The research and development communities are not good at prioritizing the evaluation and development of combination therapies. The incentives surrounding intellectual property and demands of regulators can explain much of this, and the rest is due to the primary focus on small molecules as a mode of therapy. Any two given small molecules that are individually useful are very likely to interact to produce an overall negative effect, so little work is directed towards speculatively combining drugs.
In the case of aging, however, an effective treatment must involve a package of various approaches to the repair of the cell and tissue damage that drives aging. We might expect these approaches to be more likely act in synergy. That said, it is clear that altering metabolism to slow aging suffers from the small molecule interaction problem, wherein most drugs and supplements that modestly slow aging on their own interact negatively to modestly accelerate aging. The field must focus more upon repair of damage rather than alteration of metabolism if the vision of synergistic therapies is to be realized.
Targeting multiple hallmarks of mammalian aging with combinations of interventions
Aging is currently viewed as a result of multiple biological processes that manifest themselves independently, reinforce each other and in their totality lead to the aged phenotype. Genetic and pharmaceutical approaches targeting specific underlying causes of aging have been used to extend the lifespan and healthspan of model organisms ranging from yeast to mammals. However, most interventions display only a modest benefit. The maximum known life extension of mice, resulting from a single intervention, does not exceed 50{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} (Snell mice with Pit1 knockout or Ames mice with Prop1 knockout). Even in these cases the lifespan of mice is much lower than that of similarly sized mammals with negligible senescence such as the naked mole-rat Heterocephalus glaber, indicating that none of these interventions was sufficient to stop aging. One possible explanation is that even if one underlying cause of aging is countered, the remaining aging processes will still limit the animal’s lifespan. Thus, we propose the hypothesis that combination therapies can be more efficient against aging.
Targeting multiple pathways at once can provide synergistic effects that are expected to be greater than the simple sum of independent effects. For example, chemotherapy kills cancer cells leading to proliferation of cancer-targeting T cells. However, some cancers evolve adaptations that suppress this immune response. Checkpoint inhibitors can lift this suppression allowing T cells to be more effective. Several clinical trials have revealed that chemotherapy works better when combined with this form of immunotherapy. Similar examples can be found in the field of aging research. Using the model organism C. elegans researchers have shown that a ribosomal protein S6 kinase beta deletion allele, daf-2 loss-of-function allele and their combined effects increase the worm’s lifespan by 20{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497}, 168.8{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} and 454.4{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} respectively. A combination of trametinib, rapamycin, and lithium increase the longevity of Drosophila more than each single intervention or pairs of interventions. These drugs inhibit mitogen-activated protein kinase kinase, mTOR complex 1, and glycogen synthase kinase-3 respectively, thus targeting various components of the nutrient-sensing network. Generally, as aging-related pathologies are typically comorbid, targeting multiple biological processes or their separated nodes may be more effective than targeting a single one.
Currently, the most comprehensive analysis of synergistic anti-aging interactions is provided by the SynergyAge database which contains the current state of the art collection of data on long-lived and short-lived genetic mutants with over 1800 gene combinations. However, the database does not cover pharmacological and gene therapy interventions which are arguably more relevant for practical human lifespan extending application. Here we review existing data on combinations of pharmacological and genetic interventions targeting one or many pathological processes described as the hallmarks of aging in mice. While we also discuss studies performed on other mammals, we focus on mice because they were used in the largest number of longevity intervention studies. We conclude that both additive and synergistic effects on mammalian lifespan can be achieved by combining interventions that target the same or different hallmarks of aging. However, the number of studies in which multiple hallmarks were targeted simultaneously is surprisingly limited. We argue that this approach is as promising as it is understudied.
