Linking functional decline of telomeres, mitochondria and stem cells during ageing

By Ergun Sahin, R. DePinho. Nature, 2010

748 citations recorded by the source corpus.

The study of human genetic disorders and mutant mouse models has provided evidence that genome maintenance mechanisms, DNA damage signalling and metabolic regulation cooperate to drive the ageing process. In particular, age-associated telomere damage, diminution of telomere 'capping' function and associated p53 activation have emerged as prime instigators of a functional decline of tissue stem cells and of mitochondrial dysfunction that adversely affect renewal and bioenergetic support in diverse tissues. Constructing a model of how telomeres, stem cells and mitochondria interact with key molecules governing genome integrity, 'stemness' and metabolism provides a framework for how diverse factors contribute to ageing and age-related disorders.

Subfields: Aging, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/0e1dc076148ac05e775daf22ec128478b5c4606c

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Citations in the corpus

Telomere length in early life predicts lifespan (2012, background): “Several mechanistic routes have been identified, mainly from in vitro studies, whereby shortened telomeres can accelerate aging and reduce longevity, primarily involving activation of cellular checkpoints of apoptosis, cell cycle arrest, and impaired stem cell and tissue function (2).”
Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development (2011, background): “…of telomere loss (Artandi et al., 2000; Gisselsson et al., 2001; O’Hagan et al., 2002), and the two centromeres of such dicentric chromosomes are pulled to opposite daughter cells during anaphase, forming a so-called anaphase bridge (Bignell et al., 2007; McClintock, 1941; Sahin and Depinho, 2010).”
Metabolic Plasticity in Stem Cell Homeostasis and Differentiation (2012, positive): “Stimulation of mitochondria biogenesis can overcome the differentiation block in fastdividing cells, while reducing mitochondrial content perturbs cardiomyocyte differentiation in slow-dividing cells (San Martin et al., 2011).”
The DNA Damage Response: Making it safe to play with knives (2010, background): “Similarly, the accelerated aging phenotypes of mice defective for BRCA1, Ku80, and ZMPSTE24, a nuclear membrane protease mutated in the Hutchinson-Gilford progeria syndrome, were rescued by TP53 deletion (Sahin and Depinho, 2010).”