A recent review highlights the state of combination therapies aimed at addressing multiple Hallmarks of Aging, demonstrating greater lifespan extension in animal studies compared to single treatments[1]. Such approaches present promising yet understudied avenues for enhancing the effects of anti-aging interventions.
| Key Focus | Description |
|---|---|
| Complexity of Aging | Unlike individual diseases, aging impacts the entire body and numerous molecular processes. |
| Combination Approach | Multiple therapies are needed to address the diverse biological processes of aging. |
| Improved Lifespan in Animals | Some combination therapies lead to longer lifespans and improved phenotypes in rodents. |
Why Multiple Treatments?
Aging is inherently complex, affecting multiple molecular processes and organs. Tackling aging effectively requires a multifaceted approach that combines therapies targeting different processes. While many pharmacological and genetic interventions have been tested on model organisms, their effects on lifespan are often modest.
The review emphasizes that even if one aspect of aging is successfully treated, other aging pathways may continue to limit the organism's lifespan. Therefore, to address aging comprehensively, multiple hallmarks need to be targeted.
Effectiveness of Combined Therapies
The review discusses multiple combinations of therapies tested in rodents, demonstrating improved lifespan and aging phenotypes compared to single treatments. These combinations include:
- Rapamycin and metformin: Two drugs often used in anti-aging research.
- Rapamycin and acarbose: An anti-diabetic agent.
- Simvastatin and ramipril: Cardiovascular medications.
- Glycine and N-acetylcysteine: Targeting glutathione deficiency and reducing oxidative stress.
- Overexpression of p53 and Arf: With telomerase reverse transcriptase for enhanced benefits.
- PROP1 gene deficiency and caloric restriction.
- Suppression of growth hormone and caloric restriction.
- Overexpression of antioxidant enzymes: Such as catalase and superoxide dismutase.
Not only did these combinations extend lifespan but they also improved age-related phenotypes such as cognitive function. However, some therapies demonstrated sex-specific effects.
Strategic Design of Therapies
The authors advocate for using multiple therapies targeting different Hallmarks of Aging. According to the review, current research enables studies that address up to thirteen hallmarks simultaneously in mice, nine of which do not require genetic modifications.
The LEV Foundation is one example of efforts to test combination therapies, combining treatments like rapamycin, navitoclax (a senolytic), hematopoietic stem cell transplantation (HSCT), and telomerase expression to target six hallmarks[2].
Developing Efficient Combination Therapies
The review suggests prioritizing combinations based on the following criteria:
| Criterion for Prioritization | Details |
|---|---|
| Cost & Feasibility | Therapies should be affordable and easy to administer. |
| Effectiveness & Safety | Focus on therapies with proven lifespan-extending and safe profiles. |
| Sustainability | Prefer therapies that can be sustained over long periods. |
| Applicability to Aged Organisms | Combinations effective when applied to already-aged organisms. |
Limitations and Challenges
Animal Models
Most combination therapies have been tested in mice, and the results may vary based on genetic background, living conditions, and other factors. While mice serve as key models, translatability to humans remains a challenge.
Hallmarks Framework
The use of the Hallmarks of Aging framework may be limiting, as it doesn't differentiate between primary and secondary aging causes. A more refined framework could better inform the selection of combinatory interventions.
Potential Risks
One of the main concerns with combination therapies is the potential for adverse effects. In healthy individuals, the risks may outweigh the benefits. Moreover, many interventions have not undergone thorough safety evaluations, and combining therapies adds a layer of complexity and risk.
Further Research Needed
While combination therapies present promising anti-aging approaches, more research is required to understand their molecular mechanisms, long-term effects, and potential side effects. A balanced, strategic design focusing on multiple hallmarks could provide a way forward for comprehensive anti-aging treatments.
References
- 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. ↩︎
- 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. ↩︎
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