EPIGENETIC DRIFT IN AGING AND COLON CANCER
During life-time, adult stem cells gradually accumulate epigenetic alterations, especially the can acquire or loss DNA methylation at specific CpG sites in the genome. This aging-associated epigenetic pattern is defined as epigenetic drift. In the last years, several epigenetic drifts have been identified and some of them have been used as predictors of specific mammalian features like organismal or organ-specific biological age, predisposition to specific diseases, number of cell divisions, etc..
Importantly, these epigenetic alterations can sustain to the appearance and expansion of mutant stem cell ultimately leading to tissue dysfunctions and cancers (Ermolaeva, M., Neri, F., et al., Nature Reviews MCB, 2018).
Our group is interested to understand the molecular mechanisms driving the fixation of these mutant clones and tumorigenesis, especially regarding colorectal cancers. By employing cutting-edge technologies including single-cell genome-wide experiments, we analyse primary cells and tissues to mechanistically dissect the origin and to understand the function of these DNA methylation alterations.
INTESTINAL REGENERATION & HOMEOSTASIS IN AGING
Aging is associated with a multitude of tissue dysfunctions and appearance of diseases, including several pathological conditions of the intestinal tract (impaired regeneration, diarrhea, malabsorption, cancer). Especially the aging-associated impaired regeneration is a critical phenotype that affects intestinal homeostasis leading to altered nutrient uptake and response to injury. Impaired regeneration in elderly also negatively influences the chemotherapy choice and outcome in oncologic patients.
We have recently found that the intestinal epithelium shows reduced intestinal stem cell number and functionality, aberrant differentiation priming toward secretory cells and overexpression of antigen presentation molecules (Omrani, Krepelova et al, Nat Comm, 2023). This detrimental phenotype during aging is lost following long in-vitro culturing suggesting that is driven by external factors (e.g. the gut microbiome) and that can be reverted (opening therapeutics opportunity). Moreover, we found that treating mice with an antibody anti-IFNgamma can revert the entire intestinal aging phenotype. Importantly, pre-treatment with anti-IFNg is able to improve the gut regeneration after treatment with the chemotherapeutic Fluorouracil (5FU) (Figure on the left). However, treatment with anti- IFNg antibody has poor clinical value, since must be continuous and therefore becomes expensive and potentially leading to severe side effects, like reducing the immune defenses of the patients. Therefore we are now testing other non-invasive interventions to improve intestinal homeostasis, regeneration, and functionality in old individuals.
INFLAMMAGING
Inflammaging is a chronic low-grade systemic inflammation that occurs in elderly and promote several aging-associated diseases and dysfunctions. We have recently demonstrated that inflammaging is driven by upregulation of innate immune receptors and systemic interferon gamma (IFNg) signaling (Rasa, Annunziata et al, CellReports, 2021). The origin of the inflammaging is still largely unknown, however recent studies are pointing out that the gut microbiome acquires pro-inflammatory features during aging.
Increased intestinal inflammation could drive a systemic pro-inflammatory state to the point of even causing the onset of aging-associated neurodegenerative diseases in the brain.
Our group aims to study gut microbiome dysbiosis in old individuals and how the changes in bacteria-derived metabolites alter the transcriptional and epigenetic programs of the intestinal cells. The long-term goal is to understand and prove if and how these processes how are mechanistically connected with the development of the inflammaging and the onset of neurodegenerative disorders.