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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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Exposure to human red blood cell membranes does not impact survival of Siglec-E−/− mice.Survival curves of mice intraperitoneally (IP) injected with human red blood cell membranes and Freund's adjuvant (ADJ + HRBC). Controls mice were injected with adjuvant and PBS (ADJ + PBS) or PBS only. There are no significant differences between groups. Log-rank (Mantel–Cox) test: Chi square = 1.310, df = 3, p = 0.7268. Gehan-Breslow-Wilcoxon test: Chi square = 0.6019, df = 3, p = 0.8960.DOI:http://dx.doi.org/10.7554/eLife.06184.011
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fig2s2: Exposure to human red blood cell membranes does not impact survival of Siglec-E−/− mice.Survival curves of mice intraperitoneally (IP) injected with human red blood cell membranes and Freund's adjuvant (ADJ + HRBC). Controls mice were injected with adjuvant and PBS (ADJ + PBS) or PBS only. There are no significant differences between groups. Log-rank (Mantel–Cox) test: Chi square = 1.310, df = 3, p = 0.7268. Gehan-Breslow-Wilcoxon test: Chi square = 0.6019, df = 3, p = 0.8960.DOI:http://dx.doi.org/10.7554/eLife.06184.011

Mentions: We decided to use a mouse model to seek experimental evidence for the observed correlation, as mice have a simplified CD33rSiglec profile compared to other mammalian model systems, in terms of number of genes and expression patterns. In fact, mice possess five CD33rSiglecs (namely, CD33, Siglec-E, -F, -G, -H). Among these, Siglec-E is the dominant receptor and it is strongly expressed on neutrophils, tissue macrophages (Figure 2—figure supplement 1), and microglia (Zhang et al., 2004; Claude et al., 2013). We monitored the survival of mice lacking Siglec-E (Siglec-E−/−) over the course of 100 weeks in comparison to their control wild type littermates (WT) (Figure 2A). The survival study was carried out in two sequential cohorts totaling 117 WT and 120 Siglec-E−/− mice. Overall survival of the Siglec-E−/− males was markedly reduced compared to WT (48% and 70% remaining, respectively, when the experiment was terminated). Similarly, relative to the WT, the median survival of Siglec-E−/− females decreased by 17%. In an attempt to mimic natural conditions of early exposure to inflammatory insults, we exposed all groups of mice to a non-specific antigenic challenge early in life (heterologous cell membranes mixed with Freund's adjuvant). This treatment did not affect the viability of Siglec-E−/− mice over 100 weeks (Figure 2—figure supplement 2). No differences in general appearance or body weight were noted and no signs of specific pathologies were observed during the study (Figure 2—figure supplement 3). Hematological and biochemical analysis of blood samples at periodic intervals and at termination of the study did not reveal significant differences between the two groups (Figure 2—figure supplement 4). Additionally, there was no evidence indicative of systemic chronic disease, such as increased leukocyte counts, microcytic anemia, or hypoalbuminemia. Serum creatinine levels did not suggest diminished renal function. Higher values of alanine aminotransferase were noted for Siglec-E−/− animals but were not statistically different from the controls. Similarly, systematic histological analysis of multiple organs showed no evidence of pathological abnormalities, though we observed sporadic instances of periportal liver inflammation, and a slight increase in lung inflammation compared to control mice (Figure 2—figure supplement 5). Examination of kidneys showed that more of the Siglec-E−/− mice exhibited minor age-related glomerular changes, with thickening of glomerular tufts, visible on Periodic-Acid Schiff stains. These data were in line with previous work on the same mice at a younger age (McMillan et al., 2013).10.7554/eLife.06184.009Figure 2.Absence of immunomodulatory Siglec-E aggravates aging phenotypes and reduces lifespan in mice.


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)

Exposure to human red blood cell membranes does not impact survival of Siglec-E−/− mice.Survival curves of mice intraperitoneally (IP) injected with human red blood cell membranes and Freund's adjuvant (ADJ + HRBC). Controls mice were injected with adjuvant and PBS (ADJ + PBS) or PBS only. There are no significant differences between groups. Log-rank (Mantel–Cox) test: Chi square = 1.310, df = 3, p = 0.7268. Gehan-Breslow-Wilcoxon test: Chi square = 0.6019, df = 3, p = 0.8960.DOI:http://dx.doi.org/10.7554/eLife.06184.011
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4384638&req=5

fig2s2: Exposure to human red blood cell membranes does not impact survival of Siglec-E−/− mice.Survival curves of mice intraperitoneally (IP) injected with human red blood cell membranes and Freund's adjuvant (ADJ + HRBC). Controls mice were injected with adjuvant and PBS (ADJ + PBS) or PBS only. There are no significant differences between groups. Log-rank (Mantel–Cox) test: Chi square = 1.310, df = 3, p = 0.7268. Gehan-Breslow-Wilcoxon test: Chi square = 0.6019, df = 3, p = 0.8960.DOI:http://dx.doi.org/10.7554/eLife.06184.011
Mentions: We decided to use a mouse model to seek experimental evidence for the observed correlation, as mice have a simplified CD33rSiglec profile compared to other mammalian model systems, in terms of number of genes and expression patterns. In fact, mice possess five CD33rSiglecs (namely, CD33, Siglec-E, -F, -G, -H). Among these, Siglec-E is the dominant receptor and it is strongly expressed on neutrophils, tissue macrophages (Figure 2—figure supplement 1), and microglia (Zhang et al., 2004; Claude et al., 2013). We monitored the survival of mice lacking Siglec-E (Siglec-E−/−) over the course of 100 weeks in comparison to their control wild type littermates (WT) (Figure 2A). The survival study was carried out in two sequential cohorts totaling 117 WT and 120 Siglec-E−/− mice. Overall survival of the Siglec-E−/− males was markedly reduced compared to WT (48% and 70% remaining, respectively, when the experiment was terminated). Similarly, relative to the WT, the median survival of Siglec-E−/− females decreased by 17%. In an attempt to mimic natural conditions of early exposure to inflammatory insults, we exposed all groups of mice to a non-specific antigenic challenge early in life (heterologous cell membranes mixed with Freund's adjuvant). This treatment did not affect the viability of Siglec-E−/− mice over 100 weeks (Figure 2—figure supplement 2). No differences in general appearance or body weight were noted and no signs of specific pathologies were observed during the study (Figure 2—figure supplement 3). Hematological and biochemical analysis of blood samples at periodic intervals and at termination of the study did not reveal significant differences between the two groups (Figure 2—figure supplement 4). Additionally, there was no evidence indicative of systemic chronic disease, such as increased leukocyte counts, microcytic anemia, or hypoalbuminemia. Serum creatinine levels did not suggest diminished renal function. Higher values of alanine aminotransferase were noted for Siglec-E−/− animals but were not statistically different from the controls. Similarly, systematic histological analysis of multiple organs showed no evidence of pathological abnormalities, though we observed sporadic instances of periportal liver inflammation, and a slight increase in lung inflammation compared to control mice (Figure 2—figure supplement 5). Examination of kidneys showed that more of the Siglec-E−/− mice exhibited minor age-related glomerular changes, with thickening of glomerular tufts, visible on Periodic-Acid Schiff stains. These data were in line with previous work on the same mice at a younger age (McMillan et al., 2013).10.7554/eLife.06184.009Figure 2.Absence of immunomodulatory Siglec-E aggravates aging phenotypes and reduces lifespan in mice.

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