Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants

Abstract

Many lifespan-modulating genes are involved in either generation of oxidative substrates and end-products, or their detoxification and removal. Among such metabolites, only lipoperoxides have the ability to produce free-radical chain reactions. For this study, fatty-acid profiles were compared across a panel of C. elegans mutants that span a tenfold range of longevities in a uniform genetic background. Two lipid structural properties correlated extremely well with lifespan in these worms: fatty-acid chain length and susceptibility to oxidation both decreased sharply in the longest-lived mutants (affecting the insulinlike-signaling pathway). This suggested a functional model in which longevity benefits from a reduction in lipid peroxidation substrates, offset by a coordinate decline in fatty-acid chain length to maintain membrane fluidity. This model was tested by disrupting the underlying steps in lipid biosynthesis, using RNAi knockdown to deplete transcripts of genes involved in fatty-acid metabolism. These interventions produced effects on longevity that were fully consistent with the functions and abundances of their products. Most knockdowns also produced concordant effects on survival of hydrogen peroxide stress, which can trigger lipoperoxide chain reactions.

Oncogene-induced senescence results in marked metabolic and bioenergetic alterations

“…Similar results were obtained when OIS cells were subjected to CPT1A knockdown the connection between senescence and aging, it is also important to note that recent observations also suggest that levels of FFA and certain phospholipid-derived molecules may be important determinants of longevity of simple organisms. 35,36 Our data also suggests that blocking the senescent-associated increase in mitochondrial fatty acid oxidation can selectively inhibit the secretory state that is associated with OIS. We observed high levels of cytokine production in IMR-90 cells that had undergone Ras-mediated senescence but not in replicative senescent IMR-90 cells.…”

Universal transcriptomic signature of age reveals temporal scaling ofCaenorhabditis elegansaging trajectories

“…Several mutations leading to exceptional longevity of C.elegans have been identified [21][22][23][24] and studied extensively for their remarkable elevations of both lifespan and stress-resistance traits [1,2] (see also Table Ia). To model the effects of anti-aging interventions we have tested five RNAi treatments targeting genes with the largest reported life-span extending effects (see Figure 1a and Table Ib for the summary of our confirmatory survival experiment and the lifespans reported in the original publications).…”

“…To date, the strongest lifespan extension effect is achieved in C.elegans and corresponds to almost 10-fold increase of lifespan by the mg44 nonsense mutation of age-1 gene [1,2]. That extreme hyperlongevity, however, requires two generations of homozygosity for a mutation, and thus total pre-embryonal genetic disruption.…”

“…We started by studying isogenic strains carrying the most long-lived C.elegans mutations: daf-2 (e1370 ) [strain SR806], age-1 (mg44 ) [SR808, at the first and second generations of homozygosity], and the longest-lived daf-2; daf-12 double mutant [strain DR1694] [1,2]. The average lifespans in the series range from twofold to tenfold longer than that of the wild type.…”

Relationships between locomotor activity, oxidative damage and life span in males and females of the linden bug, Pyrrhocoris apterus (Heteroptera: Pyrrhocoridae)

“…The increase in lipid peroxidation, accumulation of oxidative damage to DNA or alterations in membrane fatty acid profiles represent alternative mechanisms resulting in the association between oxidative damage in organisms and decrease in life span (Agarwal & Sohal, 1994;Magwere et al, 2006;Kregel & Zhang, 2007). In C. elegans, the abundance of short-chain saturated fatty acids (C14:0, C15:0, C16:0) increases at the expense of long-chain classes (C18:0, C20:0, C22:0) and susceptibility to oxidation decreases in the longest-lived mutants (Shmookler Reis et al, 2011). Consistent with these finding, the induction of diapause or allatectomy in P. apterus females resulted in an accumulation of phospholipids with C16:0/C18:2 acyl chains at the expense of C18:0/C18:2 molecular species (Hodkova et al, 2002).…”