Thursday, August 8, 2013

The Biology of Longevity

Most everyone aspires to living a long and healthy life.  There are certain populations of human and individuals who have had the good fortune to enjoy the benefits of longevity.  This reality has raised the inevitable question – how is this possible?  Recently, scientists engaged in basic research in an attempt to answer this question have come to have a greater understanding of the molecular mechanisms that may help account for longevity in animals and especially in humans.

Surprisingly, the animal model that has been used for this work is the tiny invertebrate worm – Caenorhabditis elegans (C. elegans); this organism grows to an adult size of ~ 1 mm and has a natural lifespan of about 20 days.  C. elegans has a rather complex lifecycle in which it goes through three separate larval stages before it reaches adulthood.  The obvious question that comes to mind is – how can using a simple invertebrate such as C. elegans as an animal can ever hope to shed light on human longevity?   Interestingly, the significant metabolic pathways that are implicated in longevity – as we shall describe shortly – are highly conserved in nature and have direct application to the human system.  The advantage of using an animal model with such a short generation span makes it ideal for studying longevity in a controlled laboratory setting.  In addition, there is mutated form of C. elegans that has a lifespan of up to 10 times the normal, or ~ 200 days.  Use of this variant has helped immeasurably in uncovering the molecular mechanisms for this state.

Dr. R. Shmookler Reiss and his associates at Departments of Geriatrics and Biochemistry and Molecular
Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas have devoted a great deal of time and effort in the pursuit of discovering biomarkers that account for this remarkably increased longevity in C. elegans.   In the painstaking process they have used such techniques as introducing so-called interfering RNA (iRNA) to knockout certain areas of the organism’s genome, adding transgenes and gene mapping.  In casting a wide net they have incorporated proteomics – the analysis of cellular protein products, transcriptomics – the analysis of all RNAs within the cell and metabolomics – an analysis of cellular metabolic pathways- in their studies.

As a result of this exhaustive analysis, they have discovered that the organisms within this high longevity mutant population lack the enzyme PI3 kinase catalytic subunit (PI3Kcs) This enzyme catalyzes the phosphorylation of Phosphatidylinositol 4, 5-bisphosphate (PIP2) to Phosphatidylinositol 3, 4, 5-triphosphate (PIP3) PIP3 resides within the cell membrane and plays a critical role in cell division.  This lack of such a key enzyme is a result of the introduction of a so-called “stop gene” within the gene responsible for the production of PIP3.  As a result of this mutation, the organism produces immature oocytes and is effectively sterile.

The question that immediately arises from this data – how can the loss of such a critical enzyme result in enhanced longevity?  The answer seems to lie in the fact that PI3K is a key component in the Insulin – IGF-1 signaling pathway that is involved in many functions that are necessary for metabolism, growth, and fertility in animal models like C. elegans and also within humans.  The disruption of the insulin -IGF-1 signaling pathway in the C. elegans longevity mutant apparently increases lifespan significantly.  One apparent explanation for this seeming paradox is that the price the organism pays for reproductive success is a diminishment of lifespan.  While this relationship between longevity and the insulin -IGF-1 signaling pathway is evidenced in C. elegans, mammals with an analogous defect are, in fact, at risk for age-related diseases and increased mortality.  This difference in effect probably relates to the more complex metabolic machinery resident in a mammal versus a small invertebrate such as C. elegans.

However, within humans and other animal models, increased longevity has been associated with the nutritional state of the organism – over nutrition apparently shifts cellular metabolism in such a way as to lead to the over production of free radicals and other metabolic byproducts that are toxic to cells and a nutritional state that meets but does not exceed the individual’s nutritional requirements enhances longevity.

Although these studies focus on very specific aspects of the longevity of organisms, they do make important inroads into the overall understanding of the biological mechanisms involved in prolonging lifespan.

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