Metabolic regulation of lifespan from a C. elegans perspective

Abstract

Decline of cellular functions especially cognitive is a major deficit that arises with age in humans. Harnessing the strengths of small and genetic tractable model systems has revealed key conserved regulatory biochemical and signaling pathways that control aging. Here, we review some of the key signaling and biochemical pathways that coordinate aging processes with special emphasis on Caenorhabditis elegans as a model system and discuss how nutrients and metabolites can regulate lifespan by coordinating signaling and epigenetic programs. We focus on central nutrient-sensing pathways such as mTOR and insulin/insulin-like growth factor signaling and key transcription factors including the conserved basic helix-loop-helix transcription factor HLH-30/TFEB.

Keywords: Aging; Autophagy; Caenorhabditis elegans; Dietary restriction; Epigenetics; HLH-30/TFEB; Longevity; Metabolism.

Fig. 1

HLH-30/TFEB regulates lipophagy during starvation in C. elegans. In response to starvation, the nutrient sensor mTOR/LET-363 is inhibited and the transcription factor HLH-30/TFEB is activated and translocates to the nucleus where it upregulates genes from the CLEAR network. This includes genes that are necessary for all three steps of lipophagy, a selective form of autophagy. In the first step of lipophagy, an autophagosome is formed, engulfing a part of a lipid droplet. In the second step, the sealed autophagosome fuses with a lysosome containing acid lipases that degrades the lipids within the autolysosome. In the final step, free fatty acids are released from the autolysosome and can be utilized for energy production by breakdown through β-oxidation. To date, regulation of β-oxidation has only been shown for TFEB and not for HLH-30 per se

Fig. 2

Fatty acid elongation, desaturation, and ceramide synthesis in C. elegans. Fatty acid synthesis is orchestrated by the multifunctional enzyme FASN-1 (red). When the fatty acid is synthesized, it can be modified in several ways or enter the synthesis of more complex lipids. Modifications include elongation of chain length by elongases (blue) and introduction of double bonds by desaturases (green). Both classes of enzymes have high specificity towards the fatty acids they modify. Illustrated here is the example of how the fatty acid palmitate (C16:0) can be further modified to monounsaturated and polyunsaturated fatty acids with variating chain length in C. elegans. Highlighted in bold are the fatty acids that have been found to be involved in longevity, monounsaturated fatty acids such as C16:1Δ9 and C18:1Δ9 and polyunsaturated fatty acids C20:3Δ8,11,14 (di-homo-γ-linoleic acid, DGLA) and C20:4Δ5,8,11,14 (arachidonic acid, ALA). Furthermore, a simplification of ceramide synthesis is illustrated. The ceramide synthesis is dependent on the enzymes FATH-1, HYL-1/2, and LAGR-1 (purple). Only a selection of fatty acid metabolism is illustrated

Fig. 3

Interconnections between metabolism, epigenetic modifications, and longevity in C. elegans. There are tight connections between nutritional status, metabolite availability, and epigenetic modifications that are changing gene expression leading to longevity. a When the nutritional status changes, metabolite availability changes too. These changes can affect the post-translational modifications on specific histones and therefore gene expression beneficial for lifespan extension. Altered gene expression can also influence the metabolite pool and induce longevity. b Specific examples of what is outlined in a Left: Upon caloric restriction, the histone deacetylase SIR-2.1 is upregulated leading to lower levels of acetylation, which has been shown to upregulate autophagy and extend lifespan. Furthermore, sirtuins have been shown to act together with AMPK, a main inducer of autophagy. Therefore, it is possible that the caloric restriction-induced SIR-2.1 activity leads to an increase in AMPK activity, upregulating autophagy resulting in longevity. Right: Impairment of the methyltransferase complex COMPASS in the germline reduces trimethylation of histone 3 lysine 4, which activates the transcription factor SBP-1/SREBP-1 in the intestine. SBP-1/SREBP-1 controls the expression of the fatty acid desaturase FAT-7 that increases the levels of monounsaturated fatty acids leading to longevity. Both examples illustrate how metabolic cues can induce longevity, either through caloric restriction lowering metabolite availability or by reduction of certain histone modifiers leading to increase in specific metabolites