THE BIDIRECTIONAL RELATIONSHIP BETWEEN TELOMERASE AND THE INFLAMMATORY RESPONSE

R. Martinotti^*

Clinical Oncology, Faculty of Medicine, Umberto I University Hospital, University of Rome “La Sapienza”, Rome, Italy.

*Correspondence to:
Riccardo Martinotti,
Faculty of Medicine,
University of Rome “La Sapienza”,
00185 Rome, Italy.
e-mail: riccardo.martinotti@uniroma1.it

Received: 01 April, 2026 Accepted: 21 May, 2026

ISSN 2279-5855 print / 3103-7364 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Chronic inflammation can accelerate telomere shortening and affect telomerase activity. Inflammatory memory maintains cells in a state of increased reactivity even after the initial stimulus has subsided. This state is associated with persistent epigenetic and metabolic changes. Oxidative stress generated by inflammation contributes to telomere damage. In some immune cells, telomerase is activated to support proliferation during the immune response. The telomerase reverse transcriptase (TERT) subunit of telomerase has functions beyond telomere maintenance. It functions as a reverse transcriptase that, using TERC RNA as a template, adds telomere sequences to chromosomes, contributing to the maintenance of genomic stability and, when deregulated, to tumor development. Mutations in the TERT promoter are extremely common; they increase telomerase activity and allow tumor cells to maintain telomeres, promoting unlimited tumor growth and aggressiveness. Telomerase may help modulate inflammatory memory, but how it does so is not yet fully understood and requires further study. In conclusion, inflammation and telomerase are closely interconnected and influence each other through cellular, metabolic, and epigenetic mechanisms. Understanding this bidirectional relationship can help clarify the processes that contribute to biological aging and the development of chronic diseases.

KEYWORDS: Telomerase, TERT, CNS, immune response, inflammation, neurodegeneration, gene expression

INTRODUCTION

Neuroinflammation is mediated primarily by immune cells in the central nervous system (CNS), such as microglia and astrocytes, the most abundant glial cells in the CNS (1). Acute inflammation in the brain can benefit tissue repair and microorganism elimination, while chronic neuroinflammation can contribute to neurodegenerative diseases with cognitive decline (2). These latter clinical conditions include multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease (3).  The aging process and cellular stress affect the function of immune cells in the brain and telomerase, a specialized enzyme that protects cells (4). Reduced telomerase activity progressively leads to premature telomere shortening with each cell division (5). Chronic inflammation can alter telomerase activity and accelerate telomere shortening, while telomerase itself, particularly its catalytic subunit telomerase reverse transcriptase (TERT), can influence the expression of genes involved in the inflammatory response (6).  This leads to a relationship between inflammatory status and telomere maintenance. The link between chronic inflammation and telomerase is complex and bidirectional: inflammation can affect telomeres and telomerase, while telomerase can modulate the inflammatory response (7) (Fig.1).

Fig. 1. There is a bidirectional relationship between telomerase and inflammatory memory induced by the cytokines IL-1, TNF, AND IL-6. Here, inflammatory memory acts on the chromosome’s telomerase, which in turn modulates inflammation and vice-versa.

TELOMERASE AND THE INFLAMMATORY RESPONSE

To maintain telomere length, which is present at the ends of chromosomes, telomerase can modulate the inflammatory response of microglia in the CNS, protect neurons from oxidative stress, contribute to cell survival, and improve mitochondrial function (8). All these functions amplify the biological action of telomerase. The catalytic component of telomerase, called TERT, is the protein subunit that gives the telomerase enzyme its enzymatic activity (9).

TERT is expressed primarily in germ cells and stem cells and is very low or absent in most adult somatic cells (10,11). TERT acts as a reverse transcriptase using the telomerase RNA called telomerase RNA component (TERC) as a template, adding new telomeric repeats to the 3′ end of chromosomal DNA (12). TERC is also found in mitochondria, where it reduces free radical damage (13). In neuroinflammation, oxidative stress increases, cells enter senescence and produce additional inflammatory molecules, and telomeres shorten more rapidly (5). These effects can lead to premature aging of the CNS. Microglia generate an innate immune response to various insults, including stress, head trauma, or infection (14). These reactions can leave epigenetic modifications that make microglia more reactive in the future.

