Sirtuins for Restoring Youthfulness and Extending Longevity

Emerging from current research on the sirtuins there is a growing appreciation that the sirtuins are playing major roles in regulating cell proliferation, cell survival and apoptosis (programmed cell death). Sirtuins block multiple key processes in neurodegeneration. Sirtuins restore protein homeostasis by reducing accumulation of toxic proteins, improve neural plasticity by elevating transcription of genes, enhance mitochondria function by reducing oxidative stress, and suppress sustained chronic inflammation with epigenetic mechanisms. In this article we review the role sirtuin genes for restoring youthfulness and extending longevity.

Calorie restriction (CR) is widely accepted as one of the methods to extend longevity and reduce the physical manifestations of aging. Calorie restriction is part of many meditation techniques (e.g. Vipassana Meditation). Regular yoga, meditation, exercise, food choices, quantities of food  and genetics among many other factors play significant role to restore youthfulness. The current findings sharpen our understanding of sirtuins as potential agent to overcome aging and possibly opening new avenues for extending longevity.

What are Sirtuins?

Sirtuins are a family of age related proteins. Sirtuins regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. In mammals, the sirtuin family has seven members (SIRT1-7).  The main function of sirtuin proteins is to promote survival and stress resistance, resulting in longevity. Many studies on yeast and mice demonstrated that caloric restrictions increase life span. The gene that was responsible to increase life span is SIR2. SIR2 was the first gene of the sirtuin family found in budding yeast. Humans don’t have SIR2, but we have a equivalent gene known as SIRT1.  The family of SIR2 and SIRT1 is collectively known as sirtuins.  The word SIR, stands for Silence Information Regulator genes. The term sirtuins is derived from the word ‘‘sir-twoins’’

Location of the Sirtuins

Sirtuins Locations and Functions

Sirtuins Locations

Among mammalian sirtuins, SIRT1, SIRT2, SIRT6, and SIRT7 are located in the nucleus. SIRT1 and SIRT2 is located in cytoplasm and three others (SIRT3, SIRT4, and SIRT5) are located in mitochondria. These mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. SIRT3 exhibits high expression in important metabolically active tissues like kidney, heart, liver, and brain. SIRT6 exhibits high expression in adipose tissue, skeletal muscle, brain, and heart.

Functions of Sirtuins

The main function of sirtuin proteins is to promote survival and stress resistance, resulting in longevity. Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD+; thus, sirtuins are classified as “NAD+-dependent deacetylases. Deacetylation is simply the reverse reaction where an acetyl group is removed from a molecule. NAD+ is the term used in the scientific literature to describe a cellular compound called nicotinamide adenine dinucleotide. Owing to the characteristic NAD requirement for their enzymatic reaction, the activity of sirtuins is directly linked to the metabolic state in the cell. High NAD+ levels convey high neuroprotective effects. NAD+ is found in every cell in the body and is essential to life. NAD+ enables the transfer of energy from the foods we eat to vital cell functions. NAD+ is also required to “turn off” genes that accelerate aging processes. Of the seven human sirtuin proteins, five (SIRT1, SIRT2, SIRT3, SIRT5 and SIRT7) are deacetylases, while the other two (SIRT4, SIRT6) function as ADP-ribosyl transferrers.

Functions of SIRT1:

Among all the sirtuins, function of SIRT1 is well studied by the scientists. SIRT1 plays prominent physiological functions in liver, muscle, pancreas, testis, ovary and adipose tissues to regulate cell proliferation, cell survival and apoptosis [1]. It is widely reported that SIRT1 can promote not only carcinogenesis but also metastasis and insulin resistance, and have beneficial effects in metabolic diseases, mediate high-density lipoprotein synthesis and regulate endothelial nitric oxide to protect against cardiovascular disease.  SIRT1 promotes replicative senescence under conditions of chronic stress.  

Mitochondria Sirtuins 

Mitochondria are cellular energy powerhouses that play important roles in maintaining cell survival, cell death and cellular metabolic homeostasis. Timely removal of damaged mitochondria via autophagy (mitophagy) is thus critical for cellular homeostasis and function.  Mitochondria are the primary site of reactive oxygen species (ROS) generation within the cell.  ROS are chemically reactive molecules containing oxygen. ROS are main one cause of aging. They are implicated in cellular activity to a variety of inflammatory responses including cardiovascular disease.

