bims-minfam 2025-04-20 papers

Issue of 2025–04–20
four papers selected by
Ayesh Seneviratne, McMaster University

Cell. 2025 Apr 17. pii: S0092-8674(25)00284-3. [Epub ahead of print]188(8): 2043-2062

From geroscience to precision geromedicine: Understanding and managing aging.

Guido Kroemer, Andrea B Maier, Ana Maria Cuervo, Vadim N Gladyshev, Luigi Ferrucci, Vera Gorbunova, Brian K Kennedy, Thomas A Rando, Andrei Seluanov, Felipe Sierra, Eric Verdin, Carlos López-Otín.

Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine. It is anticipated that, pending results from randomized clinical trials and regulatory approval, gerotherapeutics will be tailored to each person based on their genetic profile, high-dimensional omics-based biomarkers of aging, clinical and digital biomarkers of aging, psychosocial profile, and past or present exposures.

Keywords: aging; aging clocks; anti-aging drugs; atherosclerosis; cancer; cardiovascular diseases; diabetes; epigenetic clocks; genomics; neurodegeneration; oncogene; oncosuppression; primary prevention

DOI: https://doi.org/10.1016/j.cell.2025.03.011

Mech Ageing Dev. 2025 Apr 10. pii: S0047-6374(25)00035-1. [Epub ahead of print] 112059

Changing landscape of hematopoietic and mesenchymal cells and their interactions during aging and in age-related skeletal pathologies.

Abhishek Chandra, Susan F Law, Robert J Pignolo.

Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors-the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence-a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity (BMAd), reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.

Keywords: Skeletal aging; bone marrow; cellular senescence; stem cells

DOI: https://doi.org/10.1016/j.mad.2025.112059

Nat Commun. 2025 Apr 16. 16(1): 3306

Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.

DOI: https://doi.org/10.1038/s41467-025-57238-2

J Am Soc Nephrol. 2025 Apr 15.

Deciphering Clonal Hematopoiesis of Indeterminate Potential: Methods, Mechanisms, and Implications for Kidney Diseases.

Zhi Yu, Caitlyn Vlasschaert, Pradeep Natarajan.

Chronic kidney disease (CKD) afflicts over 10% of US adults, with its prevalence increasing sharply with age. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, genetically heterogeneous blood cell disorder characterized by the age-related clonal expansion of hematopoietic cells driven by leukemogenic somatic mutations yet without hematologic malignancy or dysplasia. While CHIP is a strong risk factor for future hematologic malignancy (estimated at ∼0.5% per year, compared to <0.1% for those without CHIP), it is also linked to twofold higher cardiovascular disease in epidemiologic, cell-based, and murine studies. However, more recent work has implicated CHIP with renal outcomes such as chronic kidney disease as well as acute kidney injury, independent of traditional risk factors. This review covers the observations and proposed hypotheses linking CHIP and kidney disease. The review also underscores the need for further research to elucidate the distinct pathways through which CHIP may contribute to CKD and its comorbidities, considering the heterogeneity within CKD stages and etiologies, as well as whether CHIP is a causal driver of kidney disease or a marker of aging and comorbidity. Finally, we discuss the potential of anti-inflammatory treatments to mitigate CHIP's adverse effects on kidney health, aiming to improve management strategies for patients with CHIP-associated kidney diseases.

DOI: https://doi.org/10.1681/ASN.0000000739