Editorial: Mechanistic theories of aging

The genetic theory of aging involving mutation accumulation and antagonistic pleiotropy has relatively broad support, but does not specify mechanisms. Recent progress in the study of aging in humans and model systems has provided insight into mechanistic theories of aging. Because there is no universally accepted definition of aging, an operational definition of aging is key to attempts to define aging mechanisms. This Research Topic presents a series of articles that examine mechanistic theories of aging at every level of biological organization, ranging from molecules to genes, cells, organisms and society (Figure 1).Mitochondrial dysfunction(definition) is one of 12 proposed "hallmarks" of aging , where aging is broadly defined as "...the time-dependent functional decline that affects most living organisms…" (Lopez-Otin et al., 2013). The hallmarks are phenotypes that manifest with age and that can accelerate aging when experimentally increased, and in some cases, decelerate aging when targeted with therapeutic interventions. The hallmarks include mitochondrial dysfunction, genomic instability, loss of proteostasis(definition), chronic inflammation, disabled macroautophagy, and others. These hallmarks may represent independent or semiindependent mechanisms that each contribute to aging. Alternatively, it might be argued that each hallmark results from a central mechanism involving mitochondrial maintenance failure.[FIGURE 1 HERE]The review on selectively advantageous instability (SAI) [TOWER-B REFERENCE HERE] surveys the ways that molecular instability can provide a selective advantage to cells and organisms, above and beyond the generation of energy or mobilization of building blocks . Here, aging is defined as "…an increased chance of death with age, and decreased reproductive fitness with age." One well-studied example of SAI is the removal of damaged macromolecules, a failure in which can lead to cell death. Another well-studied example of SAI is the regulated stability of stress-response factors such as SKN-1/Nrf2, which facilitates a rapid response to stress and subsequent cell survival, see [TURNER REFERENCE HERE]. SAI also promotes the maintenance of genetic diversity. For example, the instability of the male mitochondria relative to the nucleus in the male germline and fertilized zygote produces uniparental mitochondrial transmission. Because natural selection can only act to optimize mitochondrial gene function in the female, this is predicted to produce male-harming mitochondrial alleles, sometimes referred to as "mother's curse" (Frank and Hurst, 1996;Gemmell et al., 2004). It is hypothesized that this will lead to selection for compensatory nuclear alleles in males (Rand et al., 2004), and that these nuclear alleles may in turn have negative effects in females (Tower, 2006). This segregating genetic diversity is proposed to include negative alleles that contribute to aging in both males and females, as well as providing a substrate for further evolution. Fisher's principle is proposed to create a limit to the extent that male-harming or female-harming alleles might accumulate in the genome. If harming alleles accumulate to point that they reduce the viability and abundance of one sex, that sex will now have access to a greater relative abundance of possible mates. This increases the effective reproductive fitness of the limiting sex, leading to selection for production of more individuals of that sex.Edmands [EDMANDS REFERENCE HERE] reviews the experimental evidence for and against mother's curse in detail, and discusses the sexually dimorphic and energy-intensive traits most likely to be affected. The support for mothers curse was found to be limited to a few taxonomic groups, with the strongest support coming from studies of Drosophila. However, other studies of Drosophila and other taxa failed to find support. Several factors were suggested to explain the mixed results, including the likely selection for compensatory alleles in males, as discussed above.Sprason et al [SPRASON REFERENCE HERE] review the role of mitochondria in aging, and in particular the role of mitochondrial DNA (mtDNA) deletions. They begin with an operational definition of aging as "…the lifelong continuous loss of physiological homeostasis resulting in a continually increasing probability of pathology and death". mtDNA deletions increase with age in several human tissues, and mtDNA deletions are enriched in the brains of patients with Alzheimer's disease and Parkinson's disease, however, distinguishing between correlation and causation has proven challenging. Key studies are described in which mice were engineered with increased mtDNA mutations, and premature aging phenotypes were found to correlate with increase mtDNA deletions, but not mtDNA point mutations. By contrast, subsequent studies in various model systems produced mixed results regarding the causative effect of mtDNA deletions in aging. Possible reasons for the mixed results are suggested to include tissue-specific effects, and the limitations of current quantification methods.Osiewacz [OSIEWACZ REFERENCE HERE] reviews studies of the model organism Podospora anserina that provide insight into the role of mitochondria and biomembranes in aging. Here, aging is operationally defined as "…a complex process leading to functional degeneration and, ultimately, the death of the system." During P. anserina aging, the first intron of the mtDNA gene CoxI is liberated and becomes amplified. The amplified intron sequences then act a mtDNA mutagen, leading to large mtDNA deletions. Remarkably, P. anserina mutants that lack the CoxI gene are viable, and do not undergo this mtDNA rearrangement. These mutants carry out an alternative form of respiration, and appear to be immortal. This alternative respiration pathway bypasses steps that normally generate abundant superoxide. Aging in P. anserina is also associated with pronounced alterations in the architecture of the inner mit