Manipulating Mitochondrial Maintenance via NAD+

All sorts of maintenance processes operate in various parts of the cell. An important location is within the swarming herd of mitochondria, as damage there appears to be a significant cause of degenerative aging. Some forms of mitochondrial damage can evade the evolved means of repair and recycling, leading to dysfunctional mitochondria and dysfunctional cells that export harmful reactive compounds out into surround tissues. Can this process be slowed by boosting the operation of natural maintenance mechanisms, however? Arguably this is what happens in many of the methods demonstrated to extend life and slow aging in laboratory animals, such as calorie restriction, and here researchers are examining some of the relevant mechanisms in nematode worms:

NAD(+) is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD(+) levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD(+) levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD(+) prevents age-associated metabolic decline and promotes longevity in worms.

These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPR(mt)) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD(+) levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.


Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.