Since the beginning of the grant, we finalized and published a study showing that reduced energy expenditure and increased reliance on mitochondrial metabolism (identified by other groups as a universal natural pro-longevity strategy in several long-lived organisms) can extend lifespan in the short-lived nematode C. elegans when introduced through genetic manipulation. Specifically, we demonstrated that targeted reduction of ribosome biogenesis - the most energy-demanding process in eukaryotic cells, reduces overall energetic burden, remodels metabolism toward lower mitochondrial stress, attenuates mitochondrial aging, and promotes a healthier balance of triglyceride storage and utilization. Notably, this intervention strategy remained effective in conferring healthy longevity even when initiated very late in life, fulfilling one of the key objectives of this ERC grant (Sharifi et al, Nat Communications 2024, Chaudhari and Ermolaeva, NPJ Metab Health Dis
2024). This study provides proof of concept that such “natural” longevity strategies, shaped by evolution, can be implemented in shorter-lived species.
In addition, we expanded on our previous work demonstrating that mitochondrial aging is a key factor limiting the benefits of conventional pro-longevity treatments, such as dietary restriction (DR) and DR mimetics, in late life. Our goal was to understand the underlying causes of natural mitochondrial aging and assess whether these processes can be targeted by interventions. Using omics approaches, genetics and functional assays in human and nematode systems, we discovered that mitochondrial aging results from a decline in methylation-dependent synthesis of phosphatidylcholine, which alters mitochondrial membrane properties and impairs mitochondrial fusion - a process essential for metabolic plasticity and mitochondrial quality control. These discoveries fulfilled an important aim of this grant, namely, to identify the specific age-associated changes that impair the responsiveness of older organisms to conventional longevity treatments. Notably, we found that the aging-linked decline in phosphatidylcholine (PC) synthesis can be mitigated by dietary supplementation with choline or PC, resulting in improved metabolic plasticity in late life (Poliezhaieva et al, bioRxiv 2024).
