"Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Abstract

Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

Keywords: aging; bioactive lipids; cell membrane; inflammation; sirtuins; unsaturated fatty acids.

Figure 1

Scheme showing possible changes that can occur during ageing. Changes that are likely to be primary events in the causation of ageing are given in blue; responses to damage are given in orange and hallmarks of the effect of the alterations in genomic stability, telomere attrition and epigenetic changes and loss of proteostasis is given in green. Kindly note that all these events can interact with each other. In all the events associated with aging are modulated by AA (arachidonic acid, 20:4 n−6) and its metabolites.

Figure 2

(A) Scheme showing metabolism of essential fatty acids and their important products. (B) Scheme showing metabolism of AA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by cytochrome P450 enzymes. DHA, alpha-linolenic acid (ALA), LXA4 and possibly, other bioactive lipids (BALs) may inhibit sEH enzyme and thus, bring about some of their beneficial actions. Some of the beneficial actions of metabolites of AA, EPA and DHA formed due to the action of cytochrome P450 enzymes (such as 11,12-EET) is also shown. (C) Metabolism of dihomo-gamma-linolenic acid (DGLA) by cytochrome P450 enzymes. (D) Scheme showing the formation of leukotrienes (LTs) and lipoxins (LXs) in various types of cells from arachidonic acid. Similar metabolism occurs regarding EPA and DHA to form resolvins, protectins and maresins. Note the conversion of 15S-H(p)ETE to LXA4 and LTA4 to LXA4/LXB4 by the action of 5-lipoxygenase (5-LO) and 12-lipoxygenase (12-LO). This could be one potential mechanism by which leukocytes and platelets at the site of inflammation can convert pro-inflammatory leukotrienes to anti-inflammatory lipoxins and thus, initiate resolution of inflammation.

Figure 2

(A) Scheme showing metabolism of essential fatty acids and their important products. (B) Scheme showing metabolism of AA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by cytochrome P450 enzymes. DHA, alpha-linolenic acid (ALA), LXA4 and possibly, other bioactive lipids (BALs) may inhibit sEH enzyme and thus, bring about some of their beneficial actions. Some of the beneficial actions of metabolites of AA, EPA and DHA formed due to the action of cytochrome P450 enzymes (such as 11,12-EET) is also shown. (C) Metabolism of dihomo-gamma-linolenic acid (DGLA) by cytochrome P450 enzymes. (D) Scheme showing the formation of leukotrienes (LTs) and lipoxins (LXs) in various types of cells from arachidonic acid. Similar metabolism occurs regarding EPA and DHA to form resolvins, protectins and maresins. Note the conversion of 15S-H(p)ETE to LXA4 and LTA4 to LXA4/LXB4 by the action of 5-lipoxygenase (5-LO) and 12-lipoxygenase (12-LO). This could be one potential mechanism by which leukocytes and platelets at the site of inflammation can convert pro-inflammatory leukotrienes to anti-inflammatory lipoxins and thus, initiate resolution of inflammation.

