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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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Phylogeny and tree branch information.Phylogeny and tree branch information used in this study were obtained from Prasad et al. (2008) and trimmed by Archaeopteryx 0.957 (Zmasek and Eddy, 2001; Han and Zmasek, 2009) down to the same 14 species. The topology is also indicated in the Newick tree format.DOI:http://dx.doi.org/10.7554/eLife.06184.006
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fig1s3: Phylogeny and tree branch information.Phylogeny and tree branch information used in this study were obtained from Prasad et al. (2008) and trimmed by Archaeopteryx 0.957 (Zmasek and Eddy, 2001; Han and Zmasek, 2009) down to the same 14 species. The topology is also indicated in the Newick tree format.DOI:http://dx.doi.org/10.7554/eLife.06184.006

Mentions: Since closely related species may also share similar traits simply due to their common ancestry, data from different species may not be statistically independent. To control for such effects, we used phylogenetic comparative analysis using Phylogeny Generalized Least-Squares (PGLS) or Felsenstein's Independent Contrast (FIC) approaches. The correlation between CD33rSiglecs and longevity remained very strong after such phylogenetic correction (Table 1 and Figure 1—figure supplement 3). Moreover, the correlation was maintained after mathematical correction for body mass represented by average adult body weight (Table 2), another factor known to correlate with metabolic rate and lifespan (Manini, 2010). Overall, a positive correlation was shown between the residual maximum lifespan and residual CD33rSIGLEC gene numbers (controlling for both body mass and phylogeny) (Figure 1E,F). Since the time that these data were originally collected and evaluated, additional genome sequences have become available. Therefore, in order to further test the strength of the correlation, we included the data from three short-lived primate genomes (Saimiri boliviensis, Tarsius syrichta, and Otolemur garnettii). Interestingly, these genomes were found to have fewer CD33rSIGLEC genes (5, 5, and 4 genes, respectively). Addition of these data to the primary correlation did not change the statistical significance of the association between number of CD33rSIGLEC genes and maximum longevity (R2 = 0.661 in logarithmic scale, R2 = 0.752 in linear scale). Furthermore, based on the different sample size of different species tested, an adjusted value of maximum longevity of 90 years for humans was considered, in line with previous studies (Lorenzini et al., 2005). Notably, the overall correlation between number of CD33rSIGLEC genes and maximum longevity remained strong (R2 = 0.649 in the logarithmic scale, R2 = 0.843 in the linear scale).10.7554/eLife.06184.007Table 1.


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)

Phylogeny and tree branch information.Phylogeny and tree branch information used in this study were obtained from Prasad et al. (2008) and trimmed by Archaeopteryx 0.957 (Zmasek and Eddy, 2001; Han and Zmasek, 2009) down to the same 14 species. The topology is also indicated in the Newick tree format.DOI:http://dx.doi.org/10.7554/eLife.06184.006
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384638&req=5

fig1s3: Phylogeny and tree branch information.Phylogeny and tree branch information used in this study were obtained from Prasad et al. (2008) and trimmed by Archaeopteryx 0.957 (Zmasek and Eddy, 2001; Han and Zmasek, 2009) down to the same 14 species. The topology is also indicated in the Newick tree format.DOI:http://dx.doi.org/10.7554/eLife.06184.006
Mentions: Since closely related species may also share similar traits simply due to their common ancestry, data from different species may not be statistically independent. To control for such effects, we used phylogenetic comparative analysis using Phylogeny Generalized Least-Squares (PGLS) or Felsenstein's Independent Contrast (FIC) approaches. The correlation between CD33rSiglecs and longevity remained very strong after such phylogenetic correction (Table 1 and Figure 1—figure supplement 3). Moreover, the correlation was maintained after mathematical correction for body mass represented by average adult body weight (Table 2), another factor known to correlate with metabolic rate and lifespan (Manini, 2010). Overall, a positive correlation was shown between the residual maximum lifespan and residual CD33rSIGLEC gene numbers (controlling for both body mass and phylogeny) (Figure 1E,F). Since the time that these data were originally collected and evaluated, additional genome sequences have become available. Therefore, in order to further test the strength of the correlation, we included the data from three short-lived primate genomes (Saimiri boliviensis, Tarsius syrichta, and Otolemur garnettii). Interestingly, these genomes were found to have fewer CD33rSIGLEC genes (5, 5, and 4 genes, respectively). Addition of these data to the primary correlation did not change the statistical significance of the association between number of CD33rSIGLEC genes and maximum longevity (R2 = 0.661 in logarithmic scale, R2 = 0.752 in linear scale). Furthermore, based on the different sample size of different species tested, an adjusted value of maximum longevity of 90 years for humans was considered, in line with previous studies (Lorenzini et al., 2005). Notably, the overall correlation between number of CD33rSIGLEC genes and maximum longevity remained strong (R2 = 0.649 in the logarithmic scale, R2 = 0.843 in the linear scale).10.7554/eLife.06184.007Table 1.

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