Arguing for More Practical Research Based on a Hyperfunction View of Aging
Hyperfunction theories of aging have emerged in recent years from the programmed aging camp, vary considerably, and have yet to settle down into a single consensus hyperfunction theory. Roughly speaking, in this viewpoint aging is the consequence of the inappropriate continued activity or reactivation of developmental programs in adult life. This view of aging does not necessarily stand in opposition to the consensus antagonistic pleiotropy viewpoint, in which aging is the consequence of unrepaired damage that accumulates because selection pressure is too weak in late life for better repair systems to emerge. In some cases hyperfunction is seen as a part of this damage. In others, hyperfunction is seen as the underlying cause of aging, a program, while damage is a secondary consequence.
Today's example of hyperfunction theorizing is one of those that downplays the view of accumulated damage, painting damage as a secondary consequence of the underlying program of aging. The authors makes some practical suggestions regarding the way in which research should progress if hyperfunction is the driving theory: find overactivated and harmful development-associated genes and suppress their activity. Theory drives research strategy, and this is why battles over theories of aging are important. If the wrong approach to theory wins out, research and development will tend to lead to only poorly effective therapies, because those therapies fail to address causes of aging and are instead targeting side-effects of aging.
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 progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective 'shadowing' in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy.
Long-standing frameworks that ageing is caused by a passive accumulation of molecular damage have been challenged in recent years. The emergence of proposed ageing hallmarks motivated substantial scientific efforts to combat these myriad of molecular perturbations, however, yielding limited success. Understanding if the proposed hallmarks of ageing are causally involved in the physiological decline of organisms, or if they represent mere secondary symptomologies to ageing deterioration, remains an ongoing effort. Indeed, considerable model organism research suggests these traits to be poor predictors of healthy ageing. Thus, whilst features of molecular damage, oxidative stress, and mitochondrial dysfunction are sure to plays important roles in exacerbating healthspan decline, proximate molecular events that underpin the onset of healthspan decline remain largely elusive and difficult to study. Evolutionary theory has long maintained that declines in the force of natural selection after sexual maturity allow the sub-optimal expression and function of fitness-promoting genes in late-life. Thus, genomes have evolved for developmental and reproductive success, not healthy ageing.
This suggests that evolutionary neglect encompasses the proximate cause of ageing onset, yet is unable to elucidate precisely which late-acting (pleiotropic) genes contribute to physiological decline. Identifying the entirety of late-acting hyperfunctional genes will, therefore, allow thorough investigations into optimising their expression levels at the organismal and tissue-specific level at geriatric life stages. We propose that combinations of untargeted multi-omics and late-life healthspan screening of gene-by-gene inhibition is the preferred strategy for studying the roles of hyperfunction in normal physiological ageing.