Mechanisms of ageing.
Recent experimental work from a variety of biological systems, ranging from yeast to human beings, lends increasing support to the view that stochastic damage inflicted to biological macromolecules is the driving force for the ageing process. The damage is derived from small reactive molecules, most prominently reactive oxygen intermediates (ROI), that arise during normal cellular metabolism and are associated with important if not essential cellular functions. The major classes of macromolecules at risk are proteins, lipids and DNA, but damage to DNA (both nuclear and mitochondrial) may entail particularly severe consequences. Cellular dysfunction resulting from macromolecular damage can be detected as a variety of expressions, such as genomic instability, inappropriate cell differentiation events or cell death. While for post-mitotic cell types replacement of the dead cell by another cell of the same lineage is not possible, mitotic cell types may initially replace dead cells via cell proliferation. But exhaustion of the self-renewal capacity of the respective lineage, by either replication-associated or damage-associated telomere shortening, will ultimately also lead to loss of parenchymal cell mass and functional impairment of tissues, the latter being a typical feature of ageing of tissues and organs. It has been demonstrated in various experimental systems that the rate ageing of can be retarded by lowering the production of endogenous ROI or by improving cellular anti-oxidative defences. Whether augmentation of cellular DNA repair capacity will have the same effect remains to be seen.
Bürkle
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Department of Gerontology, University of Newcastle upon Tyne, Newcastle General Hospital, UK. Alexander.Buerkle@ncl.ac.uk
D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D004249:DNA Damage / Q000502:physiology*; D006801:Humans; D046911:Macromolecular Substances; D017382:Reactive Oxygen Species / Q000502:physiology
D046911:Macromolecular Substances; D017382:Reactive Oxygen Species