The role of lipid metabolism in aging, lifespan regulation, and age-related disease

Abstract

An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid-related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17-α-estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome-wide association studies have found several lipid-related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late-onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid-related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.

Keywords: biomarker; ceramides; fatty acids; healthspan; longevity; phospholipids.

Figure 1

Various aging‐relevant lipid synthesis pathways. The biosynthesis pathways for triglycerides (two different pathways), sphingolipids, fatty acids, and phospholipids are visually summarized. CK, choline kinase; CPT, CDP‐choline:1,2‐diacylglycerol cholinephosphotransferase; CT, CTP‐phosphocholine cytidylyltransferase; EK, ethanolamine kinase; EPT, CDP‐ethanolamine:1,2‐diacylglycerol ethanolaminephosphotransferase; ET, CTP‐phosphoethanolamine cytidylyltransferase; MUFA, monounsaturated fatty acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEMT, phosphatidylethanolamine methyltransferase; PS, phosphatidylserine; PSD, phosphatidylserine decarboxylase; PSS‐1, phosphatidylserine synthase‐1; PSS‐2, phosphatidylserine synthase‐2; PUFA, polyunsaturated fatty acid

Figure 2

Proposed lipid‐related pathways that could be targeted to extend human healthspan. The overexpression of lysosomal lipase enhances longevity in worms, while the overexpression of diacylglycerol lipase extends lifespan in both worms and flies. Gene inactivation or inhibition of genes encoding the sphingolipid‐relevant sphingomyelinase‐3, glucosylceramide synthase, serine palmitoyltransferase, dihydroceramide desaturase, neutral/acidic ceramidase, or ceramide synthase proteins extends life in Caenorhabditis elegans, while the inactivation of alkaline ceramidase increases lifespan in Drosophila melanogaster. Longevity can also be increased by feeding specific monounsaturated or polyunsaturated fatty acids to worms, by overexpressing fatty acid amide hydrolase in worms, or by overexpressing fatty acid‐binding protein or dodecenoyl‐CoA delta‐isomerase in flies. The overexpression of apolipoprotein D enhances survival in flies and mice, and the overexpression of the fly homolog of this gene extends lifespan in flies. In worms, RNAi knockdown against the yolk lipoprotein VIT/vitellogenin prolongs life. Survival time can also be elongated by RNAi knockdown against low‐density lipoprotein‐receptor‐related protein 1 and low‐density lipoprotein‐receptor‐related protein 2 in Drosophila. Creating a deficiency in the triglyceride synthesis enzyme acyl‐CoA:diacylglycerol acyltransferase 1 boosts longevity in mice and knockdown of the phospholipase A2 receptor improves healthspan parameters in a mouse model of progeria. Relevant to the latter finding, treating worms with phosphatidylcholine boosts longevity. Treating C. elegans with the ketone body ß‐hydroxybutyrate or feeding mice with a ketogenic diet additionally extends lifespan. There are likely additional lipid‐related healthspan targets that remain to be elucidated