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Siglec receptors impact mammalian lifespan by modulating oxidative stress.

Schwarz F, Pearce OM, Wang X, Samraj AN, Läubli H, Garcia JO, Lin H, Fu X, Garcia-Bingman A, Secrest P, Romanoski CE, Heyser C, Glass CK, Hazen SL, Varki N, Varki A, Gagneux P - Elife (2015)

Bottom Line: In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals.We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids.Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

View Article: PubMed Central - PubMed

Affiliation: Glycobiology Research and Training Center, University of California, San Diego, San Diego, United States.

ABSTRACT
Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

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Oxidation of hepatic proteins.Protein-bound oxidized amino acid content (normalized to the precursor amino acid) in proteins from liver homogenates was determined by stable isotope dilution LC/MS/MS analysis. Methyl-tyrosine (m-Tyr) is a stable adduct of phenylalanine (Phe). Brominated tyrosine (BrTyr) is formed by brominating oxidants. Di-tyrosine (Tyr) is an oxidative crosslink. Indicated is mean ± sem, n = 8.DOI:http://dx.doi.org/10.7554/eLife.06184.023
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fig4s3: Oxidation of hepatic proteins.Protein-bound oxidized amino acid content (normalized to the precursor amino acid) in proteins from liver homogenates was determined by stable isotope dilution LC/MS/MS analysis. Methyl-tyrosine (m-Tyr) is a stable adduct of phenylalanine (Phe). Brominated tyrosine (BrTyr) is formed by brominating oxidants. Di-tyrosine (Tyr) is an oxidative crosslink. Indicated is mean ± sem, n = 8.DOI:http://dx.doi.org/10.7554/eLife.06184.023

Mentions: Many types of ROS that are formed to serve a signaling or protective function can also cause damage spontaneously to lipids, nucleic acids, and proteins. Polyunsaturated fatty acids are a sensitive oxidation targets for ROS because of a damaging chain reaction that takes place once lipid peroxidation is initiated (Niki, 2009). DNA bases are also very susceptible to ROS attack, and oxidation of DNA is believed to cause mutations and deletions (Fraga et al., 1990). Most amino acids in a protein can be oxidized by ROS, with these modifications leading to a loss of function (Brennan and Hazen, 2003). Such damage occurs constantly, and cells must repair it or replace the impaired molecules. Defects that allow oxidative damage to accumulate can contribute to the origin and progression of cancers and neurodegenerative diseases, and in general contribute to the symptoms of aging (Berlett and Stadtman, 1997; Halliwell, 2013). Similarly, impairment of the processes that control ROS levels can lead to molecular damage. We looked for signs of molecular damage in the organs of the Siglec-E−/− mice, and found a 1.4-fold increase of DNA damage in liver compared to WT (Figure 4A). This was in line with the evidence that glutathione S-transferases protect cells against as much as 90% of the damage induced by electrophiles and other free radicals (Vasieva, 2011). Brain, spleen, and heart tissues also showed a slight trend towards increase in DNA damage (Figure 4—figure supplement 1). Notably, these differences were not detected in the organs of 10-week-old mice (Figure 4—figure supplement 2). We then searched for oxidative adducts in proteins elsewhere in the body and found elevated plasma protein-bound 3-nitrotyrosine levels, a marker of protein modification by nitric oxide (NO)-derived oxidants (Figure 4B). Similarly, liver of Siglec-E−/− mice showed a trend towards accumulation of oxidized amino acids in proteins compared to WT (Figure 4—figure supplement 3). Furthermore, we detected a twofold increase of F2-isoprostanes levels, including 8-iso Prostaglandin F2α and its metabolite 2,3-dinor-8-iso PGF2α in the urine (Figure 4C,D). F2-isoprostanes are generated by non-enzymatic peroxidation of arachidonic acid due to free radical species (Montuschi et al., 2004). Taken together, these data indicate that elimination of Siglec-E leads to accelerated oxidative modification of DNA, proteins and lipids at the systemic level, via elevated ROS and reactive nitrogen species (RNS) production.10.7554/eLife.06184.020Figure 4.Increased oxidative damage in mice lacking Siglec-E.


