Gene knockout of p66(Shc) is one of the many genetic alterations shown to extend mouse life span. The role of p66(Shc) in the intersection of aging and metabolism has been investigated for more than two decades now, though its ability to extend life is disputed by at least some researchers - the data isn't as reliable as is the case for some other approaches. This is a common issue for methods that alter the operation of metabolism, as metabolism is very complex, and all sorts of other factors beyond the intended genetic adjustment might have a meaningful influence.
To the extent that p66(Shc) knockout improves health and function in mice, it appears to work via an improvement in mitochondrial activity, or a slowing in the age-related mitochondrial dysfunction that affects unmodified mice. Mitochondria in older individuals produce more oxidative molecules, are less efficient at their primary task of producing chemical energy stores, and their appearance changes, all of which is slowed in p66(Shc) knockout mice. Which is interesting, but what do we get out of this at the end of the day? The papers produced as a result of research into p66(Shc) this year look little different in content and character from those of decade ago; there is little apparent likelihood of a therapy to slow the progression of aging emerging from this fundamental science in the near future.
In the last years, more cases of cooperation between reactive oxygen species (ROS) and aging-regulating genes have been established in senescence and aging development. The adaptor protein p66Shc is a genetic determinant of lifespan that regulates ROS metabolism and cellular apoptosis. p66Shc ablation in mice is translated into a significant decrease in mitochondria-produced ROS and a 30% increase in lifespan. These knockout mice for p66Shc (p66Shc(-/-)) have been shown to be thinner, to exhibit an increased metabolic rate, and to have less body fat than their wild-type littermates. And more remarkably, they have been described as an animal model of healthy aging with better cognitive abilities at adulthood in a spatial memory task and improved physical performance at senescence.
Based on the improved bioenergetics parameters observed in p66Shc(-/-) mice and the already accepted downregulated mitochondrial biogenesis in aging, it is interesting to study how p66Shc impacts on mitochondrial quantity and structure. The mitochondrial content of a sample can be determined using different methods that provide information about mitochondrial biogenesis and tissue's oxidative capacity. Mitochondrial DNA (mtDNA) content relative to nuclear DNA was determined by real-time qPCR in brain samples of the study groups and shown as a percentage of the 3-month-old wild type (WT) relative mtDNA content. During aging, mitochondrial content was reduced by 30% in the WT group, while in the p66Shc(-/-) group, a 45% increase was observed.
For both WT and p66Shc(-/-) 3-month-old mice, normal size and volume mitochondria were observed, with predominantly tubular-shaped mitochondria (70% of total measured mitochondria), while the remaining displayed round (fragmented) morphology. However, at the end of their life, the time point of maximal ROS production, 24-month-old WT mouse brain slices were characterized by decreased tubular mitochondria (-44%) and increased round-shaped mitochondria (+120%). This age effect in mitochondrial morphology was partially mitigated in 24-month-old p66Shc(-/-) mice, to the extent that both types of mitochondrial populations coexisted in this group (55% tubular mitochondria) showing an intermediate phenotype between 3- and 24-month-old WT mice.