Sirtuin 1 (SIRT1 gene)

Sirtuin may be defined as 'Any of several enzymes that act as regulatory factors that mediate the life-extending effects of a low-calorie diet.'

Sirtuin 1 which is also called the NAD-dependent deacetylase sirtuin-1 is basically a protein that is encoded in humans as the Sirtuin 1 (SIRT 1 gene). Sirtuins are basically divided into four classes. Although their functions in the humans are not clearly defined yet the yeast sirtuins regulate the epigenetic gene, suppressing the recombination of the DNA. They work as intracellular regulatory proteins which compose of the class1 of sirtuin family.

The SIRT1 gene regulates the span of life in organisms like the yeast, Caenorhabditis elegans and members of the rodent family. The findings have shown that SIRT1 which is a human homologue modifies the expectancy of human life. An experiment was conducted to study whether common allelic changes in the SIRTI gene would affect the human longevity. DNA collections of long living individuals like centenarians and nonagenarians were taken and compared with the younger ones after taking 5 (SNPs) single nucleotide polymorphisms and distributing them across the gene. The findings showed that the sirti1 had no noteworthy influence on the longevity of the German population. However this could not refute the fact that SIRTI did have a critical role in expanding the lifespan of human beings.

For the past 10 years SIRT1 gene has been a topic of great interest for biologists as it is supposed to affect the longevity of various eukaryotic species and individuals ranging from nematodes and yeast to mammals. This effect is closely related to the benefits of calorie restrictions on the longevity of life that have been observed since decades.

Initially the SIRTS or Silent Information Regulators found in yeasts were found to have something to do with their longevity. Out of these several proteins, three of them known as SIR2. SIR3 and SIR4, although dissimilar in structure, were direct implications on the effect of longevity. Ultimately it was seen that SIR1 and a gene in the nematode, remarkably close to its analogue had similar properties, that of enhancing longevity.

It was this interesting fact about its effect that they came to be known as sirtuins. It is believed that there are 7 such human proteins. They are named from SIRT1to SIRT7. Of these SIRT1, which is a histone deacetylase enzyme, has been of great interest to all. These enzymes are involved in a variety of biological processes and can effectively suppress many genes.

There are many interesting facts about sirtuins. Some of them related to calorie restrictions are as below.

To Live Long, Eat Less

It is believed that to lead a healthy life one should restrict his calorie intake. After studying certain researches done in the Harvard Medical School, along with scientists from National Institutes of Health, and Cornell Medical School, two new genes were discovered in the cells of mammals that protected the cells from aging. They acted as the guardians of our body and protected our cells from degeneration.

The author of the paper, David Sinclair who is also the associate professor of pathology at the Harvard, says, "We've reason to believe now that these two genes may be potential drug targets for diseases associated with aging." These new genes discovered by them are called SIRT3 and SIRT4, which belong to the larger variety of genes called Sirtuins. The sirtuin 1 is a mammalian sirtuin which controls an individual behavior in response to the availability of food. All the seven sirtuins in the mammalian genomes has a typical pattern of expression, physiological importance and sub cellular localization. This mammalian sirtuin SIRT1 does not only control the behavior in accordance with the CR (caloric restriction) but also “mediates the lifespan of its extension phenotype”.

Longevity has often been correlated with your ability to resist stress. Now what is ageing?

Ageing is nothing but the decrease in the ability of the body to maintain the cellular functions over time. Broadly speaking the cellular responses try to correct the problem by detecting the suboptimal conditions and activating the genes, thus maintaining the homeostasis. So the greater or stronger the response the greater will be the delay in ageing and regulating the lifespan.

The heat shock proteins play an important role in regulating the lifespan. It has now been connected to Sirtuin 1. The HSF is subject to acetylating, in mammals, where its ability to bind the DNA diminishes, but this can be overcome with the help of SIRT1.

