Ageing: Is there a role for arachidonic acid and other bioactive lipids? A review

Undurti N Das, Undurti N Das

Abstract

Ageing is inevitable. Recent studies suggest that it could be delayed. Low-grade systemic inflammation is seen in type 2 diabetes mellitus, hypertension and endothelial dysfunction that are common with increasing age. In all these conditions, an alteration in arachidonic acid (AA) metabolism is seen in the form of increased formation of pro-inflammatory eicosanoids and decreased production of anti-inflammatory lipoxins, resolvins, protectins and maresins and decreased activity of desaturases. Calorie restriction, exercise and parabiosis delay age-related changes that could be related to enhanced proliferation of stem cells, decrease in inflammation and transfer of GDF-11 (growth differentiation factor-11) and other related molecules from the young to the old, increase in the formation of lipoxin A4, resolvins, protectins and maresins, hydrogen sulfide (H2S) and nitric oxide (NO); inhibition of ageing-related hypothalamic or brain IKK-β and NF-kB activation, decreased gonadotropin-releasing hormone (GnRH) release resulting in increased neurogenesis and consequent decelerated ageing. This suggests that hypothalamus participates in ageing process. N-acylethanolamines (NAEs) and lipid-derived signalling molecules can be tuned favorably under dietary restriction to extend lifespan and/or prevent advanced age associated diseases in an mTOR dependent pathway manner. Sulfur amino acid (SAA) restriction increased hydrogen sulfide (H2S) production and protected tissues from hypoxia and tissue damage. Anti-inflammatory metabolites formed from AA such as LXA4, resolvins, protectins and maresins enhance production of NO, CO, H2S; suppress NF-kB expression and alter mTOR expression and thus, may aid in delaying ageing process. Dietary restriction and exercise enhance AA metabolism to form LXA4, resolvins, protectins and maresins that have anti-inflammatory actions. AA and their metabolites also influence stem cell biology, enhance neurogenesis to improve memory and augment autophagy to prolong life span. Thus, AA and other PUFAs and their anti-inflammatory metabolites inhibit inflammation, augment stem cell proliferation, restore to normal lipid-derived signaling molecules and NO and H2S production, enhance autophagy and prolong life span.

Keywords: Ageing; Arachidonic acid; Calorie restriction; GDF-11; Hydrogen sulfide; Hypothalamus; Inflammation; Lipids; Nitric oxide; Polyunsaturated fatty acids; Stem cells; Sulfur amino acid.

