Leader: Anita De Rossi (UNIPD); Other collaborator(s): Silvia Giunco (UNIPD)
We plan to perform cross-sectional studies to assess the role of aging biomarkers to identify subjects prone to premature aging and aging-related disease. Further longitudinal studies will provide the “aging rate” useful for choosing the most appropriate management and surveillance of frail individuals.
By using peripheral blood samples, we will evaluate telomere length, immune-senescence, thymic output, and circulating telomerase in the following two cohorts:
1- Cancer patients at diagnosis. Samples from age-matched subjects with no history of cancer will be included in the study as controls.
2- HIV-infected subjects born to HIV-infected mothers, aged from 0-30 years. Samples from age-matched HIV-uninfected-exposed born to HIV-infected mothers and HIV-unexposed-uninfected age-matched subjects will be included in the study as controls.
Brief description of the activities and of the intermediate results
Blood samples have been collected from: 1) 70 elderly (≥70 years old) colorectal cancer patients (CRC) at surgery (baseline) and 47 subjects reevaluated 1 year after radical tumor resection; 2) 55 young adults (15-30 years old) with perinatally acquired HIV (PHIVAYA) and 23 age-matched healthy controls. A multiparametric aging profile covering immunological aspects (immune senescence and activation), cellular markers (telomere length and thymic output), and circulating biomarkers of senescence (SASP) and denervation (CAF and NCAM-1) alongside emerging senescence markers (TERRA) are ongoing for both groups. Preliminary results suggest that an aged phenotype, i.e. high levels of senescent and activated T cells, elevated circulating SASP markers (particularly IL6, IL8, CXCL-1), and CAF, is prognostic of a worse clinical outcome of colorectal patients and is a valuable prognostic tool for minimally invasive monitoring of cancer patients. TERRA originating from chromosome 15q (TERRAch15) could be a potential candidate for monitoring aging and prognosis of cancer patients.
Main policy, industrial and scientific implications
Aging represents the primary risk factor for major human pathologies, including cancer. Assessing aging in peripheral blood holds paramount importance for minimally-invasive monitoring of frail patients. Identifying a comprehensive multiparametric aging profile in peripheral blood samples can facilitate the identification of patients who are biologically "aged" independent of chronological age, thus at higher risk of developing age-related diseases. Furthermore, it offers potential prognostic tools for monitoring disease progression and treatment outcomes.
Ongoing research focuses on evaluating the role of telomeric damage-induced long non-coding RNAs (dilncRNAs) in PBMCs from CRC patients in collaboration with Dr Fabrizio D’Adda di Fagagna. These RNAs are being explored as potential biomarkers for aging and prognosis, alongside investigations into TERRA responses to senescence-inducing stimuli in vitro.
In the HIV cohort, findings revealed that the PHIVAYA exhibited elevated levels of activated, senescent, and exhausted CD4 and CD8 T cells, shorter telomeres, reduced thymic output, and increased markers of inflammation and denervation compared to healthy controls. HIV-DNA levels correlated positively with T cell activation and inflammation and negatively with regulatory immune cells and telomere length. Notably, PHIVAYA with early ART initiation and sustained viral suppression under ART exhibited levels of most aging biomarkers comparable to those of healthy controls. These findings underscore the importance of early ART initiation and persistent viral suppression in reducing premature aging and age-related illnesses.
Dissemination: