Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

Abstract

Summary -The insulin/IGF-1 signalling (IIS) pathway connects nutrient levels to metabolism, growth and lifespan in eukaryotes ranging from yeasts to humans, including nematodes such as the genetic model organism Caenorhabditis elegans. The link between ageing and the IIS pathway has been thoroughly studied in C. elegans; upon reduced IIS signalling, a genetic survival program is activated resulting in a drastic lifespan extension. One of the components of this program is the upregulation of antioxidant activity but experiments failed to show a clear causal relation to longevity. However, oxidative damage, such as protein carbonyls, accumulates at a slower pace in long-lived C. elegans mutants with reduced IIS. This is probably not achieved by increased macroautophagy, a process that sequesters cellular components to be eliminated as protein turnover rates are slowed down in IIS mutants. The IIS mutant daf-2, bearing a mutation in the insulin/IGF-1 receptor, recapitulates the dauer survival program, including accumulation of fat and glycogen. Fat can be converted into glucose and glycogen via the glyoxylate shunt, a pathway absent in vertebrates. These carbohydrates can be used as substrates for trehalose synthesis, also absent in mammals. Trehalose, a non-reducing homodimer of glucose, stabilises intracellular components and is responsible for almost half of the lifespan extension in IIS mutants. Hence, the molecular mechanisms by which lifespan is extended under reduced IIS may differ substantially between phyla that have an active glyoxylate cycle and trehalose synthesis, such as ecdysozoans and fungi, and vertebrate species such as mammals.

Elevated Trehalose Levels in C. elegans daf-2 Mutants Increase Stress Resistance, Not Lifespan

“…In nematodes, carbohydrate stores primarily occur as glycogen deposits, taking up to 3.3% of the dry body mass [ 40 ], but also substantial levels of the monosaccharide glucose are found [ 41 ]. Glycogen and glucose are in close proximity to trehalose in the worm’s metabolic network [ 42 ]. Hence, we decided to follow the response of these carbohydrates to tps knockdown.…”

“…Like tps-1 , tps-2 expression was found in the intestine and body wall muscles, but also in the hypodermis and ciliated neurons. In the intestine, hypodermis and body wall muscle, TPS may readily convert the abundant glycogen and triglycerides into trehalose [ 8 , 42 ]. Trehalose may be the main transport sugar in C. elegans [ 25 ] and is likely distributed to other tissues by facilitated transport via FGT-1, a glucose transporter that is also able to carry trehalose over the plasma membrane [ 54 ].…”

“…In conclusion, we hypothesized that the metabolic switch that occurs in C. elegans daf-2 mutants, which is typical to microorganisms living in fluctuating environments [ 60 ], may be responsible for its extended lifespan [ 42 ]. Our experimental results showed that one of the major hallmarks of this metabolic switch, the accumulation of trehalose, is not required for daf-2 longevity but specifically serves its resistance to osmotic stress and partially supports its thermotolerance.…”