Targeting metabolic pathways for extension of lifespan and healthspan across multiple species

Abstract

Metabolism plays a significant role in the regulation of aging at different levels, and metabolic reprogramming represents a major driving force in aging. Metabolic reprogramming leads to impaired organismal fitness, an age-dependent increase in susceptibility to diseases, decreased ability to mount a stress response, and increased frailty. The complexity of age-dependent metabolic reprogramming comes from the multitude of levels on which metabolic changes can be connected to aging and regulation of lifespan. This is further complicated by the different metabolic requirements of various tissues, cross-organ communication via metabolite secretion, and direct effects of metabolites on epigenetic state and redox regulation; however, not all of these changes are causative to aging. Studies in yeast, flies, worms, and mice have played a crucial role in identifying mechanistic links between observed changes in various metabolic traits and their effects on lifespan. Here, we review how changes in the organismal and organ-specific metabolome are associated with aging and how targeting of any one of over a hundred different targets in specific metabolic pathways can extend lifespan. An important corollary is that restriction or supplementation of different metabolites can change activity of these metabolic pathways in ways that improve healthspan and extend lifespan in different organisms. Due to the high levels of conservation of metabolism in general, translating findings from model systems to human beings will allow for the development of effective strategies for human health- and lifespan extension.

Keywords: Aging; C. elegans; Drosophila; Metabolism; Mice; Yeast.

Fig. 1.

Schematic representation of glycolysis and related metabolic pathways. Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. Dashed line represents that multiple steps are involved. In the glycolysis pathway, glucose is broken down into pyruvate, producing ATP. Lifespan extension was associated with glycolysis inhibition through the downregulation of hexokinase (HK), glucose isomerase (GPI), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), or phosphoglycerate mutase (PGAM); or through addition of inhibitors such as 2-Deoxyglycose (2-DG) and D-glucosamine (GlcN). The hexosamine pathway converts fructose-6-phosphate to UDP-N-acetylglucosamine (UDP-GlcNAc). Lifespan extension was associated with an increased expression of glutamine-fructose 6-phosphate aminotransferase (GFAT) and O-GlcNAcase (OGA), as well as with added acetylglucosamine (GlcNAc). The methylglyoxal pathway produces methylglyoxal (MGO) from glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP). While excessive MGO can disrupt protein function, moderate supplementation was associated with increased lifespan in worms. Increased expression of triosephosphate isomerase (TPI) also increased lifespan. The pentose phosphate pathway (PPP) consists of the oxidative and nonoxidative branches. Lifespan extension was associated with downregulation of 6-phosphogluconate dehydrogenase (6PGD), ribose-5-phosphate isomerase (RPI), transketolase (TKT), and transaldolase (TALD-1), as well as with upregulation of glucose-6-phosphate dehydrogenase (G6PD). Downregulation of enzymes responsible for glycogen synthesis (glycogen synthase, GlyS; and 1,4-alpha-glucan branching enzyme 1, GBE1) extended lifespan. Increased levels of trehalose and downregulation of trehalase was associated with extended lifespan in worms.

Fig. 2.

Schematic representation of the TCA cycle and related metabolic pathways. Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. Dashed line represents that multiple steps are involved. Before entering the TCA cycle, pyruvate must be converted to acetyl-CoA through the pyruvate dehydrogenase complex (PDHc). Overexpression of the dihydrolipoamide acetyltransferase (E2 component) of the PDHc extended lifespan in yeast. In addition, downregulation of pyruvate dehydrogenase kinase (not shown), an inhibitor of PDHc, extended lifespan in worms. Threonine can be converted to acetyl-CoA through a series of reactions. Threonine supplementation, as well as downregulation of the enzymes l-threonine-3-dehydrogenase (TDH) and glycine-C-acetyltransferase (GCAT), extended lifespan in yeast. Dietary supplementation of several TCA cycle intermediates, including oxaloacetate, α-ketoglutarate, fumarate, and malate, was associated with lifespan extension. Downregulation of aconitase and isocitrate dehydrogenase, two enzymes in the TCA cycle, also extended lifespan. The electron transport chain (ETC) is a series of complexes which ultimately generates ATP through electron transfer and redox reactions. Downregulation of components of complexes I, II, IV and V was associated with lifespan extension in worms. In addition, lifespan was extended through the expression of some mitochondrial uncoupling proteins (UCPs). Gluconeogenesis is a process that allows cells to convert TCA intermediates into glucose under nutrient starvation. Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in this process, and overexpression of PEPCK extends lifespan in worms.

Fig. 3.

