Late life-applicable enhancement of longevity and fitness.

Project Information

LifeLongFit

Grant agreement ID: 101088965

DOI

10.3030/101088965

EC signature date 14 July 2023

Start date 1 November 2023

End date 31 October 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 000 000,00

EU contribution

€ 2 000 000,00

Coordinated by

LEIBNIZ-INSTITUT FUR ALTERNSFORSCHUNG - FRITZ-LIPMANN-INSTITUT EV (FLI) LEIBNIZ INSTITUTE ON AGING - FRITZ LIPMANN INSTITUTE EV (FLI)
Germany

Periodic Reporting for period 1 - LifeLongFit (Late life-applicable enhancement of longevity and fitness.)

Reporting period: 2023-11-01 to 2026-04-30

Summary of the context and overall objectives of the project

Aging represents gradual organismal decline driven by accumulation of cellular and molecular damages, including DNA damage and metabolic failures. At young and middle age, these damages are mitigated by tailored repair systems, such as autophagy and DNA damage response. The repairs can be triggered through adaptive stress responses induced by anti-aging interventions such as dietary restriction (DR) and DR mimetic metformin. Recently, we found that loss of metabolic plasticity and repair activities due to aging abrogate longevity benefits of adaptive stressors at old age. Specifically, we found that aging-linked failures of mitochondria and lipid catabolism limit metformin benefits and confer metformin toxicity in late life, and others showed comparable limitations for DR and exercise. Our findings demonstrate that anti-aging treatments do lose efficacy in old organisms, and new approaches are required to promote healthy aging in late life.
Here, we will use multi-omics, and functional tests in C. elegans, short-lived killifish and long-lived mammals to (a) probe the origin of aging-linked adaptive failures and (b) find molecular and therapeutic solutions for overcoming these failures. Omics tests and survival screens will be used to uncover mechanisms of intrinsic resilience against late life toxicity of metformin and other adaptive stressors in nematodes. We will also use available omics resources to probe the adaptive basis of the exceptional mammalian longevity in NMR and whales, followed by attempted replication of the uncovered differences in shorter-lived species (nematodes and fish) through drugs and genetic changes, with the outlook of triggering superior stress resilience and metabolic plasticity in late life. Our expertise will allow testing late life responses to diverse adaptive interventions from moderate genotoxic stress to DR mimetics and microbiome manipulation. This innovative program will illuminate novel treatments for healthy longevity that are not limited by aging.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By investigating the impact of ultraviolet-B (UVB) exposure on mitochondrial dynamics and systemic metabolism, we developed a first-in-kind, non-pharmacological intervention that mimics the complex, organism-wide benefits of dietary restriction. By integrating findings from C. elegans and human cell culture with preclinical mouse data, we demonstrated that exposure of the skin to narrow-band UVB (routinely used clinically to treat inflammatory skin diseases) induces mitochondrial remodeling in directly exposed cells that generates a systemic metabolic signal. This signal reprograms whole-body metabolism in a manner comparable to fasting (Martirosyan et al, bioRxiv 2024). Notably, whereas all currently known dietary-restriction mimetics are exclusively pharmacological, the intervention identified here is uniquely suited for individuals who may prefer or require non-pharmacological approaches, including those with high drug burden, hepatic or renal impairment, or a preference for holistic treatment strategies. Moreover, this intervention is exceptionally well positioned for rapid clinical translation, as it relies on the off-label use of an already approved and widely implemented clinical technology - narrow-band UVB skin phototherapy, thereby substantially reducing regulatory barriers, development time, and translational risk for a novel indication.