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.
Highlights
Aging is controlled partly by genetic factors, such as insulin/IGF-1, mTOR, AMPK, and Sirtuin signaling pathways (Lopez-Otin et al, 2013)
It has been experimentally shown that lifespan of eight mammalian species correlates to the ability of their primary fibroblasts to cope with stress (Kapahi et al, 1999)
As Siglecs are capable of modulating cellular inflammatory responses and the number of genes encoding CD33rSiglecs varies widely between species (Angata et al, 2004), we asked if CD33rSIGLEC gene number correlates with maximum lifespan in mammals
Summary
Aging is controlled partly by genetic factors, such as insulin/IGF-1, mTOR, AMPK, and Sirtuin signaling pathways (Lopez-Otin et al, 2013). Another important element affecting aging is thought to be cumulative damage to macromolecules by reactive oxygen and nitrogen species (ROS/RNS) induced by unbalanced cellular inflammatory responses, or generated via mitochondrial dysfunction (Berlett and Stadtman, 1997; Dizdaroglu et al, 2002).
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