Figures

Graphical abstract
Graphical abstract
Fig. 1
Fig. 1
Scheme showing metabolism of essential fatty acids, their role in inflammation and cytoprotection of endothelial cells.
Fig. 2
Fig. 2
Scheme showing metabolism of arachidonic acid. AA can react with NO and NO2 and form vicinal nitrohydroxyeicosatrienoic acids that have vasodilator actions . Even EPA and DHA may give rise to similar metabolites that are formed from AA. Fatty acid hydroxy fatty acids (FAHFAs) are newly discovered and are also called as lipokines. They can be formed from all PUFAs. So far lipokines derived from DHA, LA, palmitic acid and stearic acid have been described. But are likely to be formed form other PUFAs as well. They are present in the plasma, adipose tissue and human breast milk. Some of the DHA derived FAHFAs include: 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA. FAHFAs have the potential to improve blood sugar, protect against diabetes, and reduce inflammation. PAHSA, the combination of palmitic acid and hydroxy stearic acid, was abundantly found in the fat of diabetes-resistant mice and was significantly reduced in humans with early stages of diabetes. When fed to obese diabetic mice, 9-PAHSA was reported to contribute to glucose-insulin homeostasis and to elicit anti-inflammatory effects. FAHFAs do exist at low levels within certain foods, but are mainly synthesized in the body. FHAFAs may also form from AA. Patients with type 2 diabetes have low plasma levels of FHAFAs, AA and LXA4, which have anti-inflammatory actions. This may imply that decreased formation of AA in the elderly may render them to develop low-grade systemic inflammation, partly, due to decreased formation of FHAFAs and LXA4 from AA. N-acylethanolamine (NAE) is a type of fatty acid amide formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine. These amides can be formed from a fatty acid and ethanolamine with the release of a molecule of water. NAE can be formed due to the action of phospholipase D that cleave the phospholipid unit from N-acylphosphatidylethanolamines. Examples of N-acylethanolamines include: (i) Anandamide (N-arachidonoylethanolamine; NAE 20:4) or arachidonlyethanolamine (AEA) is the amide of arachidonic acid (20:4 ω-6) and ethanolamine. It is the ligand of both cannabinoid receptors and vanilloid receptor that attenuates pain sensation. (ii) N-Palmitoylethanolamine is the amide of palmitic acid (16:0) and ethanolamine. It has anti-inflammatory activity and also attenuates pain sensation. N-Oleoylethanolamine is the amide of oleic acid (18:1) and ethanolamine. It has anorexic effects and enables fat breakdown by stimulating PPAR-alpha. (iii) N-Stearoylethanolamine is the amide of stearic acid (18:0) and ethanolamine. It has pro-apoptotic activity. It operates independently of the known cannabinoid and vanilloid receptors targeted by anandamide. (iv) N-Docosahexaenoylethanolamine is the amide of docosahexaenoic acid (22:6) and ethanolamine. It has anti-proliferative effects on prostate cancer cell lines and promotes synaptogenesis. Thus, NAEs may be formed from PUFAs that have important biological functions.
Fig. 3
Fig. 3
Scheme showing possible relationship among PGE2, LXA4, and various PLA2 enzymes as seen in inflammation and inflammation resolution process. PGE2; LXA4; iPLA2; sPLA2; cPLA2; COX-2. All these concentrations and activities of enzymes as expected to behave during normal inflammatory process. PGE2 when inflammation persists; COX-2 when inflammation persists. LXA4 when resolution of inflammation is defective. Although possible changes in the activities of various PLA2 are not shown during persistance of inflammation or defective resolution of inflammation, they are expected to behave in tune with the concentrations of PGE2 and LXA4. It also need to be noted that despite the fact that LXA4, resolvins, protectins and maresins have anti-inflammatory actions, there could be subtle differences in their major and minor actions with some amount of overlap in their anti-inflammatory actions. Though the role of nitrolipids is not shown, it is expected to behave similar to LXA4. It is evident from the figure that there are two waves of release of AA (and other PUFAs), one in the early period of inflammation (within the first 24 h due the activation of iPLA2) that leads to the formation of PGE2 and other pro-inflammatory molecules. Once the concentrations of PGE2 reach the optimum level (say by the end of 24–48 h), a second wave of AA release occurs (due to the activation of sPLA2) that leads to the formation of LXA4 that initiates resolution of inflammation. The activation of cPLA2 occurs around 48–72 h in all probability to accelerate or continue the resolution of inflammation process. The activation of iPLA2 and formation of PGE2 are closely associated with the activation of COX-2. In this process of inflammation and resolution of inflammation there is a critical role for PGDH enzyme (see text for details). With regard to the actions of LXA4, resolvins, protectins and maresins, it is to be noted here that though all these are anti-inflammatory molecules they may have slightly but critically important differences in their actions to resolve the inflammation. For instance, LXA4 is needed to induce anti-inflammatory events (to suppress inflammation and this is not equal to resolution of inflammation. During the process of suppressing inflammation, LXA4 may inhibit leukocyte infiltration); while resolvins are needed for resolution of inflammation (such as removing the debris of wound, phagocytosis of dead leukocytes, etc.,); protectins protect normal cells/tissues from further damage); and maresins may act on stem cells for the repair process to proceed and restore homeostasis. Despite these different actions assigned to different molecules (LXA4, resolvins, protectins and maresins), all these bioactive lipids have all the enumerated actions except that the degree to which each action is brought about may be variable and it may vary from cell/tissues that are in the need of their action. It is also depicted in the figure how this sequence of orderly activation and deactivation of PLA2, COX-2 and formation of PGE2 and LXA4 are likely to get deranged in the face of failure of resolution of inflammation process. It is likely that in patients with hypertension, diabetes mellitus and ageing there is low-grade systemic inflammation as a result of sustained activation of COX2 and formation of PGE2 and failure of formation of adequate amounts of LXA4 and other anti-inflammatory compounds and corresponding activation of PLA2 at the most appropriate time. It is noteworthy that failure of the inflammation resolution process may lead to the onset of ageing associated osteoporosis, sarcopenia and when this inflammatory process is severe it can lead to sepsis and septic shock.
Fig. 4
Fig. 4
Scheme showing relationship among ageing and its associated diseases and their relationship to hypothalamus, oxidative stress, PUFAs, lipoxins, resolvins, protectins, maresins, eicosanoids, CO, NO, H2S and telomere length. High calorie diet stimulates ROS generation that may overwhelm antioxidant system protection in adipose and other tissues; augment the synthesis of pro-inflammatory cytokines, inhibit the formation of anti-inflammatory cytokines that ultimately results in low-grade systemic inflammation, enhance DNA damage and ageing. These events may lead to ageing of endothelial cells and telomere shortening, and alteration in p53 expression. These events cause endothelial dysfunction and insulin resistance leading to the development of hypertension, type 2 diabetes mellitus, atherosclerosis and ageing. High calorie diet and insulin resistance suppress Δ6 and Δ5 desaturases activity resulting in reduced formation of PUFAs, the precursors of lipoxins, resolvins, protectins and maresins. Decreased lipoxins, resolvins, protectins and maresins impair resolution of inflammation, DNA damage, telomere shortening, p53 dysfunction, and stem cell function leading to the onset and progression of ageing and age-associated diseases. These events may also decrease CO, NO and H2S production. PUFAs and their metabolites influence stem cell biology and thus, affect ageing process and ageing-associated diseases including Alzheimer’s disease (for further details see text). PUFAs can give rise to FAHFAs that have anti-inflammatory properties and may enhance NO, CO and H2S production, and mediate exercise-induced anti-inflammatory actions. PUFAs form precursors to anti-inflammatory lipoxins, resolvins, protectins and maresins that suppress production of pro-inflammatory IL-6, TNF-α and prostanoids. It is not yet known but possible that FAHFAs may suppress tumor cell growth, inhibit inflammatory events that occur in hypothalamus due to high fat diet. Though the role of p53 in ageing and diseases is not discussed in detail here, it may be noted that p53 is the guardian of the genome. PUFAs and their metabolites, cytokines, NO, CO, H2S, ROS, GDF-11, GnRH and NAE may modulate the action of p53. For instance, exercise reduces the incidence of cancer, possibly, by augmenting the production of IL-6 and TNF-α that are cytotoxic to tumor cells either by their direct action and/or enhancing the production of ROS that are tumoricidal. In addition, exercise may enhance the expression and action of p53 that leads to apoptosis of cancer cells. PUFAs have tumoricidal action and may bring about this action by augmenting free radical generation and formation of excess lipid peroxides selectively in tumor cells and augmenting the expression and action of p53.

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