You'll recall the klotho gene, and its effects on life span in mice:
The upper bound of life span extension in the study was 30% or so, in the same ballpark as the results of calorie restriction. The association with insulin suggests that both overexpression of Klotho and the gene expression changes caused by calorie restriction may work on an overlapping set of biochemical mechanisms - which certainly shouldn't prevent industrious researchers from trying both at once to see how that goes. I certainly would if I had the funds and a group of gene engineered Klotho mice.
A recent review paper summarizes the present state of knowledge, two years later. More of the field has been filled, but it still looks a lot like the state of calorie restriction biochemistry five years ago. Much more work to come, in other words.
The klotho gene functions as an aging-suppressor gene that extends life span when overexpressed and accelerates aging-like phenotypes when disrupted in mice. The klotho gene encodes a single-pass transmembrane protein
Klotho protein also protects cells and tissues from oxidative stress, yet the precise mechanism underlying these activities remains to be determined. Thus, understanding of Klotho protein function is expected to provide new insights into the molecular basis for aging, [cancer], and stem cell biology.
Regulation of metabolism involves a number of systems that interact in complex ways and that are far from completely understood. But based on the evidence to date, it does not seem unreasonable that many potential beneficial alterations to these systems exist, each capable of extending life span to the same degree as calorie restriction. The results of calorie restriction are, after all, exactly a beneficial alteration to the controlling mechanisms of metabolism.
But is this really the best path forward for aging science? Yes, all this knowledge will be useful, and help to speed many other areas of medical science. You can never know too much. But why try to reengineer metabolism to slow the damage of aging - a result of very limited use to those already old - when it is arguably no harder to work on repairing that damage of aging in the metabolism we have today?