Researchers have published a review of the current state of combination therapies that address multiple Hallmarks of Aging [1]. Some of these combined therapies were found to induce greater lifespan extension than single treatments.
A complex phenomenon calls for complex treatments
The complexity of aging cannot be underestimated. It is unlike individual diseases, which primarily affect single organs. Aging affects the entire body and does so by affecting countless molecular processes. Therefore, to slow down or reverse it, it must be attacked from multiple directions, such as by using a combination of therapies.
While there is broad research in model organisms on genetic and pharmaceutical approaches that target aging, most of the approaches result in modest lifespan increases in mammals.
The authors of the review state that “this outcome is to be expected if we consider that even if one aging process is successfully treated, other aging pathways may remain intact” and limit the organism’s lifespan. Therefore, multiple aspects of aging must be addressed at once.
More therapies are better than one
The researchers reviewed the literature to gather data on existing combination therapies targeting pathological processes in aging. They used the Hallmarks of Aging as a reference point and focused on mouse studies, since mice are the most commonly studied mammalian model organism.
The combined therapies that showed improvements compared to single treatment in rodents included rapamycin and metformin; rapamycin and acarbose (an anti-diabetic drug); simvastatin and ramipril (cardiovascular disease drugs); glycine plus N-acetylcysteine (both ameliorate age-associated glutathione deficiency and reduce oxidative stress); elevated expression of the oncosuppressors p53 and Arf, with telomerase reverse transcriptase improving them even further; PROP1 gene deficiency and caloric restriction; suppression of growth hormone and caloric restriction, and the overexpression of the antioxidant enzymes catalase and superoxide dismutase.
Some of those combinations were effective not only in lifespan extension but also in improving some age-related phenotypes, such as cognitive impairment. However, some of them had sex-specific effects.
Being strategic
The authors of this review believe that a good way to approach the design of combination therapies is by using several therapies that attack different Hallmarks of Aging.
In their paper, they mention that “the current availability and diversity of lifespan-promoting therapies allows the possibility to design studies in mice targeting at least thirteen hallmarks of aging simultaneously” and nine of them don’t require genetic manipulations of embryos.
Combination therapies are also investigated by the LEV Foundation, which is testing a combination of rapamycin, a senolytic navitoclax, hematopoietic stem cell transplantation (HSCT), and telomerase expression [2]. This strategy targets six Hallmarks of Aging.
Since there are many possible combinations, but resources and time are limited, the authors elaborate on guidelines on which combination therapies to prioritize in testing, such as cost, effectiveness, feasibility, ability to be sustained for longer periods (caloric restriction is not easily sustained), and effectiveness when applied to already-aged organisms.
The authors suggest a few strategies that can be utilized in designing combination therapies. They wish to focus on therapies that have shown the best lifespan extension individually and combine them, attempting to target a maximum of hallmarks with few treatments and then bolstering that combination with underused lifespan-extending treatments that target further hallmarks. They wish to screen combination pairs that target different Hallmarks of Aging, with a focus on widely-used therapies with proven safety in humans.
Limitations
The researchers note that one of this review’s limitations is that most of the research is done on mice. The results of those experiments often depend on the animals’ living conditions, genetic backgrounds, etc. While animal research is essential, not all of it might translate to humans.
Additionally, using the Hallmarks of Aging framework is limiting; for example, this framework doesn’t differentiate between primary and secondary causes of aging. If a better framework is created, it can aid in the improved selection of therapies for combinatorial treatments.
While combination therapies are promising anti-aging approaches, the authors also point out possible drawbacks, one of the most important being possible adverse effects, especially for healthy people for whom the risks might outweigh the benefits. They also admit that many of these therapies have not been carefully evaluated for side effects, and combining therapies adds complexity and could offset or combine side effects.
Literature
[1] Panchin, A. Y., Ogmen, A., Blagodatski, A. S., Egorova, A., Batin, M., & Glinin, T. (2024). Targeting multiple hallmarks of mammalian aging with combinations of interventions. Aging, 16(16), 12073–12100.
[2] Lewis, C. J., & De Grey, A. D. (2024). Combining rejuvenation interventions in rodents: a milestone in biomedical gerontology whose time has come. Expert Opinion on Therapeutic Targets.
