Mouse Leukocyte Telomeres May Not Shorten With Age, Study Suggests

In most actively dividing human somatic cells, telomeres—the repetitive ends of eukaryotic chromosomes—shorten with every cell division, and this progressive erosion is considered a driver of aging and aging-related diseases. A new perspective article now revisits a surprising experimental result that challenges one of the field’s most familiar assumptions in mice: that blood cell telomeres inevitably wear down as an animal grows older. Writing in the journal Discover Aging, researchers João Pessoa and Bruno Bernardes de Jesus discuss a recent study reporting that, in the domestic mouse (Mus musculus), telomeres do not shorten with age in the tail and in peripheral blood leukocytes, and they explore what this unexpected finding could mean for understanding human diseases linked to leukocyte telomere length.

The recent study at the center of the discussion examined both wild-type mice and two engineered strains with shorter telomeres. In wild-type animals, the authors of that work even observed an apparent elongation of telomeres in the tail between 2 and 23 months of age. Crucially, the leukocyte findings were validated using two independent techniques: pulsed-field gel electrophoresis (PFGE) with in-gel hybridization using a telomeric probe, and NanoTelSeq, a more recently developed assay based on long-read Nanopore sequencing of single telomeres. According to Pessoa and de Jesus, this was, to their knowledge, the first study to use a DNA sequencing approach to track age-dependent changes in leukocyte telomere length.

The perspective article is careful to spell out the limitations of the measurements. PFGE does not allow accurate estimation of telomere length, which could mask minor differences between samples. NanoTelSeq also revealed considerable spread in the data points within each experimental group, although the medians were identical between samples. Regardless of the technique used, the intrinsic variability of the samples under comparison will challenge the detection of any change. Importantly, the authors stress, a lack of detected variation does not demonstrate a true lack of variation. Still, the use of two experimental approaches in the same study strengthens the robustness of the conclusions, and the results are considered novel in that they can be replicated by other laboratories using other techniques. The authors also caution that the absence of age-related shortening may not apply to other mouse tissues, which will require further research.

The surprise is heightened because earlier reports in mice told a different story. Leukocyte telomeres had previously been reported to shorten with age, decreasing from 4 to 25 months of age, with a simultaneous increase in the percentage of short telomeres, defined as those under 15 kilobase pairs. Mice whose fraction of short telomeres increased faster had shorter lifespans, and this factor influenced lifespan more strongly than the rate of telomere shortening itself. Telomerase overexpression in mice decreases the percentage of short leukocyte telomeres and increases animal lifespan. Across several mammal and bird species, lifespan correlates better with the rate of leukocyte telomere shortening than with telomere length at birth. Most studies in laboratory mice, summarized in a table in the new article, do show a decline in telomere length over the lifetime, a decline that appears exacerbated in telomerase-deficient mice, with the greatest drop occurring predominantly from the third generation onward.

One possible explanation for the conflicting outcomes lies in how telomere length has been measured. Previous estimates relied on Southern blotting of restriction-digested DNA, fluorescence in situ hybridization (FISH), or quantitative polymerase chain reaction (qPCR). Conventional Southern blot, qPCR, and FISH methods estimate only relative telomere lengths, so whether telomeres appear to shorten with age could be affected by the choice of reference used for normalization. NanoTelSeq, by contrast, can potentially measure absolute lengths of single telomeres and detect shorter telomeres than qPCR or FISH-based techniques. Whether the different outcomes across studies resulted, at least in part, from the different techniques used remains an open question that the perspective authors say needs further attention.

The mouse result may also fit into a broader comparative picture. In shags and albatrosses, blood cell telomere length decreases from the chick stage to the breeding adult stage, but no age-related shortening is detected in adults. In free-living house sparrows, both age-related shortening and lengthening of blood cell telomeres have been observed, and blood telomere length does not differ between hatchlings and adults of the leatherback turtle. The potential lack of telomere shortening with age may therefore not be restricted to the domestic mouse and could be a conserved phenomenon in other species. Within a single species, telomere length can also vary considerably: in rats, relative telomere length and telomerase levels varied significantly between tissues and between individuals, both young and aged, with no consistent correlation between peripheral blood mononuclear cells and several solid tissues.

