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Rapamycin: A drug that may slow aging with Matt Kaeberlein, PhD





Dr. Matt Kaeberlein is the CEO of Optispan, an affiliate professor of Oral Health Sciences at the University of Washington, and co-founder of the Dog Aging Project. Dr. Kaeberlein has dedicated his career to understanding the biological mechanisms of aging and developing interventions to promote longevity and healthspan.


Scientists have identified 12 hallmarks of aging, shared across the animal kingdom.

  1. Genomic Instability – Accumulation of DNA damage due to environmental and internal stressors.

  2. Telomere Attrition – Progressive shortening of telomeres

  3. Epigenetic Alterations – Changes in gene expression

  4. Loss of Proteostasis – Decline in maintaining properly folded and functioning proteins.

  5. Deregulated Nutrient Sensing—Impaired signaling in pathways like insulin/IGF-1, mTOR, AMPK, and sirtuins affects metabolism and longevity.

  6. Mitochondrial Dysfunction

  7. Cellular Senescence – Accumulation of non-dividing but metabolically active cells that secrete inflammatory factors.

  8. Stem Cell Exhaustion – Declining regenerative capacity due to reduced stem cell function.

  9. Altered Intercellular Communication

  10. Disabled Macroautophagy – Impaired cellular recycling

  11. Dysbiosis – Age-related changes in the gut microbiome

  12. Chronic Inflammation


Rapamycin: From Discovery to Longevity

Rapamycin, first discovered in soil samples from Easter Island, is a compound that inhibits mTOR (mechanistic target of rapamycin), a protein that regulates cell growth in response to nutrient availability. Initially used as an antifungal and later as an immunosuppressant for organ transplants, rapamycin's effects on longevity were discovered almost accidentally through genetic screening experiments.


Evidence from Animal Studies

Laboratory research has demonstrated that rapamycin consistently extends lifespan across different species:

  • Mice treated with rapamycin lived up to 30% longer, even when treatment started in middle age​d (1).

  • Functional improvements in multiple tissues (heart, brain, and immune system) were observed within just 4–8 weeks of treatment in aged mice​ (2).

  • In yeast, worms, and flies, rapamycin significantly extended lifespan, confirming its impact across evolutionary diverse species (3-5)​.

  • Alzheimer's Disease & Brain Health: Rapamycin has shown neuroprotective effects in animal models of Alzheimer's disease, leading to improved cognitive function and reduced neuroinflammation​ (6).

These findings have led to increased interest in translating rapamycin research to humans.


Rapamycin and Human Health

  • Alzheimer's Disease & Brain Health: A small human study indicated that ApoE4 carriers (a genetic risk factor for Alzheimer’s) experienced improved brain volume and cerebral blood flow after short-term rapamycin use. Larger clinical trials are needed to confirm these effects (7).


Ongoing Research

The Test of Rapamycin in Aging Dogs (TRIAD) is a notable ongoing study—a parallel-group, double-masked, randomized, placebo-controlled, multicenter trial—that aims to test the ability of rapamycin to prolong lifespan and improve healthspan metrics in healthy, middle-aged dogs (8). This study represents a significant effort to translate preclinical findings into potential clinical applications.


mTOR Modulators

While rapamycin is a powerful tool, lifestyle factors also influence mTOR activity. Fasting and reducing branched-chain amino acids (like leucine) naturally lower mTOR, mimicking some of rapamycin’s effects, but may have more risks than benefits.


Balancing Science and Practicality

Despite its promise, rapamycin's translation to human use is still evolving. Dr. Kaeberlein acknowledges the need for more clinical trials but personally takes the drug off-label. He believes the significant potential benefits outweigh the relatively low risks based on current data.


The Bigger Picture

Dr. Kaeberlein's work underscores that longevity science is evolving rapidly. While rapamycin shows immense promise, the path to wider adoption requires rigorous human trials. In the meantime, people can support their longevity by embracing evidence-based lifestyle habits that target the biology of aging.


