Assessing Proteostatic Mechanisms in Long-Lived Mice

Proteostasis is the continued normal balance of protein levels and uses in cells. Aging and age-related disease by definition involve loss of proteostasis, such as through cellular damage and reactions to that damage. A wide array of mechanisms work to maintain proteostasis, and the list should probably include near all of those involved in protein production, folding, and recycling. There are far more researchers focused on this aspect of aging than on damage repair after the SENS model, in which it is argued that we should focus on fixing underlying damage, at which point proteostasis mechanisms should be free to restore the normal balance of cellular operations:

Protein turnover decreases with age, resulting in a progressive accumulation of damaged proteins and propagation of the aging phenotype. Maintaining protein homeostasis (i.e., proteostasis) through coordination of mRNA translation, protein synthesis, protein folding, and protein breakdown may be a key component of slowed, or healthy aging. Therefore, models of slowed aging may provide valuable insight into the role of proteostasis and how proteostatic mechanisms are regulated during slowed aging. We have proposed that simultaneously assessing both protein and DNA synthesis through deuterium oxide incorporation (D2O) can provide insight into what proportion of new proteins is made in new versus existing cells.

Here, we present a tissue- and sex-specific assessment of proteostasis using DNA and protein synthesis in long-lived Snell dwarf mice. We demonstrate that proteostatic mechanisms, as assessed by the new protein to new DNA synthesis ratio, were increased by threefold in skeletal muscle and heart of Snell compared to normal controls. Mean lifespan in female Snell is increased by approximately 50% compared to normal controls, while male Snell dwarfs have an approximate 29% increase in mean lifespan compared to their respective sex-specific controls. With the exception of protein synthesis in skeletal muscle, there were no sex differences in protein or DNA synthesis. Although differences in proteostatic mechanisms do not explain subtle sex differences in lifespan extension, it is important to note that both sexes have increased proteostatic mechanisms as well as significant lifespan extension. Collectively, our data further suggest proteostasis is a shared characteristic of slowed aging.



Reason, I know you like to mention "damage repair" in every post, but I'm pretty sure that this qualifies as "intracellular junk" under the SENS model.

From the looks of things, damaged proteins naturally accumulate in cells due to an imperfect homeostatic process, and the presence of this accumulated crap leads to even more problems with that process, leading to... (ad mortem). This almost certainly is the damage.

Posted by: Slicer at March 11th, 2015 5:46 PM

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