Metabolic Protein ANGPTL8 Found to Accelerate Aging of Blood Stem Cells

A protein best known for its role in fat and sugar metabolism has been unmasked as an unexpected driver of aging in the blood system. In a study published in the journal Biogerontology, researchers report that angiopoietin-like protein 8, or ANGPTL8, actively promotes the senescence of hematopoietic stem and progenitor cells, the master population in bone marrow that replenishes blood and immune cells throughout life. The finding links a circulating metabolic signal to the gradual functional decline of the hematopoietic system, and it points to a molecular pathway that could, in principle, be targeted to slow blood system aging.

The stakes are considerable. Hematopoietic stem and progenitor cells, collectively known as HSPCs, sit at the top of the blood cell hierarchy, and their sustained function underpins everything from oxygen transport to immune defense. As organisms age, HSPCs lose their regenerative power and their output skews toward the myeloid lineage, the branch that produces granulocytes and monocytes, at the expense of lymphoid cells. This myeloid skewing is accompanied by immunosenescence, the progressive deterioration of immune function that raises the incidence of cancer, cardiovascular disease, neurodegenerative disorders, and autoimmune conditions in the elderly. Previous work has shown that replacing aged HSCs with young-donor cells extends median lifespan and lowers mortality hazard in aged mice, underscoring how central the aging of this compartment is to the healthspan and lifespan of the whole organism.

ANGPTL8, also called betatrophin, RIFL, or TD26, is a secreted glycoprotein produced mainly by the liver and adipose tissue. Its expression rises after caloric intake and falls during fasting, tying it closely to feeding rhythms and to glucose and lipid metabolism. The protein is a physiological inhibitor of lipoprotein lipase, and its overexpression markedly elevates plasma triglyceride levels. Prior studies from the same group had already connected ANGPTL8 to degenerative processes: serum levels were elevated in patients with aortic dissection, the protein correlated with the grade of intervertebral disc degeneration, and in mice it promoted liver fibrosis and hepatocarcinogenesis. A clue to the new direction came from RNA sequencing of liver tissue, which unexpectedly revealed altered expression of numerous genes involved in hematopoietic differentiation when ANGPTL8 was knocked out.

To test whether ANGPTL8 influences systemic aging, the team generated ANGPTL8 knockout mice and compared them with wild-type littermates under both normal chow and high-fat diets over periods of 10 and 20 months. Quantitative PCR, Western blotting, and immunohistochemistry showed that the expression of the senescence markers P53, P21, and P16, along with components of the senescence-associated secretory phenotype, was significantly lower in the liver, lung, and spleen of knockout animals. Functional tests reinforced the molecular picture: knockout mice performed better in the Morris water maze, crossing the former platform location more often and locating it faster, and micro-CT scans of the femur revealed higher bone mineral density and bone volume fraction, suggesting protection against osteoporosis. Notably, under a high-fat diet, which stimulates ANGPTL8 secretion, knockout mice survived significantly longer than wild-type controls.

The heart of the study, however, lay in the bone marrow. Flow cytometry showed that the proportion of long-term hematopoietic stem cells, defined by the surface phenotype Lin-negative c-Kit-positive Sca-1-positive CD48-negative CD150-positive, was significantly greater in knockout mice across diet and age conditions. Cell cycle analysis revealed an increased fraction of G1-phase cells among c-Kit-positive HSPCs, indicating enhanced quiescence, a state considered essential for preserving stemness and lifelong self-renewal. In knockout HSPCs, the researchers also observed reduced levels of the cell polarity protein Cdc42 and the DNA damage marker phosphorylated gamma-H2AX, both closely associated with HSPC aging. Mitochondrial measurements added a metabolic dimension: reactive oxygen species content was markedly lower, and JC-1 probing of mitochondrial membrane potential showed less depolarization, consistent with healthier mitochondria in the absence of ANGPTL8.

Because HSPCs themselves do not express ANGPTL8, the protein must reach them through the circulation, secreted from liver and fat tissue and entering the bone marrow cavity from the blood. To model this, the team cultured sorted c-Kit-positive HSPCs with recombinant ANGPTL8 at 600 nanograms per milliliter for four days. The treated cells showed a dose-dependent rise in aging-related proteins, an increased proportion of beta-galactosidase-positive cells, a hallmark of senescence, downregulation of the proliferation marker Ki67, and elevated expression of P53, P21, P16, and SASP genes. The total number of HSPCs declined after treatment, and the cells shifted toward myeloid differentiation, producing more CD11b-positive and CD14-positive cells. Complementary assays of colony formation showed that HSPCs from knockout mice generated fewer myeloid clones, while their bone marrow contained fewer common myeloid progenitors and more common lymphoid progenitors than wild-type controls, together indicating that ANGPTL8 aggravates the myeloid bias characteristic of hematopoietic aging.

