Targeting TE in Aging and Inflammation
Even though they represent half of our DNA, Transposable Elements (TEs) have been ignored until recently. We know that they are normally silenced by protective
mechanisms in our cells, because if they become active, they can alter normal cellular function. As we get older, the systems that keep TEs under control begin to weaken. This allows certain TEs to become abnormally active, particularly in blood stem cells, which produce all blood and immune cells throughout life. When the function of these stem cells is disrupted, the body’s ability to fight infections and cancer is reduced, potentially contributing to age-related diseases.
Our research aims to understand why these protective mechanisms fail with age and how we can restore control over TE activity. In particular, we are interested in finding ways to reduce the harmful effects of TE activation over time. By better understanding these processes, we hope to develop strategies to either re-establish proper TE silencing or directly block their detrimental activity. With aging, in addition to immune dysfunction, emerging evidence suggests that TE activation may also contribute to fibrosis, a condition in which tissues become stiff and scarred. Fibrosis affects organs such as the lungs, liver, and bone marrow, and can worsen with age. Thus, understanding the contribution of TEs will allow novel therapeutic approaches to dampen fibrosis.
Ultimately, this work will lead to new treatments that improve immune function, reduce chronic inflammation and fibrosis, and enhance resilience against diseases linked to aging. By targeting the root causes of cellular decline, we aim to support healthier aging and better patient outcomes.
Transposable elements (TEs) constitute ~50% of the mammalian genome and are increasingly recognized as dynamic regulatory components rather than genomic “junk”. Under physiological conditions, TEs are tightly repressed by multilayered epigenetic mechanisms, including DNA methylation and histone modifications. This repression is essential for maintaining genomic stability and preventing aberrant transcriptional programs.
Aging is associated with a progressive decline in epigenetic integrity, resulting in the loss of TE silencing. This derepression is particularly evident in hematopoietic stem and progenitor cells (HSPCs), which sustain lifelong hematopoiesis and immune cell production. TE activation in these compartments can induce genomic instability, trigger innate immune sensing pathways (cGAS-STING, MAVS), and rewire transcriptional networks. As a consequence, HSPC function becomes compromised, leading to impaired immune output, reduced regenerative capacity, and increased susceptibility to infections, malignancies, and other age-associated pathologies.
Our research aims to define the molecular mechanisms underlying age-dependent TE derepression, with a focus on identifying the epigenetic and chromatin-based factors that fail over time. We are particularly interested in dissecting how TE-derived nucleic acids contribute to chronic sterile inflammation and, in turn, how this feeds back on stem cell dysfunction. A key objective is to mitigate the downstream consequences of TE activation by identifying specific pathways or TEs themselves.
In the context of aging, emerging evidence implicates TE activation as a driver of fibrotic remodeling across tissues. TE-derived transcripts can promote inflammatory signaling and fibroblast activation, contributing to extracellular matrix deposition and tissue stiffness. In the hematopoietic niche, fibrosis alters the stem cell microenvironment, further exacerbating HSPC dysfunction and creating a feedforward loop between TE activation, inflammation, and tissue remodeling.
Collectively, this work aims to establish TEs as central mediators of aging-associated decline in stem cell function and tissue homeostasis. By targeting TE derepression and its downstream effects, we seek to develop novel therapeutic strategies to restore immune competence, limit chronic inflammation, and mitigate fibrosis, ultimately improving healthspan and resilience to age-related diseases.