Across species, a common symptom of advanced age is loss of brain function. Aging negatively affects a broad range of neural activity, including learning (reflected in long-term potentiation), control of motor function, and memory. Wouldn’t it be nice if we could slow that process down, or halt it altogether?

A group at Kyushu University has managed to do just that. By introducing a transgene encoding a human mitochondrial transcription factor into mice, Hayashi et al. have been able to delay the onset of age-related neurological decline, as measured in a number of different assays:

Reverse of Age-Dependent Memory Impairment and Mitochondrial DNA Damage in Microglia by an Overexpression of Human Mitochondrial Transcription Factor A in Mice Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-κB (nuclear factor-κB) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1β (IL-1β) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. … Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.

Note that the title is a little bit misleading — they didn’t “reverse” the age-related decline so much as prevent it (unless I’m misunderstanding something; from what I could tell, the transgene was expressed from birth rather than turned on late in life).

The molecular details are still a mystery. The HeLa data suggest that transgene-expressing cells produce less reactive oxygen species (ROS) in response to electron transport poisons such as rotenone, but this could occur by a number of mechanisms: TFAM overexpression could result in boosted antioxidant defenses, or even simply an increase in the levels of electron transport proteins (with higher levels of these proteins in the mitochondria, it would take higher doses of a given poison to cause the sorts of malfunctions that lead to ROS production).

Mechanism aside, the result still provides strong support for the idea that cellular oxidation — and in particular, mitochondrial damage — are important causative factors in the age-related decline in neurological function. These transgenic animals, which show decreases in particular types of oxidative damage as well as significant delays in the deterioration of a wide variety of important brain functions, could help us identify the specific sorts of oxidative lesions that are the most important targets for intervention.