Maximum reproductive lifespan correlates with CD33rSIGLEC gene number: Implications for NADPH oxidase‐derived reactive oxygen species in aging

Abstract

Humans and orcas are among the very rare species that have a prolonged post-reproductive lifespan (PRLS), during which the aging process continues. Reactive oxygen species (ROS) derived from mitochondria and from the NADPH oxidase (NOX) enzymes of innate immune cells are known to contribute to aging, with the former thought to be dominant. CD33-related-Siglecs are immune receptors that recognize self-associated-molecular-patterns and modulate NOX-derived-ROS. We herewith demonstrate a strong correlation of lifespan with CD33rSIGLEC gene number in 26 species, independent of body weight or phylogeny. The correlation is stronger when considering total CD33rSIGLEC gene number rather than those encoding inhibitory and activating subsets, suggesting that lifetime balancing of ROS is important. Combining independent lines of evidence including the short half-life and spontaneous activation of neutrophils, we calculate that even without inter-current inflammation, a major source of lifetime ROS exposure may actually be neutrophil NOX-derived. However, genomes of human supercentenarians (>110 years) do not harbor a significantly higher number of functional CD33rSIGLEC genes. Instead, lifespan correlation with CD33rSIGLEC gene number was markedly strengthened by excluding the post-reproductive lifespan of humans and orcas (R 2 = 0.83; P < .0001). Thus, CD33rSIGLEC modulation of ROS likely contributes to maximum reproductive lifespan, but other unknown mechanisms could be important to PRLS. K E Y W O R D SCD33rSIGLEC, NADPH-oxidase, prolonged post-reproductive lifespan, reactive oxygen species | 1929 KHAN et Al. 1936 | KHAN et Al. ACKNOWLEDGMENTSWe thank members of the laboratory of AV for helpful discussions and suggestions.

Siglecs Modulate Activities of Immune Cells Through Positive and Negative Regulation of ROS Generation

“…Deletion of Siglec-E in mice resulted in shortened lifespan with increased generation of ROS and inhibition of ROS-detoxification systems (70). This correlation was confirmed across 26 species and held true for both activatory and inhibitory Siglecs (72).…”

Bilirubin Nanomedicines for the Treatment of Reactive Oxygen Species (ROS)-Mediated Diseases

“…These enzymes do not only highly express in phagocytes but also exist in other cell types and tissues at a low level. 31 In addition, monoamine oxidase 32 and cytochrome b5 reductase 33 were also reported to have physiological activities to promote the formation of ROS. There is an endogenous antioxidative system in organisms, which mainly consists of superoxide dismutase (SOD) (scavenges O 2 • − ), 6 glutathione peroxidase (GPx) (eliminates H 2 O 2 and lipid peroxide), 8 and catalase (catalyzes the decomposition of H 2 O 2 ).…”

Evolution of Human-specific Alleles Protecting Cognitive Function of Grandmothers

“…In keeping with the fundamental importance of reproduction for the process of biological evolution via natural selection, loss of fecundity generally coincides with the end of lifespan in almost all species studied to date. Humans and certain toothed whales like orcas are so far the only mammals known to manifest prolonged post-reproductive lifespans under naturalistic conditions [1–6]. One current explanation for such prolonged post-reproductive survival is late-life kin selection of grandmothers and other elderly caregivers of helpless young; apparently contrary to the concept of “antagonistic pleiotropy”, which posits that natural selection does not operate in late-life [7, 8].…”

“…Incidence of LOAD has been strongly associated with varied expression of CD33 isoforms in the brain of affected individuals [20, 21], where the LOAD-protective CD33 allele increases the ratio of D2-CD33 isoform relative to CD33M. CD33 is reported in almost all vertebrates, including nonhuman primates [6, 14]. While there is often high similarity in the sequence and overall genomic location, CD33 has undergone various species-specific changes.…”