Figure 3

(A) Scheme showing the metabolism of AA and how pro-inflammatory LTA4 can be converted to anti-inflammatory LXA4. Similar conversion of pro-inflammatory PGs, TXs and LTs to anti-inflammatory resolvins, protectins and maresins may occur. (B) Scheme showing interaction(s) among BALs, cytokines, glucocorticoids, and inflammatory process. (-) Indicates inhibition of action or synthesis; (+) indicates increase in synthesis or action. sEH = soluble epoxide hydrolase; VNS = vagal nerve stimulation; ROS = reactive oxygen species. α-KG = alpha-ketoglutarate. Infections, surgery, and injury activate PLA2 leading to the release of AA and other unsaturated fatty acids from the cell membrane lipid pool. Simultaneously circulating leukocytes, macrophages and other immunocytes are activated that release IL-6 and TNF-α, which stimulate PLA2 leading to release of AA (and DGLA, EPA, DPA an DHA). COX-2 and LOX enzymes convert DGLA, AA, EPA and DHA to form their respective metabolites. To balance the action of pro-inflammatory cytokines, there will be release of anti-inflammatory cytokines IL-4 and IL-10. Pro-IL-β1 released is converted to IL-β1, a pro-inflammatory cytokine. IL-β1 acts on cPLA2/sPLA2 to induce the release of second wave of AA from the cell membrane that can be converted to LXA4, an anti-inflammatory molecule. During the first 24 h of injury, infection, and surgery, iPLA2 is activated. AA and other PUFAs released due to the activation of iPLA2 are utilized mainly to form pro-inflammatory bioactive lipids. In contrast to this, 48–96 h after infection, injury, and surgery activation of cPLA2/sPLA2 occurs that induce the release of second wave of AA and other PUFAs (polyunsaturated fatty acids) that is used to form anti-inflammatory LXA4, PGD2 and PGJ2. This switchover from pro-inflammatory PGE2 and LTs to anti-inflammatory LXA4 is facilitated by PGE2. Once the local tissue and plasma concentrations of PGE2 reach the peak, it (PGE2) activates 5-LOX and 15-LOX enzymes to enhance the formation of LXA4 to initiate resolution of inflammation and enhance wound healing. If PGE2 concentrations fail to reach its peak levels, stimulation of 5- and 15-LOX fails to occur, and so inflammation persists. It is likely that once the PGE2 levels reach their peak, it stimulates cPLA2 and sPLA2 enzymes to induce second wave of AA release. EPA, DHA and DGLA may have actions like AA (not shown in the figure). EPA forms the precursor to 3 series PGs, TXs and 5 series LTs (that are less pro-inflammatory compared to 2 series PGs, TXs and 4 series LTs formed from AA but are nevertheless pro-inflammatory) and resolvins of E series that are anti-inflammatory. DHA