Abstract
There are a handful of biological questions that affect all of us directly in everyday life. How are emotions formed, what is the basis for consciousness, and why do we look the way we do? One that strikes particularly close to home is the question of how we age. The sheer complexity of this problem has had many scientists throw up their hands in frustration and most of the postulated theories have been vague and generally have involved ill-defined wear-and-tear mechanisms. But the pursuit of the biological basis of aging has been revitalized within the last decade by studies in yeast, worms, flies, and mice that have firmly established that there indeed exist specific molecular mechanisms that contribute to the aging process [1]. These efforts point to several distinct, likely interrelated, mechanisms, ranging from improper protein metabolism, to alterations of specific signaling pathways, progressive damage due to generation of oxidative free radicals, and increased genome instability.
Highlights
There are a handful of biological questions that affect all of us directly in everyday life
Much has been learned about the aging process from simple model organisms, one intuitively suspects that things might be somewhat different when it comes to human aging
The first hint to a surprising connection between nuclear architecture and aging came from yeast, when Leonard Guarente and colleagues found that a protein, Sir4, whose mutation results in extension of life span, localizes to the nucleolus, one of the most prominent subcompartments of the cell nucleus [4]
Summary
The cell nucleus in higher organisms is recognized as a complex, highly organized repository of an individual’s genetic information. The lamina is made up of A-, and B-type lamins, which are intermediate filament proteins that form an interwoven network situated at the very periphery of the nucleus underlying the nuclear membrane This structure has long been thought to act as a shield to protect the genome from mechanical stress. It could be that the mutant lamin A protein weakens the nuclear lamina and in that way reduces the resistance of the cells of HGPS patients to the types of mechanical stress encountered in the body, heralding cellular dysfunction and death. This explanation makes much sense since many of the primarily affected tissues, such as skin and vasculature, are under intense mechanical stress. Increased genome instability must be considered a wear-and-tear mechanism, but it deserves more credence than some of the other mechanisms because genome instability is a feature shared amongst virtually all premature aging disorders
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