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.

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

“…Indeed, previous investigations revealed that ketone metabolism is increased accompanied with the decrease of fatty acid oxidation in failing heart, as evidenced by the elevation of the levels of BDH1 and ketone body-derived materials, such as hydroxybutyrylcarnitine (C4OH-carnitine), βOHB-CoA and acetyl-carnitine (C2-carnitine) (28,29) (Figure 2). In addition, a number of studies have demonstrated that the intake of a ketogenic diet extends longevity and the health span (30). Shimazu et al revealed part of its mechanism.…”

Effects of Age, Gender, and Menopausal Status on Small Dense Low-Density Lipoprotein Cholesterol and Low-Density Lipoprotein Cholesterol Fractions; JMS-II Cohort Study

“…SdLDLs are regulated through multiple and complex mechanisms regarding excess adiposity, free fatty acids, apo-lipoproteins, and action of lipoprotein lipase activity and cholesterol ester transfer protein for lipoproteins. 12,16,17 In postmenopausal women, the decrease of plasma estrogen levels plays a signi cant role in reducing the clearance of LDL particles via LDL receptor and increasing TG and the number of smaller LDL particles. 21 This hormone change was related to the process of regulating sdLDL-C but there was little evidence available on the association between menopausal status and sdLDL-C or sdLDL-C/LDL-C ratio in a real-world, population setting.…”

“…10,11 Diet composition, which is affected by aging, has a signi cant effect on blood cholesterol and the absorption, synthesis, and metabolism per se of fat and lipoproteins change with age. 12,13 Asian agerelated trends of traditional lipid pro les displayed roughly an increasing trend, followed by a decreasing one at the middle-aged stage. 14,15 However, sdLDL-C has been regulated by more complex mechanisms than regulating traditional lipids and might be plateaued or increased even at the middle-aged by changed metabolic functions with aging in uencing sdLDL-C synthesis.…”

“…14,15 However, sdLDL-C has been regulated by more complex mechanisms than regulating traditional lipids and might be plateaued or increased even at the middle-aged by changed metabolic functions with aging in uencing sdLDL-C synthesis. 5,7,12,16,17 Furthermore, the detailed multiple mechanisms of metabolizing sdLDLs are unknown in the real-world, population-based setting and the age-related trend of sdLDL-C might be different from the sdLDL-C/LDL-C ratio. In other words, the ability to generate sdLDL-C from LDL-C might be different among each generation, gender, and menopausal status.…”

Study on follicular fluid metabolomics components at different ages based on lipid metabolism

“…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 lipidrelated interventions may improve human health span and that blood lipids likely represent a rich source of human aging biomarkers [37].…”