The decline of aging C. elegans male’s mating behavior is correlated with the increased excitability of the cholinergic circuitry that executes copulation. In this study, we show that the mating circuits’ functional durability depends on the metabolic regulator SIR-2.1, a NAD+-dependent histone deacetylase. Aging sir-2.1(0) males display accelerated mating behavior decline due to premature hyperexcitability of cholinergic circuits used for intromission and ejaculation. In sir-2.1(0) males, the hypercontraction of the spicule-associated muscles pinch the vas deferens opening, thus blocking sperm release. The hyperexcitability is aggravated by reactive oxygen species (ROS). Our genetic, pharmacological, and behavioral analyses suggest that in sir-2.1(0) and older wild-type males, enhanced catabolic enzymes expression, coupled with the reduced expression of ROS-scavengers contribute to the behavioral decline. However, as a compensatory response to reduce altered catabolism/ROS production, anabolic enzymes expression levels are also increased, resulting in higher gluconeogenesis and lipid synthesis.
Although the signs of aging are clear to us all, precisely why we age is less well understood. One possibility is that as cells use oxygen to fuel the breakdown of large molecules into smaller ones to release energy, they also generate by-products called reactive oxygen species that can damage DNA. As we get older, this damage gets worse. Consistent with this idea, it has been shown that a reduced calorie intake can reduce oxidative damage in certain species, in addition to extending lifespan.
Many experiments on aging have been performed on worms belonging to the species C. elegans. Male worms of this species live for an average of 11–12 days, but begin to show signs of aging—for example, a reduced ability to mate—as early as day 3 of their adult lives. Now, Guo and García have revealed that a protein called SIR-2.1, which regulates metabolism in worms, also helps to protect the animals from the effects of aging.
Male worms in which the gene for this protein has been ‘knocked out’ have a normal lifespan, but show signs of aging earlier than normal males. They are also more susceptible to the damaging effects of reactive oxygen species, suggesting that SIR-2.1 may offer protection against oxidative damage. Indeed, levels of ATP—the molecule used to move energy around inside cells—are increased in knockout worms. This suggests that certain metabolic processes and the production of reactive oxygen species, are increased in the knockout worms, which speeds up the aging process.
While the link between metabolism and aging is well known, the work of Guo and García offers insights into some of the molecular mechanisms that may form the basis of this relationship.