Telomeres help protect chromosomes but gradually shorten with each cell division. New experiments reveal that the balance between maternal and paternal telomeres may influence how these structures are adjusted in early embryos—raising new questions about inheritance, aging, and cancer. Credit: Shutterstock

A new study investigates how telomeres adjust their length during the first cell divisions of life.

Small plastic or metal tips at the ends of shoelaces, called aglets, keep laces from unraveling and protect them from wear. Chromosomes have a similar protective feature. Their ends are capped by telomeres—structures made of repeated DNA sequences and protective proteins that guard important genetic material at chromosome tips from damage or from sticking to neighboring chromosomes.

Like aglets, telomeres gradually deteriorate. Each time a cell divides, these caps become slightly shorter. When telomeres shrink past a critical point, the cell interprets this as DNA damage and permanently stops dividing. This permanent halt in cell growth, known as cellular senescence, is associated with chronic inflammation and plays a role in many age-related diseases.

For decades, scientists studying aging have examined telomere length as a possible biological marker. Telomere length varies widely between species and even among individuals of the same species. Although the relationship between telomere length and lifespan is complex and influenced by many factors, mammals that begin life with shorter telomeres generally face a higher risk of age-related illness and early death.

“On the flipside, if telomeres are too long, it can also spell trouble because cancer cells require long telomeres to become longer lived, ‘immortal,’” says Mia Levine, associate professor of biology in the School of Arts & Sciences at the University of Pennsylvania, who co-led research on the heritability of telomere lengths.

Levine and Michael Lampson, a professor of biology at Penn’s School of Arts & Sciences, wanted to understand how telomere length is passed from parents to offspring. They asked whether telomere length behaves like a typical polygenic trait, influenced by many genes such as eye color or height, or whether telomeres themselves are directly inherited through egg and sperm cells.

Rethinking How Telomeres Are Inherited

“We wanted to ask how telomeres are really inherited,” says Lampson. “Is it just the telomere DNA sequence you inherit from your parents, or is it determined by the genes that regulate telomeres? What we found doesn’t fit neatly into either box.”

In experiments reported in Current Biology, the researchers used an animal model and uncovered evidence of a parent-of-origin effect. When mothers contributed short telomeres and fathers contributed long ones, embryos lengthened their telomeres. When the situation was reversed, with long telomeres from the mother and short ones from the father, the embryos’ telomeres became shorter.

“This parent-of-origin effect is consistent with patterns we’ve seen in human studies,” Levine explains. “For example, children of older fathers tend to have longer telomeres than children of younger fathers. But teasing apart why that happens is difficult, because human studies are confounded by so many factors—diet, smoking, stress, lifestyle. That’s why we turned to a controlled animal model to test these ideas directly.”

The team worked with mice that naturally had either long or short telomeres. They carried out reciprocal crosses, switching which parent contributed each telomere type. Because the resulting offspring were genetically identical in both scenarios, any differences in telomere length could be traced to parent-of-origin effects rather than differences in DNA sequence.

“Reciprocal crossing is what lets us detangle the usual confounders,” Levine says.

In the earliest stage of development, before an embryo begins using its own genome, it relies on molecules already present in the egg and sperm. During a brief period between the first and second cell divisions, the researchers saw telomeres either lengthen or shorten. This early shift ultimately set the telomere length observed later in development.

A Possible ALT-Like Mechanism

The mechanism, the researchers report, looks less like the well-known enzyme telomerase, which adds DNA-protein complexes to chromosomal tips in germ and stem cells, and more like a pathway known as alternative lengthening of telomeres (ALT). This pathway, used by roughly 10–15% of cancers, “copies and pastes” telomeric DNA from one chromosome to another rather than building it with telomerase.

The team’s data support the idea that embryos can flip on a similar template-driven process and that it is sensitive to the asymmetry between maternal and paternal telomeres. Experimentally, only the first pairing consistently triggered ALT-like elongation. The reverse pairing produced the opposite effect, measurable shortening.

Looking ahead, the team are interested in seeing how these trends may or may not be mapping to humans.

“On the human side, we’re now taking advantage of long-read genome sequencing,” Levine says. “That lets us look directly at telomeres in family trios—mom, dad, and child—to ask if the same parent-of-origin effects we saw in mice are detectable in humans.”

They are also interested in the implications for cancer research, as their embryonic model allows them to study the initiation of the ALT pathway.

“When people study ALT in cancer cells, it’s already been happening for many generations,” Levine explains. “But in embryos, we can catch ALT at its very initiation, at the very first cell divisions. That gives us a window into how this pathway naturally gets switched on.”

Reference: “A parent-of-origin effect on embryonic telomere elongation determines telomere length inheritance” by Hyuk-Joon Jeon, Mia T. Levine and Michael A. Lampson, 19 September 2025, Current Biology.
DOI: 10.1016/j.cub.2025.08.052

The study was supported by the National Institutes of Health (GM122475 and GM124684), the Penn Center for Genome Integrity, the University Research Fund at the University of Pennsylvania, and the National Research Foundation of Korea

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