Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice.

Ramkumar Thiyagarajan, Lixia Zhang, Omar D Glover, Kyu Hwan Kwack, Sara Ahmed, Emma Murray, Nanda Kumar Yellapu, Jonathan Bard, Kenneth L Seldeen, Spencer R Rosario, Bruce R Troen, Keith L Kirkwood

Division of Geriatrics, Department of Internal Medicine and Landon Center on Aging, University of Kansas School of Medicine, Kansas City, Kansas, USA. · pubmed

Paper

Abstract

An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8-fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT-PCR. CD38 regulates NAD

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Research summary

The paper investigates the role of monocytic myeloid-derived suppressor cells (M-MDSCs) in osteoclastogenesis during aging, focusing on the underlying mechanisms such as mitochondrial dysfunction and metabolic changes. This research is relevant to longevity as it explores cellular changes associated with aging that could contribute to age-related bone loss, which is a significant aspect of aging biology. However, while the findings are solid and contribute to our understanding of aging processes, they do not present a major breakthrough or transformative implications for the field, hence the moderate impact score.

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