Sirtuins and Longevity

Introduction

The number of elderly population is increasing in our country and they form nearly 10 per cent of the total population. They suffer from many diseases such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, osteoporosis, osteoarthritis, and malignancy and succumb to them. Ageing itself acts as an important risk factor for development of many of those disorders. People are in search of things that can keep them young. They include dietary regimens and exercise programs to achieve longevity. The medical science concerned with ageing has been able to identify genes and pathways that appear to control the process of ageing.

Sir2

While studying the simple laboratory organisms such as yeast, Leonard Guavente and colleagues, in mid 1990s found that when small amounts of food is administered to them, it extended their life-span.¹ The experiments with different sets of genes enabled them to recognize a certain type of gene when administered to them increased their life span and its withdrawal led to their death. The gene was named Silent Information Regulator two (Sir2). They are proteins possessing either histone deacetylase or mono-ribosyltrasferase activity. They are essentially found in organisms from bacteria to humans. The name Sir2 has come from yeast genes as ‘silent mating type information regulator two’, which is responsible for different cellular activities. Sirtuins have been implicated in influencing ageing and regulating transcription, apoptosis and stress resistance as well as energy efficiency and alertness during low calorie diet. Often they are referred to as ‘longevity genes’. They can extend the life span in model organisms and calorie diet.

Sirtuins

Sir2-related gene products (sirtuins) were able to extend the life-span in the nematodes (Caenorhabditis elegans), in the fruit fly (Drosophila melanogaster), and in mice.^{2, 3} Sirtuins exhibit nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity, which is associated with the splitting of NAD during each deacetylation cycle.⁴ These genes suppress certain genes and repair DNA within the body. The process is referred to as ‘gene silencing’.   Sirtuins function by silencing the expression of certain other genes.⁵ This prevents wrong genes getting activated to disturb the function of the cells.

Sir2 is a protein decarboxylase that mediates transcriptional silencing at selected regions of the yeast genome, especially at the ribosomal DNA repeats, and extends its replicative life span.³ Sirutins keep cells alive and healthy in face of stress by coordinating a variety of hormonal networks, regulatory proteins and other genes. Since then sirtuins have been shown to regulate longevity in lower organisms such as flies and worms.²

Activity and functions

Mammals have seven sirtuin (SIRT1-7) orthologues that occupy different subcellular components. The sirtuins (SIRT1, 2, 3, 4, 5, and 6) exhibit NAD-dependent protein deacetylase activity.⁶ In addition, they regulate the circadian rhythm, metabolism, stress tolerance, and ageing.⁷ Sirtuins belong to the class III protein deacetylase family which are the only histone deacetylases (HDACs) that require NAD for their enzymatic activity. Owing to the characteristic NAD requirement for their enzymatic reaction, the activity of sirtuins is directly connected with the metabolic state in the cells.

SIRT4 and SIRT6 in addition exhibit ADPribosyltransferase activity. SIRT7 is found in nucleolus whose activity is undetermined.  Sirtuins have been classified as per their succession of amino acids. They act on all cellular regulation in the same manner Sir2 behaves in yeast. The location, activity and functions of different sirtuins are as follows:

Sirtuins are effective in protecting cells of human being from deterioration and in restituting injured cells.

SIRT1

SIRT1 in mammals is Sir2 orthologue and is found as a nuclear protein in most cells and takes part in deacetylation of the transcription factors and cofactors that participate in a variety of metabolic pathways. The transcriptional factors such as nuclear receptors, peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1 alpha (PGC-1 alpha) and forkhead box subgroup O (FOXO) are known to have important role in the energy metabolism.⁸ SIRT1 has an influence on the components of circadian clock and works in conjunction with AMP-kinase in limitation of energy expenditure. Further it regulates stress response by acting on p53, hypoxia-inducible factor 1 alpha and 2 alpha and heat-shock factor protein-1.⁹ SIRT1 also modulates DNA repair and inflammation. Thus the activity of SIRT1 regulates metabolism and stress response.¹⁰

Metabolism

The animal studies in rats have shown that SIRT1 could influence differentiation and fat accumulation in the adipose cell line and primary preadipocytes.¹¹ A calorie-restriction diet increases biogenesis of muscle mitochondria.¹² SIRT1 helps the activation of fatty acid oxidation. Along with PPAR-gamma SIRT1 increases insulin sensitivity.¹³ All these events are bound to slow down the rate of age-related decline.

SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.¹¹ Deletion of hepatocyte-specific SIRT1 brings about an alteration in fatty acid metabolism and causes accumulation of fat in the liver.¹³ In the liver, SIRT! appears to govern two pathways that exhibit opposing influences on gluconeogenesis. On one hand it may activate PGC-1alpha and FOXO1 to produce glucose.⁸ On the other hand the deacetylation and destabilization of the cyclic AMP decreases the production of glucose via activator/ coactivator exchange.¹⁴

In calorie restriction, the relative influences of these pathways results in a mild increase in glucose production.¹⁰ SIRT1 along with SIRT6 repress the activity of the major proinflammatory transcription factor and nuclear factor and bring about an anti-inflammatory effect.¹⁵

Cardiovascular System

SIRT1 is cardioprotective. It prevents angiotensin II-induced vascular smooth muscle cell hypertrophy in the cardia by downregulating the expression of the angiotensin-II type 1receptor (ATI).¹⁶ There is a decreased production of reactive oxygen species leading to an increased longevity of the mice¹⁷ and it is mediated by increased levels of SIRT3^.  SIRT1 causes deacetylation and activation of endothelial nitric oxide synthase (eNOS).¹² Decreased oxidative stress inhibits oxidative stress-induced premature senescence of endothelial cells that may mitigate atherosclerosis.¹⁸ Calorie restriction has a favourable effect on cardiovascular system through SIRT1 that influences the functions of eNOS, and ATI.

SIRT1 regulates the fat and cholesterol homeostasis. It triggers oxidation of fatty acids in calorie restriction.¹³ It causes deacetyalation and activation of the nuclear receptor liver X receptor (LXR), leading to up-regulation of the ATP-binding cassette transporter AI. It brings about reverse cholesterol transport (RCT) from peripheral tissues.¹⁹  In addition SIRT1 causes deacetylation and activation of the nuclear bile acid receptor farnesoid X receptor (FXR) leading to increase its dimerization.²⁰ Activation of LXR and FXR by SIRT1 brings about an increased production of high-density lipoprotein (HDL) cholesterol. It facilitates cholesterol removal and regression of atherosclerosis.

SIRT1 plays an important role in regulation of hepatic lipid metabolism. The activation of LXR by SIRT1 gives impetus to the gene encoding the sterol regulatory element-binding protein 1 (SREBP1) in liver to drive fat and cholesterol synthesis. This effect may be counteracted by an opposing action of SIRT1 through deacetylation of SRBEP1 and repression of its activity.²¹

Neurodegenerative diseases

Increased longevity is associated with development of neurodegenerative diseases including Alzheimer’s disease. An over-expression of SIRT1 in the brain is likely to cause suppression of production of toxic beta-amyloid peptde by activating the alpha secretase gene ADAM10, through deacetylation of its transcriptional activator, the retinoic acid receptor-beta and protect against the disease.²² In addition SIRT1 causes deacetylation of tau protein and bring about destabilization and reduction in tangles.²³

Mitochondrial sirtuin

SIRT3, 4, and 5 are examples of mitochondrial sirtuins that appear to mediate physiologic adaptation to reduced energy consumption. They bring about changes in the mitochondrial proteins that govern the metabolic pathways in energy deprivation. SIRT3 deacetylates long-chain acyl dehydrogenase involved in the oxidation of fatty acids. Thus SIRT3 deacetylates the components of the electron transport chain to make oxidative phosphorylation more efficient. It activates mitochondrial superoxide dismutase 2, isocitrate dehydrogenase 2 and components of the electron transport chain to suppress reactive oxygen species.

SIRT4 causes repression of the enzyme glutamate dehydrogenase (GDH) to regulate amino acid catabolism for energy.²⁴ During calorie restriction there is a decline in the activity of SIRT4 facilitating glutamine to act as a fuel source for glucose synthesis in liver and as a stimulus for insulin secretion by beta cells of islets in the pancreas. SIRT5 causes deacetylation of carbomoylphosphate synthase (CPS1) enzyme to activate the urea cycle, facilitating the disposal of ammonia when amino acids are utilized as fuel sources.

Activators of SIRT1

The studies on small-molecule activators of SIRT1 have been carried out.²⁵ Resveratrol is a polyphenol antioxidant, and a possible SIRT1 activator, found in muscadine grapes, groundnuts, berries and cocoa beans. It is found in Japanese knotweed and has been in use for several decades in Japan and China for its anti-aging properties. It activates longevity genes. It activates deacetylation of peptidyl substrates. A new class of chemically distinct classes of selective, synthetic SIRT1 activators has been identified. They possess higher potency than polyphenols. Both these compounds have the capability to increase the binding affinity of SIRT1 for the peptide substrates labeled with a chemical fluorophore group. Sirtuins are effective helping protect cells of human beings from damage and also help with restituting injured cells.