List of Longevity Genes – A Must Read for Longevity

Scientists are trying to pin point the genes responsible for longevity. There are about 200 genes that are directly associated with longevity. Twenty of them are very prominent. Out of these 20 longevity genes, IGF-1, FOXO3A, NF-kB, AMPK, CETP, SIRTUIN are most prominent. We think that, out of these six, SIRTUIN and FOXO families have major impact on longevity. In this article we will discuss more about these six prominent genes.

Genes-agingAging has normally been thought to be due to ‘wear and tear’. However, this view has changed. The interaction between genes, metabolism, and natural variations in longevity is an enormously complex subject. We all know that genetics, environmental risks, lifestyle, and strong social bonds are the major factors that helps people to live longer.  Longevity has a strong genetic component. However, this view is also gradually fading away.  The genetic underpinnings of longevity are real — it’s just that they’re far richer and more complex than we anticipated. The aging process is likely the result of tens, or hundreds, or even thousands of closely intertwined genetic factors. Here is the list of longevity genes.

Longevity Genes Summary

1. Insulin-like Growth Factor-1 (IGF-1) Gene

IGF-1 is a hormone similar in molecular structure to insulin. IGF-1 is structurally and functionally related to insulin but have a much higher growth-promoting activity.  IGF-1 deficiency is characterized by growth retardation, sensorineural deafness and mental retardation. IGF-1 is produced primarily by the liver as an endocrine hormone. IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth. The lowest levels occur in infancy and old age. Scientists observed that  insulin and IGF-1 regulate longevity in a conserved manner.

Insulin/IGF-1 signaling (IIS) pathway has been implicated in longevity for lower species. Several studies demonstrated that in invertebrate species the IIS pathway plays a major role in the control of longevity. However, its role in human longevity remains controversial. Mammals have insulin/IGF-1 receptors in many organs, but their functions are opposite if they are located in the central nervous system; whereas lower species have insulin/IGF-1 receptors signaling mainly through the nervous system. Hence, the role of IGF-1 is controversial.  In summary, the postulated aging effects of IGF-1 are not clear.

 2. FOX3A Gene

The FOX gene family provides instructions for making proteins that play a critical role in the formation of many organs and tissues before birth.  FOX proteins regulate certain gene activities in the eyes, lungs, brain, cardiovascular system, digestion system, immune system, and cell division cycle. An important function of FOXO proteins is their control of the cellular redox balance. FOXO trancription factors play important roles in a set of cellular responses, including glucose metabolism, cell death, cell cycle arrest, repair of damaged DNA , and detoxification from reactive oxygen species. Reactive oxidative species (ROS) are known to damage proteins and DNA, promote cellular aging and, as a consequence, induce the onset of age-related diseases. FOXO gene family regulates ROS is therefore important in the wider context of cellular aging and organismal lifespan.

The FOXO class of proteins consists of four members, FOXO1, FOXO3A, FOXO4, and FOXO6. FOXO3A is expressed highly in the liver and FOXO4 is highly expressed in skeletal muscle. FOXO6 is predominantly found in the brain. FOXO3a is known to be particularly important in cell cycle control and apoptosis, the immune system, fertility, and longevity. It is also established that nuclear Sirtuins interact with and under specific cellular conditions regulate the activity of FOXO gene family proteins. Many consider FOXO3A as the global factor for longevity, specially for the people who live people who live past 100 years.

3. CETP Gene

Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein. This longevity gene was discovered in 2003. CETP  regulates the HDL “good”cholesterol and the size of cholesterol particles.  As a result, CETP has been linked to longevity and lower heart disease risk.  Lowering CETP results in higher HDL, which may protect against heart disease. Increased CETP activity is a major determinant of low HDL-cholesterol.

Indeed high levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol are correlated with increased incidence of cardiovascular disease. The CETP longevity gene is also associated with less cognitive decline as people grow older.

4.AMP-activated protein kinase (AMPK) :

AMPactivated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. AMPK is expressed in a number of tissues, including the liver, brain, and skeletal muscle. Many studies with lower species have revealed that increased AMPK activity can extend the lifespan. AMPK controls whole-body glucose homeostasis by regulating metabolism in multiple peripheral tissues, such as skeletal muscle, liver, and adipose tissues. Many biochemical adaptations of skeletal muscle that take place during a single bout of exercise or an extended duration of training, such as increased mitochondrial biogenesis and capacity, increased muscle glycogen are thought to be mediated in part by AMPK when it is activated. Greer et al., 2007, observed that AMPK overexpression triggers stress response and promotes longevity.  The inhibition of NF-κB signaling by AMPK suppresses inflammatory responses.

5. NF-kB Genes

NF-kappaB (NF-kB) is the key regulator of the innate immunity. During aging, adaptive immunity significantly declines. Immunity can be improved by blocking of NF-κB signaling at various control points.  Improper regulation of NF-κB has been associated with various diseases. NF-kB is involved in brain function, particularly following injury and in neurodegenerative conditions such as Alzheimer’s disease. NF-kB can therefore be considered as one of the most important transcription factors characterized in brain to date and it might be as crucial for neuronal and glial cell function as it is for immune cells. NF-κB signaling has been implicated in controlling axon initiation, elongation, guidance and branching and in regulating dendrite arbor size and complexity during development and dendritic spine density in the adult. NF-kB is recognized as a key regulatory factor mediating the coordinate expression of genes which are part of the cellular machinery that functions to protect an organism against damage posed by physical, chemical or microbial noxae. Zhang et al., 2013 observed that the inhibition of NF-KB transcription factor reduces inflammation in hypothalamus during aging and increases mouse lifespan by 23%.

6.  SIRTUIN Genes

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. 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. 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.  SIRT6 promotes genome stability by regulating DNA repair pathways and by facilitating telomere maintenance.

Summary:

Six gene families have been shown to play a role in the genetic regulation of longevity. Out of these six the SIRTUIN and FOXO families are vital for regulating lifespan. However, more than genetic factors, caloric restriction (CR) without malnutrition is one of the most consistent strategies for increasing mean and maximal lifespan and delaying the onset of age‐associated diseases. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. Epigenetics is quickly emerging as a critical aspect of aging and longevity.

References:

1. Adult Stem Cells and Diseases of Aging
2. The Critical Role of Metabolic Pathways in Aging

 

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