Forcing Youthful Gene Expression in Old Cells Should in Principle be Beneficial

It is reasonable to expect that forcing the epigenetic regulation of gene expression in cells in old tissue into a pattern more like that of cells in young tissue could be beneficial. Some of these changes in gene expression are clearly entirely maladaptive and detrimental to the health and life span of the organism. All else being equal, reversing those changes, and only those changes, will in principle lead to improved health. In principle is one thing, but will the effect size be large enough in practice, however? We rarely argue over whether specific mechanisms and outcomes exist, but we frequently argue over whether the result of intervention will be large enough to care about.

The concern with resetting epigenetic regulation of gene expression to a more youthful configuration is twofold: firstly, some epigenetic change is beneficial and helps to minimize the impact of the underlying damage of aging. Secondly, rejuvenation of any specific set of gene expression patterns will usually not fix the underlying damage of aging that caused gene expression to change in the first place. That damage will remain, still producing all of the other issues and dysfunctions that it is capable of causing. Targeting the damage rather than the reactions to damage is likely a better strategy.

Cost-free lifespan extension via optimization of gene expression in adulthood aligns with the developmental theory of ageing

The force of natural selection is maximized during pre-reproductive development but declines after sexual maturation with advancing age. Therefore, mutations that have neutral or positive fitness effects early in life but negative fitness effects late in life can accumulate (mutation accumulation theory) or be selected for (antagonistic pleiotropy theory) in the population and lead to the evolution of ageing. While these ultimate population genetic theories of ageing are broadly accepted, the proximate routes that lead to ageing are still incompletely understood and subject to vigorous debate. The discovery of evolutionarily conserved molecular signalling pathways that regulate life-history traits, such as development, growth, reproduction, and lifespan showed that ageing is malleable, and sometimes can be modified by modulating the expression of a single gene that influences a large array of downstream physiological processes.

One proximate physiological account of the antagonistic pleiotropy theory, the disposability theory of ageing (DST), postulates that ageing and lifespan evolve as a result of optimized resource allocation between somatic maintenance and reproduction with the aim of maximizing reproductive output. This theory predicts that increased investment in somatic maintenance will increase survival at the cost of reduced reproduction, and vice versa, since they are assumed to compete for the same pool of resources. The predominance of this theory has been increasingly challenged in recent years. Studies in different model organisms have suggested that increased longevity and reduced reproduction can be uncoupled.

Nevertheless, researchers proposed a different mechanism underlying antagonistic pleiotropy, by suggesting that the declining force of selection with age can result in suboptimal levels of gene expression in late life. Because selection is strongest during development and declines after the onset of reproduction, selection can never fully 'optimize' age-specific gene expression resulting in ageing via the action of otherwise beneficial genes. This developmental theory of ageing (DTA) maintains that the decline in selection gradients with age results in suboptimal regulation of gene expression in adulthood, leading to cellular and organismal senescence.

There is an important distinction between these two physiological explanations of how antagonistically pleiotropic alleles work. The DST rests on the competitive allocation of resources between the body and the germline resulting in imperfect repair of cellular damage; this theory predicts that genetic and environmental manipulations that increase allocation to somatic maintenance (hence lifespan) result in reduced allocation to the immortal germline (hence reproduction). The DTA instead focuses on imperfect age-specificity of gene expression and predicts that optimizing gene expression in adulthood can improve somatic maintenance as well as the germline. Increased understanding of the evolutionarily conserved molecular pathways that control many different aspects of organismal life cycle allows direct testing of these two explanations. Since the DTA is based on the assumption that gene function affects fitness differently across the life course of the organism, perhaps the most straightforward way to test it is to modify the gene expression at different stages across the life course and assess the effects on fitness-related traits and on individual fitness.

Here we tested these predictions directly by modifying the age-specific expression of five well-described 'longevity' genes in Caenorhabditis elegans nematode worms that play key roles in different physiological processes: nutrient-sensing signalling via insulin/IGF-1 (age-1) and target-of-rapamycin (raga-1) pathways, global protein synthesis (ifg-1), global protein synthesis in somatic cells (ife-2), and mitochondrial respiration (nuo-6). Downregulation of these genes in adulthood and/or during post-reproductive period increases lifespan, while we found limited evidence for a link between impaired reproduction and extended lifespan. Our findings demonstrate that suboptimal gene expression in adulthood often contributes to reduced lifespan directly rather than through competitive resource allocation between reproduction and somatic maintenance. Therefore, age-specific optimization of gene expression in evolutionarily conserved signalling pathways that regulate organismal life histories can increase lifespan without fitness costs.

Comments

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.