Cellerino Group

Ribosomes as a central hub of brain aging

Neuronal function depends on the precise balance between protein synthesis and degradation and on the proper functioning of mechanisms that detect and remove misfolded protein (Proteostasis). We detected a gradual decline in the correlation between mRNA and corresponding protein levels, largely attributed to traslational deregulation. Although the synthesis of some proteins was enhanced, there was a widespread reduction of proteins enriched in positively charged (basic) amino acids. including DNA and RNA binding proteins. This phenomenon correlated with increased ribosome stalling and affected transcripts coding for ribosomal subunits and proteins involved in DNA repair, transcription, chromatin maintenance, and RNA splicing and export, which all mediate processes influenced by aging. 

Our work identified altered translation elongation and impaired protein biogenesis as hallmarks of brain aging in killifish. This mechanism thereby links translation and proteostasis decline to other hallmarks of aging and hits all the steps that are necessary for protein synthesis: synthesis of tRNAS, DNA repair, transcription, RNA processing and translation thereby representing a possible mechanism acting upstream of a multitude of aging hallmarks. We are currently investigating how experimental manipulations of ribosome stalling the ameliorate brain aging.

Diapause and aging

N. furzeri lives in seasonal ponds. A key adaptation these ephemeral habitats is the ability arrest embryonic development, a phenomenon called diapause, to delay hatching in order to match the seasonal inundations. Interestingly, a significant an overlap between the transcript and protein regulation observed in diapause and aging exist, suggesting that molecular mechanism that are adaptive during diapause are reactivated and become maladaptive during aging.

Similarities between aging and diapause transcriptomes and the negligible effects of diapause length on post-hatch lifespan suggests that aging occurs during diapause and is then reversed upon diapause exit. We are currently using multiomic profiling techniques to reveal the mechanisms that link diapause and aging. 

Aging clocks and pharmacologial interventions

In recent years, ageing research has been transformed by computational models known as Aging Clocks, which estimate age and mortality risk from molecular or physiological data. As these powerful tools are not available for killifish, we set to create two clocks: one based on DNA methylation and one based on transcriptome.  

Both aging clocks were able to predict mortality in longitudinal studies of killifish. The DNa methylation clock shows high precision but lacks explainability while the transcriptomic clock is based on expression of genes with orthologs in humans with known functions and therefore is explainable and transferrable.

We are currently exploring the use of these aging clocks as biomarkers in pharmacological interventions. 

To this end, we have developed a long-term organotypic culture system of N. furzeri brains. These cultures survive several weeks and replicate a whole host of cellular aging markers providing the first ex vivo model of brain aging. 

The Greenland shark as a model of extreme longevity

The Greenland shark is a giant (>5 m) iconic abyssal species that inhabits the North Atlantic depths and the Arctic Ocean. Based on radiocarbon dating, females show an extraordinary lifespan estimated at 392 ± 120 y. In collaboration with the Hoffman group, we sequenced the genome of the Greenland shark and of a comparison short-lived shark to identify possible genomic adaptations linked to exceptional longevity. 

While exceptional longevity is often attributed to resistance to aging, whereby organisms avoid age-related damage, an alternative mechanism is resilience—the capacity to maintain normal physiological function despite such damage. We address the resilience/resistance dichotomy by studying the expression of aging hallmarks and aging lesions in the heart and the brain of the Greenland shark.