Functional consequences were tested through transplantation. Bone marrow cells from knockout or wild-type donors were injected into lethally irradiated BALB/c recipients, and early hematopoietic regeneration was assessed 15 days later. Recipients of knockout marrow showed significantly higher proportions of donor-derived hematopoietic cells, LSK HSPCs, lymphoid cells, myeloid cells, and granulocytes in both bone marrow and spleen. Conversely, when wild-type HSPCs were pre-treated with recombinant ANGPTL8 before transplantation into irradiated C57BL/6 recipients, the proportions of total hematopoietic cells, LSK cells, myeloid cells, and granulocytes were significantly reduced in recipient marrow, and lymphoid, myeloid, and granulocytic populations were diminished in the spleen. In short, exposure to ANGPTL8 impaired the regenerative and engraftment capacity of HSPCs, while its absence enhanced it.

The mechanistic thread runs through the PI3K/AKT signaling pathway, a canonical regulator of cell survival, growth, and aging. RNA sequencing of knockout and wild-type HSPCs identified the PI3K/AKT pathway as the most enriched set of differentially expressed genes, with knockout mice showing significantly upregulated pathway activity. Western blotting confirmed that the ratios of phosphorylated to total PI3K, AKT, and the downstream kinase mTOR were all elevated in knockout HSPCs and bone marrow cells, and reduced in cells treated with recombinant ANGPTL8 in vitro. Crucially, a PI3K activator, YS-49, reversed the senescence effects of recombinant ANGPTL8, lowering the percentage of beta-galactosidase-positive cells, dampening the expression of age-related molecules, and correcting the myeloid differentiation bias. This rescue experiment establishes the pathway as the functional mediator of ANGPTL8’s pro-aging action in HSPCs.

The final piece identified the receptor. Paired immunoglobulin-like receptor B, or PirB, the mouse ortholog of human LILRB2, is known to bind several angiopoietin-like proteins and is highly expressed on the HSPC membrane. Co-immunoprecipitation demonstrated that recombinant ANGPTL8 directly interacts with PirB on HSPCs, and treatment with the recombinant protein increased PirB expression. Recombinant PirB alone reduced phosphorylation of PI3K and AKT, while knocking down PirB with two distinct siRNAs not only raised PI3K/AKT phosphorylation on its own but also blocked the inhibitory effect of recombinant ANGPTL8. The authors note that PirB has independently been implicated in aging of the nervous system, where it is upregulated in the aged hippocampus and represses the PI3K/AKT/mTOR axis, suggesting a conserved role for this receptor in tissue aging that now extends to the blood-forming system.

The work carries clear translational implications, though the authors are careful about its limits. Because ANGPTL8 secretion rises after eating and caloric restriction is among the most effective anti-aging interventions in animal models, reducing ANGPTL8 through dietary approaches or direct pharmacological targeting may represent promising strategies to alleviate hematopoietic aging. The protein’s dual role in lipid metabolism adds another layer, since triglyceride accumulation is a prominent lipidomic signature of human aging and impaired lipoprotein lipase function has been shown to damage the HSPC compartment. The team acknowledges that HSPC subpopulation heterogeneity remains incompletely characterized and that the PirB mechanism, while supported by in vitro rescue and knockdown experiments, will require conditional knockout models and competitive transplantation assays for full in vivo validation. Even so, the identification of a circulating, diet-responsive metabolic protein that ages blood stem cells through a defined receptor-pathway axis offers a concrete new target in the effort to keep the aging immune system younger for longer.

Subject of Research: The role of ANGPTL8 in inducing senescence of hematopoietic stem and progenitor cells via PirB-mediated inhibition of PI3K/AKT signaling

Article Title: ANGPTL8 induces the aging of hematopoietic stem/progenitor cells

Article References: Chen, M., Zhang, M., Mei, H., Bai, X., Wang, X., Tang, Y., Jiang, H., Zhang, L., Zhou, C., & Yuan, Y. (2026). ANGPTL8 induces the aging of hematopoietic stem/progenitor cells. Biogerontology, 27(5), Article 174. https://doi.org/10.1007/s10522-026-10517-x

Image Credits: AI Generated

DOI: 10.1007/s10522-026-10517-x

Keywords: ANGPTL8, hematopoietic stem cells, aging, cellular senescence, PI3K/AKT pathway, PirB, myeloid skewing, immunosenescence, SASP, bone marrow, mitochondrial ROS, caloric restriction