Discovery of molecular and genetic/epigenetic signatures underlying resistance to age-related diseases and comorbidities

    Project: Research project

    Project Details


    Aging is accompanied by a chronic low-grade inflammatory state. This phenomenon is mainly attributed to an antigenic stimulation that contributes to chronic inflammation and progressive changes in the T-cell and B-cell systems. These changes correlate also with a high prevalence of diseases of aging, as for Alzheimer disease (AD) and sarcopenia. Long-Lived Individuals (LLIs) delay or escape age-related disability and various age-related diseases likely due to the phenomenon of demographic selection leaving behind a cohort of selected survivors. These individuals have a favourable genetic profile that could disclose how genes, such as APOE and FOXO3A, influence aging and related diseases. Our on-going efforts include the recruitment of LLIs, their genetic and epigenetic characterization at genome-wide level, and the identification and initial characterization of a Longevity Associated Variant (LAV) in BPI Fold Containing Family B, Member 4 (BPIFB4) that enhances eNOS phosphorylation, endothelial function and migration. Furthermore, epigenetic variations, such as CpG methylation, histone modifications and non-coding RNAs, may also be central to controlling changes in gene expression and genomic instability during aging. For this proposal, we plan: i) to potentiate the ongoing efforts on LLI population characterization, through the integration of pre-existing data with exome sequencing to identify common and rare genetic variants, and ii) to analyse mRNA and non-coding RNA expression profiles, as well as DNA methylation status, in mononuclear cells (MNCs) of de novo recruited LLIs and middle-aged-MACs (healthy, AD, and sarcopenic patients) and young (YCs) controls. In addition, the role of the inflammosome, the immune and vascular repair processes point at the need for functional characterization of CD34+ pro-angiogenic MNCs and T cells from de novo recruited LLIs, MACs and YCs. Finally, the new longevity variants identified by exome sequencing and epigenetic studies will be validated in vitro and in vivo in cardiovascular system. The goal of our collaboration is to identify genetic/epigenetic signatures associated with healthy aging and AD and sarcopenia in order to understand how they influence inflammosome, CD4+ and C34+ cells and protection from cardiovascular and immunological diseases. This will lead to a better understanding of the common mechanisms underlying age-related diseases and their relevance for co-morbidities.

    Layman's description

    The study of LLIs has already begun to disclose how genes, such as APOE and FOXO3A, influence aging and aging-related diseases.The main objective of this proposal is therefore to study, at the genome-wide level, the genetics and epigenetics of LLIs, MACs and YCs in order to identify and characterize longevity-and age-associated variants with a specific impact on the nervous, cardiovascular and immune systems. We will focus on the nervous, cardiovascular and immunological impact because diseases of these systems are prevalent and interconnected in the aged. Nevertheless, results of this study will indirectly benefit the understanding of other pathologies associated with aging.In recent years, networks have become increasingly used to describe complex biological systems. Thus, the main scope of this project is the discovery of novel genetic variants and epigenetic modifications that underlie healthy aging, using LLIs as a model, and age related diseases (AD and sarcopenia) through a multidisciplinary approach that includes the study of immunological and repair systems.Endotelial Progenitor Cells (EPC) number decreases in their original niches and in the circulation with age, through mechanisms that are still not completely understood but that are at least in part dependent on NO generation via eNOS. We will further explore and quantify CD34+ pro-angiogenic and CD4+/CD25+/Foxp3+/Treg cells of LLIs, MACs and YCs thoroughly characterizing them through in vitro and in vivo functional assays. We will also further characterize LAV-BPIFB4 and novel genetic targets for endothelial repair and function, the immune system and metabolism.

    Key findings

    Effective start/end date2/5/172/4/20