Protein-Repair and Hormone-Signaling Pathways Specify Dauer and Adult Longevity and Dauer Development in Caenorhabditis elegans

Abstract

Protein damage that accumulates during aging can be mitigated by a repair methyltransferase, the l-isoaspartyl-O-methyltransferase. In Caenorhabditis elegans, the pcm-1 gene encodes this enzyme. In response to pheromone, we show that pcm-1 mutants form fewer dauer larvae with reduced survival due to loss of the methyltransferase activity. Mutations in daf-2, an insulin/insulin-like growth factor-1-like receptor, and daf-7, a transforming growth factor-β–like ligand, modulate pcm-1 dauer defects. Additionally, daf-2 and daf-7 mutant dauer larvae live significantly longer than wild type. Although dauer larvae are resistant to many environmental stressors, a proportionately larger decrease in dauer larvae life spans occurred at 25°C compared to 20°C than in adult life span. At 25°C, mutation of the daf-7 or pcm-1 genes does not change adult life span, whereas mutation of the daf-2 gene and overexpression of PCM-1 increases adult life span. Thus, there are both overlapping and distinct mechanisms that specify dauer and adult longevity.

Defective responses to oxidative stress in protein l-isoaspartyl repair-deficient Caenorhabditis elegans

“…Pcm-1 deletion mutant C. elegans show normal adult lifespan and no defects in development or fecundity when grown under standard conditions (Kagan et al, 1997; Banfield et al, 2008). However, mutant nematodes are at a competitive disadvantage when co-cultured with wild-type animals (Kagan et al, 1997).…”

“…Significant effects have been seen in pcm-1 mutant nematodes under environmental stress: the survival of L1 larvae under starvation conditions is reduced in the mutants (Gomez et al, 2007). Pcm-1 mutant nematodes also show defects in the dauer phase (Banfield et al, 2008; Gomez et al, 2008). Under unfavorable conditions, such as low food supply and oxidative stress, C. elegans enter dauer diapause, an alternate third larval stage in which nematodes are more resistant to environmental stress; as dauer larvae, they have SDS-resistant cuticles and enhanced expression of enzymes involved in resistance to oxidative stress (Cassada and Russell, 1975; McElwee et al, 2003).…”

Working with dauer larvae

“…However, daf-7(e1372) mutants do differ from wild-type in the following ways. First, daf-7 dauer larvae live longer than N2 dauer larvae (Banfield et al, 2008). Second, daf-7(e1372) can be used to force dauer formation in Daf-d mutant backgrounds in the insulin-like pathway, even though these Daf-d mutants fail to form dauers on starved plates (Vowels and Thomas, 1992; Larsen et al, 1995).…”

“…The canonical allele, daf-2(e1370) , is a Class II allele that is the most commonly used as a tool to induce dauer formation. daf-2(e1370) is similar to daf-7(e1372) in a number of ways: 1) ~100% of daf-2(e1370) larvae enter dauer at 25 °C (Gems et al, 1998); 2) daf-2(e1370) can be used to force dauer formation in Daf-d backgrounds, in this case, the TGFb pathway (Vowels and Thomas, 1992; Larsen et al, 1995; Ogg et al, 1997); 3) daf-2(e1370) dauer larvae do not all recover from dauer when shifted to 15 °C, and those that do recover do so asynchronously; and 4) daf-2 dauer larvae live longer than wild-type dauer larvae, although the allele examined was m41 , not e1370 (Banfield et al, 2008). …”

Non-repair Pathways for Minimizing Protein Isoaspartyl Damage in the Yeast Saccharomyces cerevisiae

“…Overexpressing PCMT in E. coli (30) or Drosophila melanogaster (31) results in an increase in longevity under stress conditions. Similarly in Caenorhabditis elegans, PCMT mutant L1 larvae have decreased survival in minimal medium (32) and developmental defects with oxidative stress (33), whereas PCMT-overexpressing animals up-regulate Daf-16-dependent stress response genes and have increased heat stress survival (34,35). Finally and most striking, homozygous PCMT knock-out mice rapidly accumulate isoaspartyl-damaged polypeptides in the brain, heart, testis, and erythrocyte cells and have fatal tonic-clonic seizures at ϳ42 days of age (7, 36 -40).…”