism and stress – two key factors known to influence the process of aging . Emerging studies also highlight the role of Sirtuins in the treatment and prevention of age-associated pathologies including cancers, metabolic disorders, cardiovascular and neurodegenerative diseases.
In mammals, the Sirtuin family is so far known to contain 7 proteins – SIRT1-7 – with SIRT1 and SIRT3 the most studied and investigated of all the Sirtuins. The mammalian Sirtuins are located in different areas in the cells. SIRT1, 6 and 7 are predominately found in the nucleus, SIRT2 is localized in cytoplasm (but also shuttles between nucleus and cytoplasm), and SIRT3, 4, and 5 are located in the mitochondria.
What do Sirtuins Do?
It is not so simple to describe the role of Sirtuins in our body, but studies show that the main function of Sirtuins is to regulate expression of various genes involved in:
- Metabolic pathways
- Cellular defense mechanisms during stress
- Cell reproduction, repair and renewal
- Energy production in mitochondria
While the main function of Sirtuin proteins is to protect the cells from every day stress and promote survival, self-preservation and stress-resistance, each of the seven Sirtuins may have unique roles to play and different outcomes to achieve in the body.
Calorie Restriction and Sirtuins
The anti-aging benefits of calorie restriction are believed to be partly orchestrated by Sirtuins. Calorie restriction (low calorie intake) is widely accepted as one of the proven methods to extend the life span in humans.
Of course, one of the main theories is that calorie restriction reduces the formation of damaging free radicals, generated when cells process oxygen and nutrients in the mitochondria to generate energy. However, there seems to be more to the question of how calorie restriction extends life span. It is believed that a low-calorie diet triggers some very specific biological responses that endorse cell preservation and cell survival under duress. And one of these mechanisms involves activation of Sirtuins .
Sirtuins are NAD+ dependent
What is also interesting is that Sirtuins require NAD+ as an essential cofactor to perform their diverse functions. For example, Sirtuins require NAD+ to remove acetyl groups from proteins through a process called deacetylation. Sirtuins deacetylate proteins – ranging from histones to transcriptional regulators – intricately involved in regulating stress, metabolism and cell survival pathways.
Understanding Acetylation and Deacetylation
Histone acetylation and deacetylation are important reactions involved in gene regulation. Histone deacetylases are enzymes that make these reactions happen. Sirtuins are NAD+ dependent histone deacetylases.
A quick run-down on gene expression and gene regulation.
- Our DNA contains tens of thousands of genes.
- These genes contain information that will result in the formation of proteins.
- The resulting proteins are responsible for how we are going to look, grow, reproduce and survive. For example, these proteins are responsible for our traits, such as height and the color of hair, skin and eyes etc.
- The information in the gene is stored as a particular sequence of DNA bases. There are 4 bases in DNA, namely adenine (A), thymine (T), guanine (G) and cytosine (C). The base on one strand of DNA pairs up with a base on the second strand of DNA to give rise to the double helix structure. Now, A only pairs with T and G only pairs with C – resulting in a particular sequence of these bases or nucleotides.
- This sequence acts as a blueprint or set of instructions to synthesise a protein.
- One gene can code for thousands of proteins.
In simple words, gene expression can be defined as the process by which the instructions in the gene are used to create proteins responsible for many functions, mechanisms and processes in the body. This genetic information is also used to create cellular structure. And gene regulation is a term for complex cellular processes that control the rate and manner of gene expression .
How Sirtuins fit in here? For that we need to get a quick insight into what histones are. Histones are proteins that serve as spools for thread-like DNA to wrap around. These protein spools package DNA into tight units called nucleosomes. When acetyl groups are added to the histone (acetylation process), DNA is not as tightly packaged, and wraps loosely around the histone and becomes more available for the process of gene expression. When acetyl groups are removed from the histone (deacetylation), DNA is wound tightly around the protein spool and less available for copying or expression. Sirtuins, by the process of deacetylation, inhibit the expression and regulation of certain genes involved the process of aging.
Summing up various functions of ‘NAD+ dependent’ Sirtuins:
- Removes acetyl groups from proteins (histones to transcriptional regulators).
- Repairs double-stranded DNA breaks
- Controls physiological responses to metabolic instability and stress.
- Improves mitochondrial functions, especially during the time of stress, for example caused by fasting, oxidative stress and DNA damage
- Interferes with inflammatory pathways and reduces inflammation, the root cause of many chronic disorders.
- The dependency of Sirtuins on NAD+ suggests that boosting NAD+ levels in the body may be a beneficial strategy to activate Sirtuins and prevent and manage a plethora of diseases.
- Akiko Satoh, Liana Stein, Shin Imai. The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity. Handb Exp Pharmacol. 2011; 206: 125–162.
- Seongjoon Park, Ryoichi Mori, Isao Shimokawa. Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction. Mol Cells. 2013 Jun 30; 35(6): 474–480.
- Gene Expression and Regulation. Virtual Genetics Education Centre. University of Leicester.