forms precursor to resolvins, protectins and maresins all of which are potent anti-inflammatory molecules. DGLA is the precursor of PGE1, an anti-inflammatory molecule, that has actions like LXA4 (see Table 1 and Figure 3C). This figure is modified from reference [37]. (C) Scheme showing the metabolism of DGLA and their metabolites. PGH1 has pro-inflammatory actions but is less potent compared to PGH2 and PGE2. PGE1 is anti-inflammatory in nature. (D) PGH1 stimulates Ca²⁺ mobilization in CRTH2 transfected and primary eosinophils. It is evident that PGH1 is less potent compared to PGH2 and so is less pro-inflammatory compared to PGH2 and PGE2. This data is taken from PLoS ONE 2012, 7, e33329, doi:10.1371/journal.pone.0033329. (E) Summary of metabolites formed from AA, DPA, EPA and DHA and possible timeline of their formation during inflammation and resolution phases of inflammation. It may be noted that once the resolution process of inflammation starts, there is a need for removal of debris, regeneration of tissues (stem cells need to move to the site of inflammation, proliferate, differentiate and induce repair of damaged tissues and restore homeostasis). It is likely that lipoxins are needed for inhibition of inflammation; resolvins for resolution of inflammation; protectins for protecting normal tissues; and maresins for stem cell function. All these events may occur simultaneously but in a highly coordinated and regulated fashion. It is proposed that the concentrations of various molecules involved in inflammation and its resolution and restoration of homeostasis is as follows: 24 h: PGE2↑↑↑↑; LXA4↑; RSVs$\boxed{\leftrightarrow }$; PRTs$\boxed{\leftrightarrow }$; MaRs$\boxed{\leftrightarrow }$. 48 h: PGE2↑↑↑; LXA4↑↑; RSVs↑; PRTs↑; MaRs↑. 72 h: PGE2↑↑; LXA4↑↑↑; RSVs↑↑; PRTs↑↑↑; MaRs↑↑↑. 96 h: PGE2↑; LXA4↑↑; RSVs↑↑↑; PRTs↑↑↑; MaRs↑↑↑↑. >96 h: PGE2↑; LXA4↑; RSVs↑↑; PRTs↑↑; MaRs↑↑↑. The actions of these compounds in the inflammation and wound healing process can be as follows: LXA4 → anti-inflammatory >resolution >protection >proliferation. RSVs → resolution > anti-inflammatory >protection >proliferation. PRTs → protection > resolution > anti-inflammatory > proliferation. MaRs → proliferation > protection > resolution > anti-inflammatory. Resolution refers to resolution of inflammation. Protection refers to protection of normal cells/tissues from injurious agents. Proliferation refers to proliferation of stem cells and other cells to replace damaged cells/tissues. Even though all compounds have similar and overlapping actions and possess anti-inflammatory properties, each lipid may show one particular action more compared to the other actions.

