Proximate Causes of Ageing Are Likely Evolutionarily Bound and Appropriate Countermeasure Design Requires New Approaches

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with a progressive loss of biochemical processes and degeneration of molecular material, however, the mechanisms of diminishing function are not simply a result of aberrant expression of these pathways. Natural selection pressures are at their highest in youthful periods to select genes advantageous to maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene function once beneficial for developmental growth, but pathogenic later in life. Due to this selective shadowing in ageing, mechanisms to counter hyperfunctional genes are unlikely to evolve within a given species. These genetic run-on programmes are not dysfunctional per se and, in fact, remain highly robust. Thus, interventions capable of optimising gene function during the ageing process represent as attractive therapeutic modalities. Caenorhabditis elegans offers a unique model to explore high-throughput screening of interventions to combat hyperfunctional pathways involved in ageing. However, the majority of research to date employ whole-life vs late-life pathway manipulation of developmental/growth-related systems to claim ageing attenuation, despite significant impairments in early-life fitness and discordance with healthspan. Here, we discuss data supporting hyperfunctional changes at a global molecular and functional level in C. elegans, and how classical lifespan-extension mutants alter these dynamics. We later discuss the relevance of such mutant models for exploring mechanisms of ageing, highlighting that post-reproductive gene manipulation represents a far more translatable approach for C. elegans research not routed within pleiotropic constraints. More so, lifespan has become a routine readout for quantifying ageing, however, we make the argument that a compression of gerospan vs lifespan extension is a more meaningful goal for anti-ageing regimes with current knowledge. Similarly, mechanisms governing lifespan are distinct from those regulating health, and slowing senescent pathology accumulation appears more applicable for the abstraction to human ageing.