bioRxiv : the preprint server for biologyJul 29, 2026

Reducing aged cell buildup helps improve aging in bone marrow

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

Updated Aug 3, 2026

Abstract

Pharmacologic clearance of senescent cells with the compound 753b reverses key aging markers in hematopoietic stem cells.

The aging hematopoietic system shows impaired stem cell function and increased vulnerability to conditions like anemia and infections.
Treatment with 753b restores balanced lineage output and reverses several functional characteristics of hematopoietic aging.
Single-cell RNA sequencing indicates that 753b reduces aging-related gene activity in hematopoietic stem cells.
753b selectively removes senescent, pro-survival niche cells while maintaining overall niche composition.
The compound also decreases inflammatory signals from both niche and hematopoietic cells, promoting a healthier bone marrow environment.

Simplified

Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.

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Reducing aged cell buildup helps improve aging in bone marrow

Abstract

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