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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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Related in: MedlinePlus

Deletion of Siglec-E does not affect locomotor activity.WT and Siglec-E−/− mice show habituation of activity (a significant decrease) across the 2 hr test in the activity chamber. There are no differences between the groups. Indicated are mean ± sem, * indicates p < 0.05, n = 7–11.DOI:http://dx.doi.org/10.7554/eLife.06184.015
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fig2s6: Deletion of Siglec-E does not affect locomotor activity.WT and Siglec-E−/− mice show habituation of activity (a significant decrease) across the 2 hr test in the activity chamber. There are no differences between the groups. Indicated are mean ± sem, * indicates p < 0.05, n = 7–11.DOI:http://dx.doi.org/10.7554/eLife.06184.015

Mentions: We submitted the mice to a series of analyses to test if Siglec-E−/− animals exhibited exacerbated age-related defects. First, 80-week-old Siglec-E−/− mice showed a threefold increase in error rate in the Barnes maze test compared to controls (Figure 2B,C). These results are consistent with previous reports of impairments in learning and in spatial memory in aged mice (Kennard and Woodruff-Pak, 2011). Deficits in the Barnes maze were not due to alterations in locomotor activity (Figure 2—figure supplement 6). Secondly, a blind test involving three independent observers noted increased hair graying in Siglec-E−/− males compared to WT (Figure 2D). Hair graying is related to incomplete maintenance of melanocyte stem cells through loss of the differentiated progeny that occurs physiologically during aging (Nishimura et al., 2005). After termination of the survival study, immunohistochemistry of liver tissues revealed an increased frequency of focal expression of beta-galactosidase, a marker of senescent cells (Figure 2E). Moreover, examination of the epidermis revealed a 50% reduction in thickness in animals lacking Siglec-E (Figure 2F). Epidermis tends to thin with increasing age through mechanisms that possibly involve senescent cells (Lopez-Otin et al., 2013). Collectively, these data indicate that deletion of Siglec-E results in a faster progression of aging and, consequently, to increased frailty leading to an earlier death.


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)

Deletion of Siglec-E does not affect locomotor activity.WT and Siglec-E−/− mice show habituation of activity (a significant decrease) across the 2 hr test in the activity chamber. There are no differences between the groups. Indicated are mean ± sem, * indicates p < 0.05, n = 7–11.DOI:http://dx.doi.org/10.7554/eLife.06184.015
© Copyright Policy
Related In: Results  -  Collection

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

fig2s6: Deletion of Siglec-E does not affect locomotor activity.WT and Siglec-E−/− mice show habituation of activity (a significant decrease) across the 2 hr test in the activity chamber. There are no differences between the groups. Indicated are mean ± sem, * indicates p < 0.05, n = 7–11.DOI:http://dx.doi.org/10.7554/eLife.06184.015
Mentions: We submitted the mice to a series of analyses to test if Siglec-E−/− animals exhibited exacerbated age-related defects. First, 80-week-old Siglec-E−/− mice showed a threefold increase in error rate in the Barnes maze test compared to controls (Figure 2B,C). These results are consistent with previous reports of impairments in learning and in spatial memory in aged mice (Kennard and Woodruff-Pak, 2011). Deficits in the Barnes maze were not due to alterations in locomotor activity (Figure 2—figure supplement 6). Secondly, a blind test involving three independent observers noted increased hair graying in Siglec-E−/− males compared to WT (Figure 2D). Hair graying is related to incomplete maintenance of melanocyte stem cells through loss of the differentiated progeny that occurs physiologically during aging (Nishimura et al., 2005). After termination of the survival study, immunohistochemistry of liver tissues revealed an increased frequency of focal expression of beta-galactosidase, a marker of senescent cells (Figure 2E). Moreover, examination of the epidermis revealed a 50% reduction in thickness in animals lacking Siglec-E (Figure 2F). Epidermis tends to thin with increasing age through mechanisms that possibly involve senescent cells (Lopez-Otin et al., 2013). Collectively, these data indicate that deletion of Siglec-E results in a faster progression of aging and, consequently, to increased frailty leading to an earlier death.

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