Mitochondria, you will recall, are the power plants of our cells, churning out stored energy in the form of ATP molecules, and pollution in the form of damaging free radicals or reactive oxygen species (ROS). Mitochondria have their own DNA, separate from the DNA in the nucleus of our cells, a legacy of their origin as free-roaming bacteria. Free radicals are very reactive, which means that they can tear apart the biochemical machinery of cells by reacting with crucial components. This free radical pollution is at the heart of the mitochondrial free radical theory of aging, which presents a large component of the aging process as essentially a runaway feedback loop: mitochondria damage themselves via their own free radicals, making them produce even more free radicals. This in turn leads to cells overtaken by that pollution, and which throw free radicals out into the body to cause widespread harm as the years pass.
Thus mitochondria are considered to be important: changes in genes that alter the operation of mitochondria can cause dramatic shifts in life span in mice. Differences in mitochondrial biochemistry are correlated with differences in life span between similar species. Mitochondria are involved with cellular programmed death mechanisms, and mitochondrial damage is possibly a cause of the telomere shortening that happens with age. Everywhere you look in the metabolism of aging, there are roads that lead to the thousands of mitochondria that flock within each of your cells.
If you look back into the 2007 Fight Aging! archives, you'll find an introductory post on p66Shc, a mitochondrial longevity mutation in mice that has been known for a decade or so. This might be viewed as a lever with which researchers can pry open the secrets of mitochondrial operation and its relationship to life span - and pry they have. It's slow work, however:
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.
In that post, I go on to make my usual point: that this is a good illustration of the nature of metabolic manipulation as a way to enhanced human longevity. It's hard, and it's a very, very long road. A better road exists - meaning the Strategies for Engineered Negligible Senescence and similar work that focuses on reversing known biochemical changes of aging rather than trying to re-engineer our genes and metabolism to merely slow the rate at which those changes occur.
But in any case, if you haven't bought into that point of view by now, one more repetition isn't going to do it. Let me instead return to p66Shc, and a recent open access paper (with a PDF version) in which researchers peel away another layer of the onion:
A decrease in Reactive Oxygen Species (ROS) production has been associated with extended lifespan in animal models of longevity. Mice deficient in the p66Shc gene are long-lived, and their cells are both resistant to oxidative stress and produce less ROS.
Thus, p66Shc deficiency causes a defect in activation of the PHOX complex that results in decreased superoxide production. p66Shc-deficient mice have recently been observed to be resistant to atherosclerosis, and oxidant injury in kidney and brain. Since phagocyte-derived superoxide is often a component of oxidant injury and inflammation, we suggest that the decreased superoxide production by PHOX in p66Shc-deficient mice could contribute significantly to their relative protection from oxidant injury, and consequent longevity.
Superoxide is, as they point out, sufficiently reactive and dangerous to biochemical constructs to be used as a kill mechanism by the immune system. The proposed longevity-inducing mechanism in the paper above adds to two other proposed mechanisms in the archive post I pointed out - everything in the biochemistry of our cells is connected to multiple processes and structures, and removing p66Shc does more than just lower superoxide production. Nothing is simple in biology!
Tomilov, A., Bicocca, V., Schoenfeld, R., Giorgio, M., Migliaccio, E., Ramsey, J., Hagopian, K., Pelicci, P., & Cortopassi, G. (2009). Decreased superoxide production in macrophages of long-lived p66Shc-knockout mice Journal of Biological Chemistry DOI: 10.1074/jbc.M109.017491