The biology of leukocytes themselves offers a plausible mechanistic explanation. Leukocytes are a heterogeneous group of blood cells with different functions, abundances, and lifetimes. In mice, the most abundant leukocytes are lymphocytes, making up 70 to 80 percent of the pool, although this proportion may fall with age as neutrophils increase. Mouse neutrophils have an estimated half-life of about 11.4 hours, and telomerase activity has been detected in mouse lymphocytes, though it can be suppressed by oxidative stress. Any lack of telomere shortening in mouse leukocytes could thus reflect telomerase activity in their most abundant cells. In humans, neutrophils are the most abundant leukocytes at 40 to 70 percent, with an estimated half-life of 13 to 19 hours, and they lack telomerase—but because these cells die so quickly, their telomeres are not expected to shorten appreciably. B and T lymphocytes do show telomerase activity, especially upon activation, which may explain why T lymphocytes have longer telomeres than neutrophils despite similar shortening rates.

Leukocytes are continuously renewed from hematopoietic stem cells, which possess telomerase activity, and leukocyte life usually ends through apoptosis rather than senescence. Yet senescence does occur in some leukocyte subsets: senescent CD8-positive T cells were detected in roughly 64 percent of humans in their sixties, compared with about 30 percent in people in their twenties, and effector memory CD8-positive T cells expressing CD45RA show senescent properties, including negligible proliferation and a senescence-associated secretory phenotype, while retaining potent cytotoxic activity. Some T cell subsets can even elongate telomeres without telomerase, by acquiring telomeres through vesicles donated by antigen-presenting cells. CD4-positive T cells can receive these vesicles and release them into the bloodstream as so-called telomere rivers, reported to promote tissue rejuvenation in multiple organs; in a pre-print study, telomere rivers produced by a mouse model were transplanted into other mice and extended their lifespan by about 17 months. Activated mouse T cells expanded through repeated vaccination and transfer retained their responsiveness and preserved telomere length. Aging also alters hematopoietic stem cells and raises the risk of clonal hematopoiesis, and the combination of long telomeres with mutations in POT1, a protein that binds telomeric DNA, could also induce the condition—mechanisms that change leukocyte composition with age and may affect telomere length.

The stakes of resolving this question are highest for human medicine. In humans, leukocyte telomere length is partly inherited, likely more through the father than the mother, and healthy newborns have an estimated length of about 9.50 plus or minus 0.70 kilobase pairs. Length decreases at roughly 32 to 46 base pairs per year, falling to around 6 kilobase pairs by age 90, and a length of 5 kilobase pairs has been defined as a telomeric brink associated with a high risk of imminent death. Shortening is fastest between birth and age five, slowest between ages five and about 25, and intermediate thereafter. Women are born with longer leukocyte telomeres and shorten them more slowly until the sixth decade, after which they shorten faster than men. Shorter leukocyte telomeres have been correlated with increased risk of chronic heart failure, higher prevalence of coronary artery calcification, higher cardiovascular mortality in elderly men, and decreased bone mineral density and osteoporosis risk in women, while longer telomeres were associated with increased risk of soft tissue sarcomas, and leukocyte telomere length was decreased in spinocerebellar ataxias 1 and 3 but increased in spinocerebellar ataxia 2. Even as a biomarker of human aging, telomere length carries multiple limitations and low predictive capability.

Uncovering whether leukocyte telomeres truly shorten with age will require measuring telomerase activity in the most abundant leukocyte types and their hematopoietic stem cell progenitors, tracking leukocyte composition over time, and accounting for the limitations of each measurement technique, including the fact that FISH-based methods involve cell manipulation while whole-blood DNA methods do not. The authors also argue that future work should assess structural features that total length measurements miss, such as the 3′ guanine-rich overhang and the telomere loop, and that measurement techniques should include appropriate controls such as telomerase knockout or overexpression models. Because telomerase activity is sensitive to oxidative stress, antioxidant treatment of cultured human leukocytes could reveal conditions in which telomeres are maintained. In humans, air pollution and stress have promoted leukocyte telomere shortening, while physical exercise and dietary interventions, including calorie restriction and increased intake of fiber or antioxidants, had the opposite effect. Comparative studies of mouse models with and without age-related leukocyte telomere shortening, the authors conclude, could yield new insights into the pathophysiology of diseases associated with leukocyte telomere length.

Subject of Research: Age-related telomere shortening in mouse and human leukocytes and the measurement techniques used to study it

Article Title: Leukocyte telomere shortening in mice revisited

Article References: Pessoa, J., & Bernardes de Jesus, B. (2026). Leukocyte telomere shortening in mice revisited. Discover Aging, 1(1), Article 10. https://doi.org/10.1007/s44518-026-00010-5

Image Credits: AI Generated

DOI: 10.1007/s44518-026-00010-5

Keywords: telomeres, leukocytes, aging, telomerase, mice, NanoTelSeq, hematopoietic stem cells, biomarkers, cellular senescence, clonal hematopoiesis, oxidative stress, telomere measurement