Michael Rera

Ageing is characterised at the molecular level by six transcriptional ‘hallmarks of ageing’, that are commonly described as progressively affected as time passes. By contrast, the ‘Smurf’ assay separates high‐and‐constant‐mortality risk individuals from healthy, zero‐mortality risk individuals, based on increased intestinal permeability. Performing whole body total RNA sequencing, we found that Smurfness distinguishes transcriptional changes associated with chronological age from those associated with biological age. We show that transcriptional heterogeneity increases with chronological age in non‐Smurf individuals preceding the other five hallmarks of ageing that are specifically associated with the Smurf state. Using this approach, we also devise targeted pro‐longevity genetic interventions delaying entry in the Smurf state. We anticipate that increased attention to the evolutionary conserved Smurf phenotype will bring about significant advances in our understanding of the mechanisms of ageing.

A major challenge in the biology of aging is to understand how specific age-onset pathologies relate to the overall health of the organism. The integrity of the intestinal epithelium is essential for the wellbeing of the organism throughout life. In recent years, intestinal barrier dysfunction has emerged as an evolutionarily conserved feature of aged organisms, as reported in worms, flies, fish, rodents and primates. Moreover, age-onset intestinal barrier dysfunction has been linked to microbial alterations, elevated immune responses, metabolic alterations, systemic health decline and mortality. Here, we provide an overview of these findings. We discuss early work in the Drosophila model that sets the stage for examining the relationship between intestinal barrier integrity and systemic aging, then delve into research in other organisms. An emerging concept, supported by studies in both Drosophila and mice, is that directly targeting intestinal barrier integrity is sufficient to promote longevity. A better understanding of the causes and consequences of age-onset intestinal barrier dysfunction has significant relevance to the development of interventions to promote healthy aging.