Telomerase appears to have protective effects on neurons and mitochondria, and chronic neuroinflammation may contribute to brain aging and neurodegenerative diseases (15). Inflammatory memory begins with high-affinity T cells that undergo clonal expansion during the primary effector response; some of these cells die, while others become long-lived memory cells (16). Low-affinity cells almost entirely undergo apoptosis (17). The immune system and other tissue can develop inflammatory memory, meaning they can remember past inflammation and respond more quickly and intensely to stimuli. Inflammatory memory is expressed by various immune cells, including T and B lymphocytes, innate immune cells (macrophages and natural killer (NK) cells), and cells that are not part of the immune system (epithelial cells, endothelial cells, and stromal cells) (18). Inflammatory memory is expressed to protect the body, but if persistent, it can contribute to inflammation, autoimmune diseases, and aging.

Telomerase also has extratelomeric functions that can influence immune and inflammatory activity (19). The relationship between neuroinflammation and telomerase is bidirectional, as chronic inflammation accelerates telomere wear, and reduced telomerase function promotes senescence and cell death (7).  Its activity can modulate the survival and proliferation of immune cells, the expression of genes involved in inflammation, and the response to oxidative stress. However, the full function of telomerase and its relationship to inflammatory memory remain unclear. For example, it is not known if telomerase’s effect depends primarily on telomere-maintenance or on telomere-independent functions, and which molecular pathways directly link telomerase to the epigenetic changes that sustain inflammatory memory. Chronic neuroinflammation is known to accelerate biological aging of the brain (20). Regulating the action of telomerase could have many interesting biological effects, including regulating inflammatory memory and other neuro-pathological activities.

TERT is elevated in many cells, including stem cells and cancer cells, but is very low or absent in most somatic cells (21). Approximately 87% of tumors exhibit telomerase activity; TERT expression allows tumor cells to avoid replicative senescence and proliferate indefinitely (22). Mutations in the TERT gene are seen in many tumors, including glioblastomas (21). Biologically, TERT activity in glioblastoma is of fundamental importance, both from a diagnostic and biological perspective. In glioblastoma, a highly aggressive, grade IV malignant brain tumor that originates from the brain’s glial cells, one of the most frequent genetic alterations affects the TERT gene promoter, specifically the region that controls protein expression (23). The most common mutations are those in C228T and C250T, which do not alter the TERT protein sequence but increase gene transcription, leading to increased telomerase production (24).  In glioblastoma, increased telomerase activity prevents progressive telomere shortening, resulting in tumor cells’ ability to proliferate virtually perpetually and promote tumor progression (25). TERT promoter mutations are the most common and aggressive form (IDH-wild type) of glioblastoma, while they occur much less frequently in astrocytoma with IDH mutations (26). At the diagnostic level, the World Health Organization (WHO) has reported that certain parameters, such as TERT promoter mutations, chromosome 7 gain associated with chromosome 10 loss (+7/−10), and EGFR development, are important for the molecular diagnosis of glioblastoma, although prognosis may depend on other factors (27).

Today, we know that higher TERT levels can protect neurons from inflammatory damage, and reduced telomerase activity is associated with telomere shortening, which increases the risk of cognitive decline and neurodegenerative diseases (8). However, there are currently no approved therapies that increase telomerase in the CNS to treat neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (28).

CONCLUSIONS

Inflammatory memory and telomerase are linked primarily through mechanisms that regulate the persistence of cellular responses over time. Chronic inflammation and inflammatory memory can alter telomerase activity and accelerate telomere deterioration. In turn, telomerase can modulate the expression of inflammatory genes, creating a bidirectional feedback loop between cellular maintenance and the inflammatory response.

Conflict of interest

The author declares that they have no conflict of interest.

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