Siglec receptors impact mammalian lifespan by modulating oxidative stress.

Schwarz F, Pearce OM, Wang X, Samraj AN, Läubli H, Garcia JO, Lin H, Fu X, Garcia-Bingman A, Secrest P, Romanoski CE, Heyser C, Glass CK, Hazen SL, Varki N, Varki A, Gagneux P - Elife (2015)

Oxidation of hepatic proteins.Protein-bound oxidized amino acid content (normalized to the precursor amino acid) in proteins from liver homogenates was determined by stable isotope dilution LC/MS/MS analysis. Methyl-tyrosine (m-Tyr) is a stable adduct of phenylalanine (Phe). Brominated tyrosine (BrTyr) is formed by brominating oxidants. Di-tyrosine (Tyr) is an oxidative crosslink. Indicated is mean ± sem, n = 8.DOI:http://dx.doi.org/10.7554/eLife.06184.023
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fig4s3: Oxidation of hepatic proteins.Protein-bound oxidized amino acid content (normalized to the precursor amino acid) in proteins from liver homogenates was determined by stable isotope dilution LC/MS/MS analysis. Methyl-tyrosine (m-Tyr) is a stable adduct of phenylalanine (Phe). Brominated tyrosine (BrTyr) is formed by brominating oxidants. Di-tyrosine (Tyr) is an oxidative crosslink. Indicated is mean ± sem, n = 8.DOI:http://dx.doi.org/10.7554/eLife.06184.023
Mentions: Many types of ROS that are formed to serve a signaling or protective function can also cause damage spontaneously to lipids, nucleic acids, and proteins. Polyunsaturated fatty acids are a sensitive oxidation targets for ROS because of a damaging chain reaction that takes place once lipid peroxidation is initiated (Niki, 2009). DNA bases are also very susceptible to ROS attack, and oxidation of DNA is believed to cause mutations and deletions (Fraga et al., 1990). Most amino acids in a protein can be oxidized by ROS, with these modifications leading to a loss of function (Brennan and Hazen, 2003). Such damage occurs constantly, and cells must repair it or replace the impaired molecules. Defects that allow oxidative damage to accumulate can contribute to the origin and progression of cancers and neurodegenerative diseases, and in general contribute to the symptoms of aging (Berlett and Stadtman, 1997; Halliwell, 2013). Similarly, impairment of the processes that control ROS levels can lead to molecular damage. We looked for signs of molecular damage in the organs of the Siglec-E−/− mice, and found a 1.4-fold increase of DNA damage in liver compared to WT (Figure 4A). This was in line with the evidence that glutathione S-transferases protect cells against as much as 90% of the damage induced by electrophiles and other free radicals (Vasieva, 2011). Brain, spleen, and heart tissues also showed a slight trend towards increase in DNA damage (Figure 4—figure supplement 1). Notably, these differences were not detected in the organs of 10-week-old mice (Figure 4—figure supplement 2). We then searched for oxidative adducts in proteins elsewhere in the body and found elevated plasma protein-bound 3-nitrotyrosine levels, a marker of protein modification by nitric oxide (NO)-derived oxidants (Figure 4B). Similarly, liver of Siglec-E−/− mice showed a trend towards accumulation of oxidized amino acids in proteins compared to WT (Figure 4—figure supplement 3). Furthermore, we detected a twofold increase of F2-isoprostanes levels, including 8-iso Prostaglandin F2α and its metabolite 2,3-dinor-8-iso PGF2α in the urine (Figure 4C,D). F2-isoprostanes are generated by non-enzymatic peroxidation of arachidonic acid due to free radical species (Montuschi et al., 2004). Taken together, these data indicate that elimination of Siglec-E leads to accelerated oxidative modification of DNA, proteins and lipids at the systemic level, via elevated ROS and reactive nitrogen species (RNS) production.10.7554/eLife.06184.020Figure 4.Increased oxidative damage in mice lacking Siglec-E.

Bottom Line: In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals.We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids.Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

View Article: PubMed Central - PubMed

Affiliation: Glycobiology Research and Training Center, University of California, San Diego, San Diego, United States.

ABSTRACT
Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan.

Show MeSH
Related in: MedlinePlus