Regulation of Heat Shock Factor by SIRT1

The cells need to be protected by the damages caused due to protein damaged by stress or misfolded proteins which lead to ageing. This can be prevented by Heat Shock Factor (HSF). The DNA binding activity is negatively regulated when the HSF1is inducibly acetylated at a critical residue, when the deacetylase and longevity factor of SIRT1 is activated establishing a role for SIRT1 in protein homeostasis.

Prostate cancer can be treated by modulating the excess produce of androgen. Gradually this disease becomes progressive and stops responding to androgen ablation therapy. It has been found after a lot of research that sirtuin 1 is required to suppress the growth of prostrate by androgen antagonistic- mediated transcriptional repression. The androgen receptor (AR) recruits SITR1 and AR responsive promoters to deacetylate histone H3 as the prostate antigen promoter, locally, further increasing the sensitivity of the genes responsive to androgen causing stimulation, and enhancing the sensitivity to androgens , decreasing the sensitivity of prostate cancer cells. These findings clearly identify SIRT1 as a corepressor of AR elucidating a new pathway for the treatment of prostate cancer.

It has been proved that SIRT1 gene plays an important role in aging and in diseases that lead to aging, and the pathways that lead to the treatment of aging, caused by diabetes, insulin signaling, and fat mobilization. Prostate is also considered to be a disease of aging because the rate of prostate cancer increases more rapidly with age, compared to other kinds of cancers. The link between the aging of cells and SIRT1 protein has been observed and it has been found that endogenous SIRT1 protein diminishes with aging. Thus fetal tissues have a higher expression of SIRT1 than adult tissues. It is possible therefore that decline in SIRT1 due to age may be the cause for abnormal activity in promoting cancer of the prostate during aging.

Role of SIRT1 in Stem Cell Aging

New discoveries are being made focusing on mitochondrial metabolism and gene silencing to bring about improvement in geriatric medicine. This can be done by regulating the sirtuin family of protein deacetylases. There is hardly any information on the role of sirtuins in stem cell biology. Studies are being made on the information derived on sirtuins, the role they play in aging and metabolism of several tissues and species and an effort to anticipate its role in stem cell aging.

Latest Findings

Restriction in calorie intake increases ones span of life, due to the reorganisation of mitochondrial metabolism, thus reducing the levels of radical oxygen species which cause macro molecule damage, a major cause of aging. Little is known about stem cells except that sirtuin influences their maintenance and growth-factor. Calorie restricted lifespan requires Sirtuin 1 to induce extension of life in mice while in humans it regulates the calorie restriction. It also influences the cellfate decisions of stem cells by redox status.

Sirtuin 1 is chromatin silencing factor and a stress response and is also involved in nuclear events like DNA replication, transcription and DNA repair.

The SIRT1 also controls the gluconeogenic pathways of the liver as a response to fasting signals. When we fast, a nutrient signalling response is mediated to induce SIRT1 protein in liver. When it is induced, it intreracts with deacetylates in a dependant manner, but does not regulate its effects on mitochondrial genes. Thus having identified a molecular mechanism it functions in glucose homeostasis as a modulator.

It was found that SIRT1 played a very important role in angiogenesis in vitro, in mice and in zebrafish. During blood vessel growth in mouse vasculature, where the angiogenic activity of endothelial cells was controlled, SIRT1 was highly expressed. Loss of SIRT1 blocked the branching morphogenesis of endothelial cells in humans and sprouting angiogenesis, resulting in down regulation of genes which were involved in the development and remodelling of blood vessels. Any kind of disruption of SIRT1 in mice and zebrafish resulted in the formation of defective bloodvessels, and neovascularisation induced by blunted ischemia.

To assess the role of calorie restriction for SIRT1, the food intake of wildtype and knockout mice was measured and they were fed ad libitum, lacking functional SIRT1. The food allotted to all the restricted mice was restricted to 60% of the ad libitum values. They were fed only once a day. It was found that after 9 months of restriction, there was greater physical activity in wild type mice after a period of nine months. Whereas no change was found in the physical activities of the SIRT1 knockout mice who were given a calorie restricted diet. The glucose and triglyceride levels were reduced in both. This showed that for the upregulation of physical activity the gene that coded for SIRT1 was essential.