Mitochondrial dysfunction is linked with aging and age related diseases. Recent work suggests that sirtuins can modulate ROS levels notably. There is increasing research evidence that mitochondrial sirtuins (SIRT3–5) regulates aging and age related diseases. Most studies focused on SIRT1 and SIRT3. Among these, SIRT3 has received much attention for its role in metabolism and aging. SIRT3 gene reduces oxidation, suppresses tumor growth and helps to renew old mitochondria in a process called mitogenesis.  SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. SIRT3 protein levels in skeletal muscle are sensitive to diet. SIRT3 exhibits high expression in important metabolically active tissues like kidney, heart, liver, and brain.  SIRT3 expression increases by exercise,  fasting and caloric restriction and decreased by high-fat diet. There is growing evidence linking mitochondrial sirtuins with regulating energy usage and even human lifespan. Although both sirtuins and ROS have been implicated in the aging process, their precise roles require further research.

Sirtuins and Neural Plasticity

Much of the brain’s ability to adapt or modify itself in response to experience and environment lies in the plasticity of synaptic connections, both short-term and long- terms. Sirtuins regulate neuro-plasticity in the brain in three ways: by BDNF, via microRNA and through CERB-SIRT1 axis.  Several studies in the past two decades have demonstrated that brain-derived neurotrophic factor (BDNF) plays a critical role in enhancing plasticity is enhanced by SIRT1.  SIRT1 regulates BDNF  in hippocampus. SIRT1 also modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism [2]. MicroRNA is responsible for fine-tuning of gene expression. SIRT1 deficiency reduces BDNF expression by upregulating the microRNA. CREB-SIRT1 axis is also emerging as a critical player for neuronal plasticity.  Increased SIRT1 levels, enhance CREB-dependent expression of genes involved in neuronal metabolism, survival, and plasticity.

Telomeric Regulation:

Telomeres are protective DNA sequences at the ends of chromosomes that ensure genomic stability during cellular replication. Over time, due to each cell division, the telomere ends become shorter. Telomeres act as the aging clock in every cell. In young humans, telomeres are about 8,000-10,000 nucleotides long. They shorten with each cell division. Proper telomere maintenance is the secret of youthfulness. Although genetics play an important role in determining telomere length, lifestlyle, diet and exercises are the key elements to extend telomeres and reverse the aging process. Scientist observed that SIRT6 is required for maintenance of telomere position in human cells [3]. Increasing evidence supports SIRT6 as the key modulator of telomere structure, DNA repair, metabolism, and NF-kappa B pathway in aging. Inactivation of SIRT6 leads to loss of telomere protection. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation.

Anti-inflammatory Function of Sirtuins

Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation or swelling. Inflammation is the body’s attempt at self-protection to remove harmful stimuli and begin the healing process. Inflammation is a protective immunovascular response that involves immune cells, blood vessels, and molecular mediators. The purpose of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair. Inflammation is tightly regulated by the body.  Acute inflammation protects and heals the body. When acute inflammation is not resolved, the inflammation may pass to a longer term chronic phase. Chronic inflammation is often long-term inflammation, which can last for several months and even years. Chronic inflammation may be root cause of many age-related diseases. Research indicates that heart disease, clogged arteries, stroke and diabetes may be linked to chronic inflammation. Many age-related neurodegenerative diseases, such Alzheimer’s disease, Parkinson’s disease etc. exhibit prolonged inflammatory responses. Researchers observed SIRT1 genes are linked in inflammatory responses. SIRT1 can block the neuropathogenic inflammatory loops.

 How to extend longevity and stay young

Caloric restriction and fasting has been found to extend the lives of animals in laboratories. Researchers observed that  proteins such as SIRT3 are activated by oxidative stress, which is triggered when there are more free radicals produced in the body. The variability of telomere length may be partially explained by lifestyle practices, including dietary patterns. They observed that small levels of free radicals can be beneficial: When the body undergoes stress such as fasting — small levels of oxidative stress can trigger protective pathways. Recent study suggested that eating a single serving of berries every day could add an extra year to our lifespan. The available evidence also suggests that eating nuts may extend our life by years. A plant based diet overall is thought to be capable of reversing heart disease and, thus, extending the lifespan. Besides diet, sleeping 7 hours a night may maximize longevity.  Consuming milk and other animal products may increase the risk of a variety of age-related problems. Antioxidant pills have almost no effect on aging.

Overall, regular yoga, meditation, walking, exercise, food choices, quantities of food  and genetics among many other factors play significant role to restore youthfulness and extend longevity. Eating Mediterranean diets are helpful.   Fruits, vegetables, olive oils and nuts are the key components of a Mediterranean diet.

Sirtuins have emerged as key anti-aging genes in organisms. All the sirtuins respond epigenetically to a variety of environmental factors. Existing evidence strongly supports sirtuin involvement in longevity, age-related diseases, obesity, cardiovascular and neurological function. Scientists are trying to learn how they can modulate sirtuins, so that they can control which cells live and which undergo programmed cell death.

Top Ten Sirtuin Foods

References:

Function of Sirtuins in Biological Tissues
2. A novel pathway regulates memory and plasticity via SIRT1 and miR-134.
3. SIRT6 is required for maintenance of telomere position effect in human cells

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