Advanced science (Weinheim, Baden-Wurttemberg, Germany)Oct 15, 2026

Bone Marrow Immune Cell Signaling Connects Fat Growth in Bone Marrow to Energy Loss and Bone Formation Decline in Aging

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 16, 2026

Abstract

Bone marrow macrophage STING signaling has a dual role in skeletal aging, being harmful early but protective against age-related bone loss from middle age onward.

BMM STING deficiency negatively impacts early bone development and maturation.
In middle age and beyond, BMM STING activation may protect against age-related bone loss.
Bone marrow adipocytes release soluble dipeptidyl peptidase 4 (sDPP4), which activates STING signaling in BMMs.
STING activation triggers a pathway that increases CD38 levels, promoting bone marrow inflammation.
Elevated CD38 activity may reduce the availability of nicotinamide mononucleotide (NMN), which is essential for bone formation.
Combining STING inhibition with NMN supplementation shows potential to reduce bone loss in preclinical models.

Simplified

Reversing the destructive remodeling of the bone marrow microenvironment during aging remains a major challenge. Here, we reveal an age-dependent dual role of bone marrow macrophage (BMM) STING signaling during skeletal aging. While BMM STING deficiency is detrimental during early bone development and maturation, it paradoxically confers protection against age-related bone loss from middle age onward. Mechanistically, accumulating bone marrow adipocytes secrete substantial soluble dipeptidyl peptidase 4 (sDPP4). This sDPP4 functions as an extracellular ligand for Toll-like receptor 4 on BMMs, thereby collaborating with endogenous mitochondrial DNA to activate STING signaling. This STING activation concurrently induces a CD38-dependent salvage synthesis pathway. Importantly, this STING-driven upregulation of CD38 not only amplifies bone marrow inflammation but also, through its ecto-nicotinamide adenine dinucleotide (NAD⁺) activity, depletes the precursor nicotinamide mononucleotide (NMN) required for NAD⁺ salvage synthesis, thereby impairing NMN availability and osteogenic capacity in neighboring bone marrow mesenchymal stem cells. Finally, therapeutic intervention combining STING pharmacological inhibition with NMN supplementation effectively attenuated bone loss in preclinical models. Thus, we propose BMM STING signaling as a direct nexus connecting marrow adipose accumulation, innate immune inflammation, and diminished bone formation, and emphasize its targeting potential for managing the aged bone marrow microenvironment.

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Bone Marrow Immune Cell Signaling Connects Fat Growth in Bone Marrow to Energy Loss and Bone Formation Decline in Aging

Abstract

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