Ouroboros on Sirtuins

I suggest you steer yourself over to Ouroboros to take a look at a trio of recent posts on sirtuins, the present focus of much of the research into the biochemistry of calorie restriction.

Sirtuins and Senescence:

Two recent papers describe a relationship between the lifespan regulator Sirt1 (ortholog of the yeast Sir2p, member of the creatively named "sirtuin" family of proteins) and cellular senescence: As cells lose their ability to divide, they downregulate Sirt1.


The papers also suggest a connection between "lifespan" as it is considered in two different senses, proliferative/replicative lifespan (of a cell line) and organismal lifespan (of a body) - that are not necessarily synonymous, despite their interchangeability in some contexts (yeast) and the propensity of some scholars in the field to treat replicative senescence as though there were an evidence-based consensus that it is an explicit model for organismal aging per se.

Thank you SIR, may I have another:

Continuing with yesterday's sirtuin and aging theme, here are three more recent papers that further expand the Sirt1/aging literature.

Sirtuins in the mitochondria of the pancreas:

Sirt1 gets a lot of attention, and is unquestionably the best-studied of the human homologs of the canonical yeast SIR2 gene. SIR2 was originally identified in yeast as a Silent Information Regulator, a member of a multi-gene complex involved in repression of the silent mating type loci and in telomeric silencing. In the early 90s, Leonard Guarente's lab discovered that SIR2 also governs the replicative lifespan of yeast, allowing biogerontologists to deploy what the late Ira Herskowitz called the "awesome power of yeast genetics" into the field of aging. Since then, sirtuins (as the metazoan homologs of SIR2 are called: "sir-two-ins") have been shown to regulate lifespan in worms, flies, and the mouse. Most of these studies have focused on Sirt1.


Breathtakingly, there are five other sirtuins in humans that have barely been studied. Watch this space for further developments.

The utility of studying the biochemistry of cellular aging in yeast has grown greatly since 5000 different gene knockout varieties were created. Having the opportunity to study what each gene does in isolation - by suppressing or removing it - has been a large step forward towards developing a detailed blueprint for the cell. Such blueprints are the foundation for accelerated progress in all fields of medicine and biotechnology. This is precisely why scientists are accelerating their attempts to do the same for mice:

The National Institutes of Health has awarded a five-year cooperative agreement worth approximately $23 million to a consortium of the Children's Hospital Oakland Research Institute; UC Davis; and the Wellcome Trust Sanger Institute, England.

The group plans to create lines of embryonic mouse stem cells in which 5,000 individual genes will be systematically turned off, or "knocked out." Those embryonic stem cells will then be used to breed live mice that lack those genes.


Scientists have been making knockout mice since 1988, but so far these cover only about 5,000 genes, or about 25 percent of the mouse genome, said Kent Lloyd, a principal investigator on the grant and associate dean for research at the School of Veterinary Medicine.

"The technology is now here to do this on a high-throughput basis," Lloyd said. "Within five years, through this and related projects around the world, scientists will have access to knockouts of the whole mouse genome."

Ten thousand genes that are most closely shared between mice and humans are a high priority for the NIH. Studying how those genes work in mice can give insights into human health and disease.

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