The laboratory of Dr. Jennifer Trowbridge at The Jackson Laboratory published a paper that describes how a genetic mutation that alters the function of mitochondria may provide a target for slowing aging.

Blood cells routinely wear out and must be replaced. Hematopoietic stem and progenitor cells (HSPCs) are critical to maintaining an adequate supply of mature blood cells. During aging, these long-lived stem and progenitor cells tend to accrue somatic mutations that give them a selective advantage. This condition is clonal hematopoiesis (CH). Most humans develop detectable CH by the age of 60, and this contributes to serious health conditions that occur during aging.

The Trowbridge team examined a mutation in the gene for DNA methyltransferase (DNMT3A) that is commonly associated with CH in humans. The team tested a mouse model that they engineered to carry the Dnmt3a mutation. They found that HSPCs from mice with the mutation had higher levels of mitochondrial activity than the same cells in wild-type mice. This was a surprising result since Dnmt3a had never been associated with mitochondrial function.

They found that molecules that disrupt the enhanced mitochondrial function in mutant cells, such as MitoQ and d-TPP, reduced CH in mice and in human cells. This was also true when using metformin, which impacts mitochondrial metabolism and is commonly used to treat type 2 diabetes. This work enhances knowledge of how blood stem cells contribute to aging and may provide a new therapeutic strategy for treating age-associated diseases, such as cancer, diabetes, and heart disease.

 

Reference

Young KA, Hosseini M, Mistry JJ, et al. (2025) Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis. Nat Commun 16: 3306. https://doi.org/10.1038/s41467-025-57238-2

 

Mito-World talks to Dr. Trowbridge

The metformin result is especially interesting since it is already widely used. Do you think it will become a treatment?

Indeed, the results with metformin were very exciting and provocative. While we have shown this to be effective over the short term in mouse models and in human cells in a dish, more studies are needed in human patients to determine whether there is long-term benefit to metformin. If metformin turns out not to be the best option, the good news is that our work has identified other molecules and drugs that target mitochondrial metabolism that could also be tested for efficacy.

 

Can you speculate on the mechanism behind this connection? You suggest involvement of DNA hypomethylation and increased gene expression of the electron transport chain and respiratory supercomplex formation.

It appears that hematopoietic stem and progenitor cells that carry somatic mutations that provide them with a selective advantage with aging do so, at least in part, through enhancing mitochondrial metabolism. In our study, we observed a connection between DNA hypomethylation and production of the molecules that drive mitochondrial metabolism. However, other somatic mutations that cause CH also enhance mitochondrial metabolism through what are likely different mechanisms. This may represent an example of ‘convergent evolution’ where the mechanisms may differ but the end result—enhanced mitochondrial function—is the same.

 

Do you plan to follow up the Phase II clinical studies with the various compounds? Of course, metformin, tamoxifen, and diclofenac are already safe in humans.

We are actively collaborating with clinicians that are doing prospective controlled studies to assess CH in individuals receiving metformin over time. In addition, we are pursuing collaborations to assess CH in ongoing placebo-controlled trials where aged individuals are receiving MitoQ for other indications.

 

The connection to hematopoiesis is clear, but a connection to other diseases (e.g., cancer, diabetes) is less so. Any thoughts?

The connection between CH and risk of diseases, such as cancer and heart disease, is very well-established. In the field, we have made an educated guess that reducing or controlling the development of CH will reduce the incidence and risk of these other diseases; however, long-term prospective studies in humans are needed to definitively prove this.

 

Extrapolating from mice to humans has not always been successful. Do you have any plans to look at human cells or tissues?

Our paper does include examination of primary human hematopoietic stem and progenitor cells and shows that DNMT3A-mutant human cells have the same phenotypes as Dnmt3a-mutant mouse cells with respect to enhanced mitochondrial metabolism. We also show that MitoQ is effective in suppressing the competitive advantage and growth of human DNMT3A-mutant cells. What we have found, in my opinion, is a fairly rare example where the phenotypes are remarkably similar in mice and in humans. Moving forward to test these interventions in long-term mouse and long-term human studies are the clear next steps.