The effort to understand how exactly metabolic processes determine longevity is a frustrating business. Researchers are at the stage in the game where they can increase or reduce longevity in many different ways through various genetic and epigenetic manipulations in mice, worms, flies, and other laboratory species. They can obtain mountains of data from these longer-lived or shorter-lived animals: gene expression patterns and any number of different measures of metabolism and the operation of organs and cells. Making sense out of all this data is the challenge.
For example, some interventions boost the free radical output of mitochondria and extend life. Others raise that free radical output and reduce life span. The interplay of different systems in the body is far too complicated for simple models of "more of X is bad" to survive for long. Extra damaging free radicals might a bad thing in one context, but in another they happen to trigger enough of an extra effort from cell maintenance processes to cause a net gain in robustness and longevity in the organism. More of a specific regulatory protein in circulation might be beneficial in one amount, harmful in a slightly greater amount, and those threshold levels will change depending on the levels of four or five other proteins. It's a complicated business.
Here is an example of a life-extending and memory-improving genetic alteration in mice that reduces mitochondrial function (generally thought to be a bad thing) and increases the output of damaging free radicals from the mitochondria (also generally thought to be a bad thing):
Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults.
In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation.