Mitochondrial processes - especially those involving free radical production, damage and propagation - are deeply implicated in the advance of aging. Aging is damage at the cellular and molecular level throughout your body, and one form of that damage is caused by the normal operation of your mitochondria, the cell's power plants.
So it is with interest that we watch the efforts of scientists to pick apart the complex web of biochemicals and regulatory pathways relating to mitochondria and shed light on how one might go about building a better mammal - one more resistant to aging:
The 66-kilodalton isoform of the growth factor adapter Shc (p66Shc) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signaling link between cellular stress and mitochondrial proapoptotic activity of p66Shc was not known. We demonstrate that protein kinase C beta, activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66Shc causes alterations of mitochondrial Ca2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signaling route that activates an apoptotic inducer shortening the life span and could be a potential target of pharmacological approaches to inhibit aging.
That might be a little dense for some of you; decompacting it, we have that free radicals (a category that includes reactive oxygen species) lead to oxidative stress, a term for damage caused to cellular mechanisms by these chemicals. Cells destroy themselves via apoptosis in response to excess oxidative stress, a process initiated in the mitochondria, so as to prevent their own failing mechanisms causing further damage to the body - but the processes of identifying just when is most advantageous to do so are quite varied and complex.
The protein p66Shc is very involved in apoptosis, as noted in the paper above. It is an important part of one scheme by which a cell starts in on destroying itself. This paper suggests putting off apoptosis is a way to extend healthy life span - but lengthing the life of cells is not necessarily a good thing, especially if those cells are being damaged; it might just be the case that you're better off with dead cells than with live cells running ragged. But as it turns out, removing p66Shc from the equation does seem to extend healthy life in mice:
Additionally, p66Shc is phosphorylated on Ser36 within its unique amino-terminal region in response to oxidative stress, an event that markedly sensitizes cells to apoptosis. One way p66Shc seems to enhance oxidative stress-induced apoptosis is by participating in the phosphorylation-induced repression of Forkhead transcription factors, which regulate expression of several antioxidant enzymes. Consistent with this, p66Shc knockout mice exhibit higher catalase activity. Another way is likely mediated by a mitochondrial pool of p66Shc because evidence suggests that activation of this pool leads to further ROS generation by inducing mPTP opening and cytochrome C release.
Remarkably, p66Shc knockout mice not only show increased resistance to oxidative stress, but a 30% increase in life span.
So removing p66Shc extends life - but is this because of a lowered rate of apoptosis with oxidative stress, or is it in fact the higher levels of catalase, an antioxidant that helps soak up the free radicals before they break things? As I'm sure regular readers recall, engineering mice to have more catalase in their mitochondria is good for a 20-30% boost in life span:
The catalase soaks up some portion of free radicals before they can attack your vulnerable mitochondrial DNA. Damage to this [DNA] leads to an unfortunate chain of events that causes entire cells to rabidly produce damaging free radicals and export them throughout the body. But stop a fraction of the original mitochondrial free radicals from attacking their birthplace, and you have slowed the rate at which one cause of aging happens - you have slowed down aging, and extended healthy life.
If you look back in the literature available online, you'll see going on for ten years of work on the topic of p66Shc; scientists picking away at the knot, inch by inch. It's a complex subject. But the discussions are not that much further along now - the general outline is much the same - and I don't hold out a great deal of hope that they'll be significantly and materially advanced in 2017 either. There are only so many scientists, and a great deal of biochemistry to cover. In many ways, the tools of modern biotechnology have already greatly exceeded the management capacity of the scientific community - we can collect far more data per unit time than can be usefully turned into knowledge at this time.
The better mammal - the better human, the version 2.0 that ages a good deal more slowly due to improvements in the fundamentals of metabolism and biochemistry - lies somewhere in the future, but there is a daunting amount of work between here and there. If the scientific community can't fully categorize and understand all the biochemistry surrounding a small, simple chunk of complexity like p66Shc in ten years, one amongst thousands or tens of thousands of equal importance, what makes us think we can roll out safe, significant upgrades to human metabolism in time to help those reading this now?
Changing metabolism, building better, more age-resistant humans, is a very long term exercise. We should be looking at other avenues of development and more promising strategies for rapid progress if we want to see meaningful healthy life extension - of decades or more - within our lifetime.