Schematic representation of tryptophan and NAD metabolism (A), BCAAs metabolism (B), and tyrosine metabolism (C). Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. Dashed line represents that multiple steps are involved. (A) Supplementation of tryptophan, as well as downregulation of the enzymes tryptophan 2,3-dioxygenase (TDO) and kynureninase (KYNU) was associated with lifespan increase. The Preiss-Handler and salvage pathways can synthesize NAD + from pyridine bases. Increased levels of nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR) and NAD+, as well as expression of nicotinamidase (NAMase) and nicotinamide phosphoribosyltransferase (NAMPT) were associated with lifespan extension. (B) Branched-chain amino acids (BCAAs) are degraded through a series of reactions, resulting in succinyl-CoA (valine) or acetyl-CoA (leucine, isoleucine). Valine, leucine, and isoleucine supplementation was associated with lifespan extension in mice, yeast, and worms, while downregulation of the enzyme branched-chain amino acid transferase (BCAT) extended lifespan in worms. (C) The tyrosine degradation pathway converts tyrosine into fumarate and acetoacetate. Supplementation of tyrosine and downregulation of the tyrosine degradation enzymes tyrosine aminotransferase (TAT), 4-hydroxyphenylpyruvate dioxygenase (HPD), and homogentisate 1,2 dioxygenase (HGO) resulted in lifespan extension in flies.

Fig. 4.

Schematic representation of methionine metabolism. Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. In the methionine cycle, methionine is converted to S-adenosyl-l-methionine (SAM), which acts as a methyl donor for methyltransferases, forming S-adenosyl-l-homocysteine (SAH), and finally, homocysteine. Downregulation of methionine adenosyltransferase (SAMS) and S-adenosyl-l-homocysteine hydrolase (ACHY), and overexpression of Glycine N- methyltransferase (GNMT) were associated with lifespan extension. In the methionine salvage pathway, methionine can be regenerated from SAM, forming polyamines during the cycle. Supplementation of the polyamines spermine and spermidine was associated with lifespan extension in several species. In the transsulfuration pathway, homocysteine is converted into cysteine, which can then be metabolized into taurine, pyruvate, and glutathione. Upregulation of cystathionine-β-synthase (CBS) and glutamate-cysteine ligase (GCL), as well as supplementation with the cysteine donor N-acetylcysteine (NAC) were associated with lifespan increase.

Fig. 5.

Schematic representation of purine metabolism. Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. Dashed line represents that multiple steps are involved. During de novo synthesis, ribose-5-phosphate is converted to inosine monophosphate (IMP), which can then be converted to adenine and guanine nucleotides. In worms, downregulation of PAICS increased lifespan. In flies, heterozygous mutations of adenylosuccinate synthetase (AdSS), adenylosuccinate lyase (AdSL), adenine phosphoribosyltransferase (Aprt), adenosine kinase (AdenoK), and adenylate kinase (AdK) increased lifespan. The degradation pathway converts the purine nucleotides into xanthine, which can then be metabolized to uric acid. Downregulation of xanthine dehydrogenase increased lifespan in flies, while supplementation with hypoxanthine, uric acid and allantoin increased lifespan in worms.

Fig. 6.

Schematic representation of pyrimidine metabolism. Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. Dashed line represents that multiple steps are involved. In de novo pyrimidine synthesis, glutamine is converted to orotate, which can then be converted to uridine nucleotides. Feeding worms with pyrimidine synthesis intermediates including orotate, uridine, thymine, cytidine, and β-aminoisobutyrate increased lifespan, while downregulating dihydropyrimidine dehydrogenase (DPYD) and uridine phosphorylase (UPP1) also increased lifespan.

Fig. 7.

Schematic representation of lipid metabolism. Underlined are metabolites and enzymes that were associated with lifespan extension. Red font color represents downregulation or depletion from food, while green font color represents overexpression or supplementation. Dashed line represents that multiple steps are involved. (A) In fatty acid metabolism, triglycerides can form saturated or unsaturated fatty acids. Higher levels of mono-unsaturated fatty acids (MUFAs) were associated with increased lifespan. Downregulation of diacylglycerol O-acetyltransferase (DGAT), elongases (ELO), and a desaturase converting MUFAs to PUFAs (FAT), as well as upregulation of the lipase LIPL was associated with lifespan extension. (B) In sphingolipid metabolism, palmitoyl-CoA is converted to ceramides, which can then form sphingomyelins. Downregulation of several enzymes, including serine palmitoyltransferase (SPT), sphingomyelinase (SMase), sphingomyelin synthase (Smsynthase), glucosylceramide synthase (PDMP), ceramidase, and ceramide synthase was associated with lifespan increase. (C) In diacylglycerol metabolism, diacylglycerol can be converted to 2-arachidonoyl-sn-glycerol (2-AG) or phosphatidic acid (PA). PA promotes TOR activity. Diacylglycerol lipase (DAGL-1) overexpression and diacylglycerol kinase (DGK) downregulation were associated with lifespan extension in worms.