Molecular Biology

20000922
Judith Campisi. Science Vol 289. Sciencemag.org.

Takeaway:

Calorie restriction slows down entropy in a cell lineage. CR increases SIR2p activity, which maintains heterochromatin, which protects DNA.

Ideas presented:

• In yeast, calorie restriction (CR) increased longevity requires genes NPT1 and SIR2.
• NPT1 gene encodes one of two enzymes in yeast that produce NAD.
• SIR2 gene encodes a protein that promotes a compact chromatin structure (histone deacetylase), silencing gene transcription, including at the rDNA locus.
• Accumulation of extra-chromosomal rDNA circles and DNA fragments is a major cause of yeast aging.
• Circles and fragments are excised during homologous recombination, especially from regions like the rDNA locus.
• If rDNA locus is silenced by SIR2p, then fewer circles formed.
• CR invokes higher levels of NAD, which increases SIR2p activity
• CR reduces the impact of Mitochondrial Reactive Oxygen Species (ROS), which also increases SIR2p activity (how is not explained).
• In mammals, age related loss of silencing occurs with age, such as with the X chromosome.
• Telomere shortening occurs more rapidly on human X chromosomes, which could contribute to the age-dependent reactivation of X chromosome loci.

— Marcos Reyes 2019/04/04 12:07

“Although ERC formation has been widely suggested to drive ageing in yeast, there is little mechanistic data regarding the potential pathological activity of ERCs. It seems very likely to us that one result of rDNA amplification through ERC accumulation is to titrate histones and histone binding factors, and this will provide an important focus for future studies into age-linked gene expression change.” (Cruz et al 2018 https://elifesciences.org/articles/34081)