Convergent mechanisms of longevity across mammalian species

• Applicant: Domenico Di Fraia, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Bioinformatics and Theoretical Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550649363

Aging is a multifactorial process causing organismal decay and the collapse of cellular proteostasis. The importance of understanding its mechanisms stems from the fact that aging underlies increased risks for multiple diseases, including neurodegenerative ones and cancer. Although of crucial importance, the biological determinants of the aging process are unknown. Remarkably, one of its fascinating aspects is how aging varies across the tree of life. Mammals, for example, display a wide range of variations regarding maximum lifespans, from ~3.2 years for the lab mouse to >200 years for the bowhead whale. Several studies have tried to characterize specific molecular signatures of long- and short-lived organisms at the genome, transcriptome, or proteome levels. However, how these different modes of regulation interconnect across lifespans and the molecular mechanisms by which natural selection promotes the evolution of long-lived organisms remain unknown. Therefore, in this proposal, I aim to resolve this knowledge gap by determining the convergent mechanisms of lifespan control across mammalian species. In this proposal, I will investigate how genomic signatures and gene structure variation across a wide range of mammalian species reflect variations in the transcriptomes, proteomes, and metabolomes and how those differences correspond to improved longevity. This project, a unique collaboration between Prof. Andreas Beyer's laboratory in CECAD, Cologne, and Prof. Vera Gorbunova's laboratory in Rochester, USA, proposes a new approach to studying lifespan control across mammals. I will utilize quantification of the transcriptome (through RNA-Seq), proteome (through Mass Spectrometry), and metabolome (through Mass Spectrometry) from 47 mammalian species spanning different lifespans that Vera Gorbunova's lab has already collected. Andreas Beyer from CECAD, Cologne, will oversee the computational aspects of the project. The strength of this proposal lies in its innovative integration of the complete gene expression program with longevity and its evolutionary dimension. This research proposal is composed of two distinct aims. In the first part of my research, I will analyze and integrate the transcriptome, proteome, and metabolome data. This will help us understand how variability in the post-transcriptional regulation of specific biological processes can influence lifespan. In the second part, I will investigate how specific genomic features of long-lived mammals, such as codon composition, codon optimality, and gene structure, reflect in the modulation of transcription and post-transcriptional regulation of molecular pathways in long-lived species.

• DFG Programme: WBP Position