Figure 3

(A) Scheme showing the metabolism of AA and how pro-inflammatory LTA4 can be converted to anti-inflammatory LXA4. Similar conversion of pro-inflammatory PGs, TXs and LTs to anti-inflammatory resolvins, protectins and maresins may occur. (B) Scheme showing interaction(s) among BALs, cytokines, glucocorticoids, and inflammatory process. (-) Indicates inhibition of action or synthesis; (+) indicates increase in synthesis or action. sEH = soluble epoxide hydrolase; VNS = vagal nerve stimulation; ROS = reactive oxygen species. α-KG = alpha-ketoglutarate. Infections, surgery, and injury activate PLA2 leading to the release of AA and other unsaturated fatty acids from the cell membrane lipid pool. Simultaneously circulating leukocytes, macrophages and other immunocytes are activated that release IL-6 and TNF-α, which stimulate PLA2 leading to release of AA (and DGLA, EPA, DPA an DHA). COX-2 and LOX enzymes convert DGLA, AA, EPA and DHA to form their respective metabolites. To balance the action of pro-inflammatory cytokines, there will be release of anti-inflammatory cytokines IL-4 and IL-10. Pro-IL-β1 released is converted to IL-β1, a pro-inflammatory cytokine. IL-β1 acts on cPLA2/sPLA2 to induce the release of second wave of AA from the cell membrane that can be converted to LXA4, an anti-inflammatory molecule. During the first 24 h of injury, infection, and surgery, iPLA2 is activated. AA and other PUFAs released due to the activation of iPLA2 are utilized mainly to form pro-inflammatory bioactive lipids. In contrast to this, 48–96 h after infection, injury, and surgery activation of cPLA2/sPLA2 occurs that induce the release of second wave of AA and other PUFAs (polyunsaturated fatty acids) that is used to form anti-inflammatory LXA4, PGD2 and PGJ2. This switchover from pro-inflammatory PGE2 and LTs to anti-inflammatory LXA4 is facilitated by PGE2. Once the local tissue and plasma concentrations of PGE2 reach the peak, it (PGE2) activates 5-LOX and 15-LOX enzymes to enhance the formation of LXA4 to initiate resolution of inflammation and enhance wound healing. If PGE2 concentrations fail to reach its peak levels, stimulation of 5- and 15-LOX fails to occur, and so inflammation persists. It is likely that once the PGE2 levels reach their peak, it stimulates cPLA2 and sPLA2 enzymes to induce second wave of AA release. EPA, DHA and DGLA may have actions like AA (not shown in the figure). EPA forms the precursor to 3 series PGs, TXs and 5 series LTs (that are less pro-inflammatory compared to 2 series PGs, TXs and 4 series LTs formed from AA but are nevertheless pro-inflammatory) and resolvins of E series that are anti-inflammatory. DHA forms precursor to resolvins, protectins and maresins all of which are potent anti-inflammatory molecules. DGLA is the precursor of PGE1, an anti-inflammatory molecule, that has actions like LXA4 (see Table 1 and Figure 3C). This figure is modified from reference [37]. (C) Scheme showing the metabolism of DGLA and their metabolites. PGH1 has pro-inflammatory actions but is less potent compared to PGH2 and PGE2. PGE1 is anti-inflammatory in nature. (D) PGH1 stimulates Ca²⁺ mobilization in CRTH2 transfected and primary eosinophils. It is evident that PGH1 is less potent compared to PGH2 and so is less pro-inflammatory compared to PGH2 and PGE2. This data is taken from PLoS ONE 2012, 7, e33329, doi:10.1371/journal.pone.0033329. (E) Summary of metabolites formed from AA, DPA, EPA and DHA and possible timeline of their formation during inflammation and resolution phases of inflammation. It may be noted that once the resolution process of inflammation starts, there is a need for removal of debris, regeneration of tissues (stem cells need to move to the site of inflammation, proliferate, differentiate and induce repair of damaged tissues and restore homeostasis). It is likely that lipoxins are needed for inhibition of inflammation; resolvins for resolution of inflammation; protectins for protecting normal tissues; and maresins for stem cell function. All these events may occur simultaneously but in a highly coordinated and regulated fashion. It is proposed that the concentrations of various molecules involved in inflammation and its resolution and restoration of homeostasis is as follows: 24 h: PGE2↑↑↑↑; LXA4↑; RSVs$\boxed{\leftrightarrow }$; PRTs$\boxed{\leftrightarrow }$; MaRs$\boxed{\leftrightarrow }$. 48 h: PGE2↑↑↑; LXA4↑↑; RSVs↑; PRTs↑; MaRs↑. 72 h: PGE2↑↑; LXA4↑↑↑; RSVs↑↑; PRTs↑↑↑; MaRs↑↑↑. 96 h: PGE2↑; LXA4↑↑; RSVs↑↑↑; PRTs↑↑↑; MaRs↑↑↑↑. >96 h: PGE2↑; LXA4↑; RSVs↑↑; PRTs↑↑; MaRs↑↑↑. The actions of these compounds in the inflammation and wound healing process can be as follows: LXA4 → anti-inflammatory >resolution >protection >proliferation. RSVs → resolution > anti-inflammatory >protection >proliferation. PRTs → protection > resolution > anti-inflammatory > proliferation. MaRs → proliferation > protection > resolution > anti-inflammatory. Resolution refers to resolution of inflammation. Protection refers to protection of normal cells/tissues from injurious agents. Proliferation refers to proliferation of stem cells and other cells to replace damaged cells/tissues. Even though all compounds have similar and overlapping actions and possess anti-inflammatory properties, each lipid may show one particular action more compared to the other actions.

