Sirtuins and Lamin A from Ouroboros

I should point you to a pair of good posts from Chris Patil of Ouroboros, a blog that should be on your reading list if it is not so already.

Lamin A mutation and the cell cycle: A connection between progeria and normal aging:

Indeed, an extensive body of work over the past 5 years has clearly demonstrated that a particular mutation in the lamin A gene (LMNA) results in severe nuclear malformation. In humans, this mutation gives rise to a devastating disease, Hutchinson-Gilford progeria syndrome (HGPS).


Progerin [the mutated form of lamin A] is generated at some rate in normal cells (probably because the splice site ablated in the mutant is not 100% efficient), and when it accumulates to a detectable level, the same cell cycle interference and mitotic failures seen in HGPS can occur in an otherwise normal cell.

If the binucleated progeny of these cell divisions escape apoptosis, they will presumably undergo some type of permanent cell cycle arrest (e.g. senescence), and persist in the tissue - unable to divide further, but certainly available to cause damage to their microenvironment and contribute to age-related decline in tissue function.

Progeria now appears to be a grand exaggeration of a process that occurs at a low level in all our cells; learning to defeat progeria may just lead to a small portion of the medical technology needed for the defeat of all age-related degeneration. It continues to be the case that extreme examples of mutation or biochemical behaviors have a lot to teach us about the more normal workings of our cells and bodies.

Moving on:

Two on Sirtuin-2:

The sirtuins are a family of proteins named (somewhat unfortunately, in my opinion) after their founding and first-described member, the yeast histone deacetylase SIR2. In mammals, there are seven family members, SIRT1-7. Over the past few years, characterizing the function of each protein in every tissue it happens to be expressed has become something of a cottage industry: at the Cold Spring Harbor aging conference last fall, easily 25% of the talks were sirtuin-related.


This happens to be Sirt2’s week in the sun, with two independent studies revealing the protein’s role in regulating the cell cycle and differentation of the glial cells where it is expressed.

Modern biotechnology enables researchers to generate enormous amounts of data given starting points like sirtuins and a complex system like metabolism; the real challenge in the years ahead is the efficient synthesis of this data into new knowledge. For all the data collection, we don't yet have a clear understanding of how sirtuins fit into the way in which calorie restriction (or resveratrol, or other calorie restriction mimetics) produce beneficial effects on health and longevity.

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