The hallmarks of aging paper described a categorization of aging into discrete forms of damage and change, strongly influenced by more than a decade of work to popularize the SENS view of aging as a catalog of forms of molecular damage. The hallmarks are distinct from the SENS categorization, incorporating a number of items that are downstream from the molecular damage that causes aging, but the two overlap to some degree. We might also consider the seven pillars taxonomy of aging, and I'm sure that more similar overviews will arise in the future as various categories start to show promise in the development of therapies to treat aging as a medical condition. The challenge facing the effective use of any such taxonomy of facets of aging is that there are few to no animal models that exhibit just one of those facets, or in which a facet is easily manipulated in isolation of all of the others. Everything in cellular biochemistry connects to everything else.
In this open access paper, researchers review the current state of animal models from a hallmarks of aging perspective, finding it lacking. This is just as true for the SENS view of aging. In both cases, generating animal models that exhibit to at least some degree of physiological levels of only one of the forms of damage will be important. It is also important to understand that models that exhibit far greater than normal levels of damage observed in the usual course of aging may or may not be helpful. This is the situation for lineages with reduced DNA repair activity in the nucleus or mitochondria, where the animals exhibit far greater levels of mutational damage than normally occurs even in late old age. Despite existing for quite some time, these models have not to date resulted in a definitive outcome in the debate over nuclear DNA damage, and it is still the case that using them for studies of aging requires a very careful consideration of the details of the experiment to avoid misleading results.
The use of model organisms in aging research has been essential to achieve a key milestone in the field: the aging process can be modulated. Instead of just a passive, undefined decline of physiological functions, aging has turned out to be the result of a complex interconnection of genetic and biochemical mechanisms that have recently been categorized in 9 molecular hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Although we are still far from understanding how this intricate network of pathways inexorably coordinates organismal deterioration, in vivo studies in animal models have proven that single genetic manipulations can extend lifespan or ameliorate certain age-related phenotypes. Also, external interventions, that is, caloric restriction, which target specific pathways, have demonstrated that aging can be delayed in a variety of species.
For several years, the use of invertebrate animal models-such as the worm Caenorhabditis elegans or the fruit-fly Drosophila melanogaster-has led aging research by providing the first insights into those molecular pathways that are determinant in the aging process and for lifespan extension. Despite the great progress achieved by using simple model organisms carrying mutations in specific genes, increasing efforts have been made during recent years to address whether these fundamental mechanisms are also shared by mammalian systems. In this regard, mouse models have become an excellent tool in aging research because of their relative short lifespan (which allows the monitoring of the aging process in a reasonable window frame) and to the feasibility of performing genetic manipulations. Also, mice share many of the age-related phenotypes found in human subjects, including the increased risk to develop certain diseases with age, such as cancer. Nevertheless, those age-related pathologies frequently found in elderly humans and absent in aged mice, such as certain cardiovascular (ie, atherosclerosis) or neurodegenerative (ie, Alzheimer's) diseases, can be studied using the appropriate genetically modified mouse model already created to mimic these common human disorders. Accordingly, in this review, we revisit the hallmarks of aging through the prism of those biological insights provided exclusively by gain- and loss-of-function mouse models.
We have focused on those genetic interventions that have a direct impact on a specific hallmark and discuss how this manipulation affects the aging process. Of note, the pleiotropic function of certain genes together with the inherent interconnection of some hallmarks makes sometimes difficult to point at a single molecular pathway/hallmark once a gene has been deleted or overexpressed. Finally, we have primarily highlighted those genetically engineered mice that shorten or increase healthy lifespan, keeping in mind that certain features of mouse models showing accelerated aging are not present in normal aging and vice versa. We have found examples of existing animal models for the majority of hallmarks of aging. However, this analysis has also surfaced some weaknesses and many challenges ahead.