The major hallmarks of aging are a decline of physiological function and a concomitant increase of age-specific death rate. The detailed molecular mechanism(s) of aging remain unrevealed, but it is widely assumed that molecular damage due to reactive oxygen species may play a key role in this process.  It is currently thought that the balance between oxidative damage due to reactive oxygen species, and the potential to resist such damage, determines the pace of the age-related metabolic and physiological decrements.

We have used the nematode Caenorhabditis elegans as a model for studying the age-associated metabolic decline.  A range of metabolic parameters were analyzed in cohorts of several long-lived mutants such as daf-2 and clk-1.  The major conclusion is that long lifespan is not correlated with low metabolic rates, as was predicted by the rate-of-living hypothesis [publications].  In daf-2 mutants, a metabolic shift was found that suggested high coupling efficiency (unaltered oxygen consumption and low heat production).  Mitochondrial function in long-lived mutants is now studied in more detail [more info].

Mutants of the Ins/IGF-like pathway showed increased levels of superoxide dismutase and catalase, two oxygen radical scavenging enzymes [publications].  Superoxide can also be converted to hydrogen peroxide and to some extent to water by the salen manganese compound EUK-8.  In contrast to an earlier report in Science, we (and the Gems Lab) found that this compound was inable to extend lifespan in C. elegans [more info].  On the contrary, it showed a dose dependent toxicity. We are currently interested in the mechanism by which EUK-8 acts in the cell and whether it can prevent molecular damage per se.

A variety of macromolecules (such as nucleic acids, lipids and proteins) are sensitive to oxidative damage.  Carbonylation is a prominent form of oxidative protein modification.  It has been shown in a wide variety of organisms that levels of carbonylated proteins increase with age.  This kind of damage might underlie the molecular mechanisms of age-related physiological decline.  We are investigating the role of protein damage and turnover in the aging process of Caenorhabditis elegans [more info].

Caloric restriction (CR) increases lifespan in a wide variety of organisms.  The molecular mechanism of CR remains to be elucidated.  In our lab, we found that lifespan extension due to CR is independent of Ins/IGF-like signaling [more info].  Dietary restricted animals did not show a decreased metabolic rate but exhibited enhanced stress resistance (oxidative, thermal, UV).  The effect of CR on gene expression in C. elegans will be studied with microarray analysis [more info].

In the near future we also plan to continue our metabolic measurements on aging cohorts of other species such as Podospora, Drosophila and Saccharomyces [more info].