Mouse study links telomerase activity to a truncated RHAMM isoform, suggesting potential for safer modulation of cellular aging.
Telomeres – the protective end caps of chromosomes – have long captured the attention of longevity researchers. Their gradual shortening with each cell division is a known contributor to cellular senescence and age-related dysfunction, and while the enzyme telomerase can restore these caps, its activation is a double-edged sword. Uncontrolled telomerase activity is a hallmark of many cancers, making therapeutic modulation a high-stakes endeavor.
Now, a new study published in Frontiers in Aging reveals that a truncated isoform of RHAMM – the receptor for hyaluronan-mediated motility – can enhance telomerase activity and regulate shelterin proteins in mouse cells. The isoform, RHAMMΔ163, not only increased the expression of telomerase reverse transcriptase (TERT) but also modulated a suite of telomere-protective proteins, placing it squarely on the radar of aging researchers and regenerative biologists alike [1].
Longevity.Technology: A telomere regulator that wears multiple hats – oncogenic in one context, rejuvenative in another – might sound like a confusing plotline, but the RHAMMΔ163 isoform may just have that narrative complexity. This paper marks the first direct evidence that a RHAMM variant can switch on telomerase via shelterin pathways – a finding that may well seed a new class of biologics aimed at telomere restoration and regenerative repair. The twist? This truncated isoform, expressed in mice, has a human counterpart best known for its unfortunate role in cancer – which means that any therapeutic ambitions must navigate the knife-edge of benefit and risk with the utmost caution.
Still, the data from the IPF model, using a function-blocking peptide, are intriguing; a telomerase-modulating agent with anti-fibrotic effects – and potential reversibility – hints at a future in which we might recalibrate cell aging without simply flooring the accelerator. That’s no small promise in a field where telomerase reactivation has long been seen as too hot to handle. Whether RHAMMΔ163 becomes the next frontier in safe telomere therapeutics or another fascinating molecular footnote remains to be seen – but in longevity science, it’s often the tangled pathways that yield the richest insights. To find out more about this research, we sat down with the paper’s author, Kaustuv Basu.
A new isoform on the block
RHAMM is a multifunctional protein implicated in motility, mitosis and – more recently – aging. It exists in multiple isoforms, but the Δ163 variant, which lacks the first 163 amino acids of the full-length protein, behaves quite differently. “This study is the first to establish a direct connection between RHAMM and telomerase activity,” Basu tells us.
Working with mouse fibroblasts and cancer cell lines, the team found that RHAMMΔ163 increased TERT expression and stimulated telomerase activity through upregulation of SIRT1 and key shelterin proteins such as TPP1 and POT1a. Interestingly, the full-length version of RHAMM did not have these effects – in fact, it seemed to act as a brake rather than a throttle.
Basu suggest that RHAMMΔ163’s influence may stem from its ability to interact with the HATABD domain, a region involved in binding to ERK and other components of telomere regulation. In short, it’s a case of structure dictating function – and isoform determining outcome.
Therapeutic potential and a peptide with promise
To probe translational relevance, the team deployed a function-blocking RHAMM peptide known as NP-110 in a mouse model of idiopathic pulmonary fibrosis – a disease marked by TERT deficiency. The peptide, which targets the leucine zipper sequence within the HATABD domain, enhanced mTert expression and shifted collagen profiles in the lung.
“NP-110 showed no overt toxicity and successfully modulated RHAMM activity,” Basu notes. While cautious about extrapolating to humans, he is optimistic about the broader implications: “My data suggest that a function-blocking RHAMM peptide exhibits therapeutic promise for age-associated diseases.”
Whether RHAMMΔ163 or its human analog could be safely harnessed for telomerase modulation in clinical settings remains an open question.
“Peptide-based inhibitors like NP-110 are generally reversible by design,” says Basu, “but long-term telomerase reactivation could have lasting epigenetic or proliferative effects, so reversibility must be validated in human systems.”
However, caution is warranted, particularly in cancer-prone tissues. “This kind of modulation must be tested carefully,” he adds, “especially in tissues with oncogenic potential.”
A new biomarker for biological age?
RHAMMΔ163’s regulatory influence on telomerase and shelterin components raises the prospect of using RHAMM isoforms as biomarkers of telomere dysfunction or biological age. Although the Δ163 isoform itself is murine, Basu believes its human equivalent – also expressed in cancer cells – could be worth investigating.
“I proved a direct link between RHAMM and telomerase,” he says. “This suggests RHAMM has potential as a biomarker for biological aging or telomere dysfunction – but this needs to be tested in human cells.”
An evolutionary thread worth tugging
The study also includes an intriguing in silico analysis of RHAMM’s HATABD domain across long- and short-lived species, revealing amino acid modifications in long-lived ectothermic reptiles. While speculative, these findings hint that subtle variations in telomere regulatory domains might shape lifespan across the animal kingdom. “Applying such molecular corrections may open new paths for personalized aging,” Basu explains.
From mice to humans – and the questions in between
The RHAMMΔ163 story is, for now, still very much in the mouse house – but the questions it raises are human in scale. Can telomerase be modulated safely and reversibly? Might isoform-specific regulators allow for precision interventions in aging tissues? And can the cancer risks be effectively mitigated or even avoided entirely?
Basu’s work adds a thoughtful new dimension to the telomere conversation – one that favors selective modulation over wholesale activation, and structural nuance over one-size-fits-all strategies. As ever in geroscience, the devil is in the domains.
[1] https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2025.1604051/full