Through his research, Dr. Kaeberlein inspires hope that science can unlock the secrets of aging, empowering people to live longer, healthier lives — and perhaps, one day, make interventions like rapamycin a cornerstone of healthy aging.


Dr. Matt Kaeberlein Instagram: optispanpodcast


References:

  1. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., Pahor, M., Javors, M. A., Fernandez, E., & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395. https://doi.org/10.1038/nature08221

  2. Bitto, A., Ito, T. K., Pineda, V. V., LeTexier, N. J., Huang, H. Z., Sutlief, E., Tung, H., Stangl, T. J., Yen, P. M., & Kaeberlein, M. (2016). Translational fidelity is a determinant of longevity in mammals. Nature Communications, 7(1), 11686. https://doi.org/10.1038/ncomms11686

  3. Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes & Development, 20(2), 174–184. https://doi.org/10.1101/gad.1381406​en.wikipedia.org

  4. Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A. L., Orosz, L., & Muller, F. (2003). Genetics: Influence of TOR kinase on lifespan in C. elegans. Nature, 426(6967), 620. https://doi.org/10.1038/426620a​

  5. Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., & Benzer, S. (2004). Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Current Biology, 14(10), 885–890. https://doi.org/10.1016/j.cub.2004.03.059

  6. Caccamo, A., Majumder, S., Richardson, A., Strong, R., & Oddo, S. (2010). Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: Effects on cognitive impairments. Journal of Biological Chemistry, 285(17), 13107–13120. https://doi.org/10.1074/jbc.M110.100420

  7. Flemister, A., Xing, X., Overschmidt, J., Cassani, J., Green, S. J., Beversdorf, D. Q., Woods, C., Grinstead, J. W., Altes, T. A., Lin, A., & Govindarajan, M. (2025). Short-term Sirolimus treatment restores hippocampus and caudate volumes and global cerebral blood flow in asymptomatic APOE4 carriers compared with non-carriers [Poster presentation]. Alzheimer's & Dementia: The Journal of the Alzheimer's Association, 20(S9). https://doi.org/10.1002/alz.094114​

  8. Kaeberlein, M., Creevy, K. E., & Promislow, D. E. L. (2024). The Test of Rapamycin in Aging Dogs (TRIAD): A randomized clinical trial. Aging Cell, 23(1), e13901. https://doi.org/10.1111/acel.13901

  9. Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Sahu, J., Kumar, D., Farmer, J., Kornfeld, J., & Barzilai, N. (2019). Topical rapamycin reduces markers of senescence and aging in human skin: An exploratory, prospective, randomized trial. Geroscience, 41(6), 861-869. https://doi.org/10.1007/s11357-019-00115-6

  10. Kraig, E., Flowers, A., Wortley, M., et al. (2024). Effects of weekly rapamycin on muscle function and exercise performance in older adults: A randomized controlled trial. The Journal of Gerontology: Medical Sciences, 79(2), 238-248. https://doi.org/10.1093/gerona/glaa015

  11. Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., Lonetto, M. A., Maecker, H. T., Kovarik, J., Carson, S., Glass, D. J., & Klickstein, L. (2014). mTOR inhibition improves immune function in the elderly. Science Translational Medicine, 6(268), 268ra179. https://doi.org/10.1126/scitranslmed.3009892

  12. Mannick, J. B., Morris, M., Hockey, H.-P., Roma, G., Beibel, M., Kulmatycki, K., Watkins, M., Moller, A., Drucker, J., & Glass, D. J. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. Science Translational Medicine, 10(449), eaaq1564. https://doi.org/10.1126/scitranslmed.aaq1564


Disclaimer: 

The information in this blog is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. All content, including text, graphics, images and information, contained on or available through this blog is for general information purposes only. Modrn med and Dr. Mary Pardee make no representation and assume no responsibility for the accuracy of information contained in or made available through this blog, and such information is subject to change without notice. This blog does not provide medical services, diagnosis or counsel. You are encouraged to confirm any information obtained from or through this email with other sources, and review all information regarding any medical condition or treatment with your physician. Never disregard professional medical advice or delay seeking medical treatment because of something you have read on or accessed through this information.


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