Figure 3

(A) Scheme showing the metabolism of AA and how pro-inflammatory LTA4 can be converted to anti-inflammatory LXA4. Similar conversion of pro-inflammatory PGs, TXs and LTs to anti-inflammatory resolvins, protectins and maresins may occur. (B) Scheme showing interaction(s) among BALs, cytokines, glucocorticoids, and inflammatory process. (-) Indicates inhibition of action or synthesis; (+) indicates increase in synthesis or action. sEH = soluble epoxide hydrolase; VNS = vagal nerve stimulation; ROS = reactive oxygen species. α-KG = alpha-ketoglutarate. Infections, surgery, and injury activate PLA2 leading to the release of AA and other unsaturated fatty acids from the cell membrane lipid pool. Simultaneously circulating leukocytes, macrophages and other immunocytes are activated that release IL-6 and TNF-α, which stimulate PLA2 leading to release of AA (and DGLA, EPA, DPA an DHA). COX-2 and LOX enzymes convert DGLA, AA, EPA and DHA to form their respective metabolites. To balance the action of pro-inflammatory cytokines, there will be release of anti-inflammatory cytokines IL-4 and IL-10. Pro-IL-β1 released is converted to IL-β1, a pro-inflammatory cytokine. IL-β1 acts on cPLA2/sPLA2 to induce the release of second wave of AA from the cell membrane that can be converted to LXA4, an anti-inflammatory molecule. During the first 24 h of injury, infection, and surgery, iPLA2 is activated. AA and other PUFAs released due to the activation of iPLA2 are utilized mainly to form pro-inflammatory bioactive lipids. In contrast to this, 48–96 h after infection, injury, and surgery activation of cPLA2/sPLA2 occurs that induce the release of second wave of AA and other PUFAs (polyunsaturated fatty acids) that is used to form anti-inflammatory LXA4, PGD2 and PGJ2. This switchover from pro-inflammatory PGE2 and LTs to anti-inflammatory LXA4 is facilitated by PGE2. Once the local tissue and plasma concentrations of PGE2 reach the peak, it (PGE2) activates 5-LOX and 15-LOX enzymes to enhance the formation of LXA4 to initiate resolution of inflammation and enhance wound healing. If PGE2 concentrations fail to reach its peak levels, stimulation of 5- and 15-LOX fails to occur, and so inflammation persists. It is likely that once the PGE2 levels reach their peak, it stimulates cPLA2 and sPLA2 enzymes to induce second wave of AA release. EPA, DHA and DGLA may have actions like AA (not shown in the figure). EPA forms the precursor to 3 series PGs, TXs and 5 series LTs (that are less pro-inflammatory compared to 2 series PGs, TXs and 4 series LTs formed from AA but are nevertheless pro-inflammatory) and resolvins of E series that are anti-inflammatory. DHA forms precursor to resolvins, protectins and maresins all of which are potent anti-inflammatory molecules. DGLA is the precursor of PGE1, an anti-inflammatory molecule, that has actions like LXA4 (see Table 1 and Figure 3C). This figure is modified from reference [37]. (C) Scheme showing the metabolism of DGLA and their metabolites. PGH1 has pro-inflammatory actions but is less potent compared to PGH2 and PGE2. PGE1 is anti-inflammatory in nature. (D) PGH1 stimulates Ca²⁺ mobilization in CRTH2 transfected and primary eosinophils. It is evident that PGH1 is less potent compared to PGH2 and so is less pro-inflammatory compared to PGH2 and PGE2. This data is taken from PLoS ONE 2012, 7, e33329, doi:10.1371/journal.pone.0033329. (E) Summary of metabolites formed from AA, DPA, EPA and DHA and possible timeline of their formation during inflammation and resolution phases of inflammation. It may be noted that once the resolution process of inflammation starts, there is a need for removal of debris, regeneration of tissues (stem cells need to move to the site of inflammation, proliferate, differentiate and induce repair of damaged tissues and restore homeostasis). It is likely that lipoxins are needed for inhibition of inflammation; resolvins for resolution of inflammation; protectins for protecting normal tissues; and maresins for stem cell function. All these events may occur simultaneously but in a highly coordinated and regulated fashion. It is proposed that the concentrations of various molecules involved in inflammation and its resolution and restoration of homeostasis is as follows: 24 h: PGE2↑↑↑↑; LXA4↑; RSVs$\boxed{\leftrightarrow }$; PRTs$\boxed{\leftrightarrow }$; MaRs$\boxed{\leftrightarrow }$. 48 h: PGE2↑↑↑; LXA4↑↑; RSVs↑; PRTs↑; MaRs↑. 72 h: PGE2↑↑; LXA4↑↑↑; RSVs↑↑; PRTs↑↑↑; MaRs↑↑↑. 96 h: PGE2↑; LXA4↑↑; RSVs↑↑↑; PRTs↑↑↑; MaRs↑↑↑↑. >96 h: PGE2↑; LXA4↑; RSVs↑↑; PRTs↑↑; MaRs↑↑↑. The actions of these compounds in the inflammation and wound healing process can be as follows: LXA4 → anti-inflammatory >resolution >protection >proliferation. RSVs → resolution > anti-inflammatory >protection >proliferation. PRTs → protection > resolution > anti-inflammatory > proliferation. MaRs → proliferation > protection > resolution > anti-inflammatory. Resolution refers to resolution of inflammation. Protection refers to protection of normal cells/tissues from injurious agents. Proliferation refers to proliferation of stem cells and other cells to replace damaged cells/tissues. Even though all compounds have similar and overlapping actions and possess anti-inflammatory properties, each lipid may show one particular action more compared to the other actions.

Figure 4

Effect of various polyunsaturated fatty acids (PUFAs) on LXA4 secretion by RIN cells (rat insulinoma cells) treated with alloxan and streptozotocin. Alloxan and streptozotocin-induced inhibition of LXA4 secretion by RIN cells is restored to near normal by GLA, AA, EPA and DHA compared to control. (A) RIN5F cells were treated with various doses (1, 2, 4, 6 mM) of alloxan for 1, 2, 4 h. The LXA4 was estimated by ELISA in the supernatant of cultures. (B) RIN5F cells were treated with 10 μg/mL GLA, AA, EPA and DHA and alloxan (6 mM) for 1 h. Streptozotocin (21 mM) treated RIN cells (for 24 h) were exposed to 10 μg/mL of various PUFAs (C). The LXA4 was estimated in the supernatant of the cell cultures. * p < 0.05 compared to untreated control, # p < 0.05 compared to alloxan, compared to STZ. It is seen that at 10 μg/mL dose of EPA and DHA treatment there is no increase in LXA4 secretion by RIN5F cells in vitro in the presence of alloxan (6 mM) (Figure 4A). However, when RIN5F cells were supplemented with 15 μg/mL of EPA and DHA there is a significant increase LXA4 secretion even in the presence of alloxan (Figure 4B). In contrast 10 μg/mL of PUFAs could increase LXA4 secretion to near normal by RIN cells (Figure 4C) (AA > GLA > EPA > DHA). It is seen from this data that GLA, EPA and DHA can augment LXA4 formation but are less potent compared to AA. This suggests that some of the anti-inflammatory actions of GLA, EPA and DHA could be due to their action to enhance LXA4 formation in addition to their ability to give rise to PGE1 (from GLA); resolvins of E series from EPA and resolvins of D series, protectins and maresins from DHA. This data is taken from references [35,36].

Figure 4

Effect of various polyunsaturated fatty acids (PUFAs) on LXA4 secretion by RIN cells (rat insulinoma cells) treated with alloxan and streptozotocin. Alloxan and streptozotocin-induced inhibition of LXA4 secretion by RIN cells is restored to near normal by GLA, AA, EPA and DHA compared to control. (A) RIN5F cells were treated with various doses (1, 2, 4, 6 mM) of alloxan for 1, 2, 4 h. The LXA4 was estimated by ELISA in the supernatant of cultures. (B) RIN5F cells were treated with 10 μg/mL GLA, AA, EPA and DHA and alloxan (6 mM) for 1 h. Streptozotocin (21 mM) treated RIN cells (for 24 h) were exposed to 10 μg/mL of various PUFAs (C). The LXA4 was estimated in the supernatant of the cell cultures. * p < 0.05 compared to untreated control, # p < 0.05 compared to alloxan, compared to STZ. It is seen that at 10 μg/mL dose of EPA and DHA treatment there is no increase in LXA4 secretion by RIN5F cells in vitro in the presence of alloxan (6 mM) (Figure 4A). However, when RIN5F cells were supplemented with 15 μg/mL of EPA and DHA there is a significant increase LXA4 secretion even in the presence of alloxan (Figure 4B). In contrast 10 μg/mL of PUFAs could increase LXA4 secretion to near normal by RIN cells (Figure 4C) (AA > GLA > EPA > DHA). It is seen from this data that GLA, EPA and DHA can augment LXA4 formation but are less potent compared to AA. This suggests that some of the anti-inflammatory actions of GLA, EPA and DHA could be due to their action to enhance LXA4 formation in addition to their ability to give rise to PGE1 (from GLA); resolvins of E series from EPA and resolvins of D series, protectins and maresins from DHA. This data is taken from references [35,36].

Figure 5

Aged mice show reduced resolvins, protectins and maresins and LXA4 in the peritoneal lavage of zymosan challenged animals. * p < 0.05 compared to young mice. This data is taken from reference no. 73.

Figure 6

Scheme showing potential relationship among AA, PGE2, LXA4, desaturases and cytokines with age. It can be seen that with advancing age there is a gradual decrease in the activity of desaturases and a steady fall in the concentrations of AA and LXA4 and a gradual increase in that of PGE2, LTB4 and TNF-α and IL-6. Thus, with advancing age there is gradual and steady increase in pro-inflammatory status and an increase in age-related diseases and a decline in the ability of tissues/cells/organs/humans to fight or ameliorate inflammation due to a decline in anti-inflammatory molecules/capacity. It is envisaged that under normal physiological conditions a delicate balance is maintained among all these molecules/enzymes to maintain homeostasis.

Figure 7

Scheme showing potential relationship between SITs (sirtuins) and BALs and their role in various age-related diseases. For details see text.