Aging vs. Cancer: Lifespan Constraints and Tradeoffs
Does avoiding cancer explain most of what happens in aging?
A new perspective article in the journal Nature Reviews looks at the evolutionary tradeoffs between cancer and aging. The author, João Pedro de Magalhães, explains his theory that the lifespan of species is under constraints imposed by the need to reduce cancer risk.
In other words, the mechanisms in place for preventing cancer may be what drives aging and limits lifespan. Essentially, natural selection favors cancer resistance such that tumor suppression during the reproductive years is prioritized over maintaining health and cell growth during later years. 1
The paper gives a few examples of trade-off mechanisms, including:
Telomere shortening - this limits how many times cells can divide, and thus prevents out-of-control growth in cancer. However, this also limits a cell’s regenerative capacity.
Cellular senescence - permanently stopping damaged cells from dividing is another cancer prevention mechanism. But the tradeoff is that excess cellular senescence contributes to inflammaging and organ dysfunction.
Tumor suppresor pathways - while good for suppressing cancer, they also can limit the ability to regenerate tissue in aging
What about long-lived species? How do they escape these constraints?
The bowhead whale is one of the largest animals on earth, and it has a maximum lifespan of more than 200 years. That’s a lot of cells that divide for a long time.
However, the bowhead whale doesn’t often get cancer, and a new study in Nature explains why: they have “enhanced DNA double-strand break repair capacity and fidelity”. This means that DNA mutations are fixed before they can cause cancer. CIRBP (cold inducible RNA binding protein), a protein abundant in whales and dolphins, seems to be key to the whales’ ability to repair their DNA. This prevention of mutation mechanism for longevity is different than other long-lived animals that rely on increased tumor suppressors to kill off cancer cells.
Humans also have CIRBP, but it is mainly activated as a stress response protein activated by mild hypothermia or hypoxia.2 Bowhead whales live in the cold Arctic waters, which may be why this adaptation has developed in them.
My thoughts:
Studies on long-lived animals and the theoretical ideas behind lifespan constraints are interesting, but for me, it comes down to how this applies to my goal of staying healthy in aging.
As I dig into the realistic changes that I can make to reduce the ravages of time, I often do weigh the tradeoffs — the risk of cancer vs. the benefits of a supplement or medication.
Here are a few examples of common supplements that I perceive to have tradeoffs:
Hormone replacement therapy- There are undeniable positive effects of HRT in perimenopause and menopause. I know women who claim it to be life-changing for them. However, estrogen promotes growth. As a hormone, its role is to turn on genes for transcription, many of which are related to cell growth. Some studies show that HRT increases the risk for ovarian and breast cancer, while decreasing the risk for liver and colon cancer.34
Folic acid, folate, methylfolate - A number of studies show that natural folate intake and/or folic acid is good for heart health and overall cellular function. But folate is also used by cells for growth, and folic acid and folate are linked to an increased risk of colon cancer and polyps in the colon. Higher folate intake in areas with nitrates in the drinking water also increases breast cancer risk. An excess may not be a good idea.567
Beta carotene - Carrot juice is tasty, but supplemental beta-carotene has been shown in phase II and phase III clinical trials to increase the risk of lung cancer and stomach cancer. It is also associated with increased overall mortality. Again, excess may not be a good idea.8
Peptides that promote growth - This gets a little murkier. A lot of peptides that have good results in animal studies can also promote tumor growth. However, that isn’t always a good indication that the same will happen in humans. But without solid, long-term human studies, I’m left with a lot of questions. 910
I’m sure there are other examples as well — share them in the comments if you know of any.
Where does this leave me?
It’s long been apparent that there’s a balance between youthful, growth-promoting substances and avoiding cancer growth. Animal studies are not always a good model for this, since everything seems to cause tumor growth in mice. My personal precautionary principle is to err on the side of caution - or to cycle supplements so that I’m not taking them for the long term.
I’m going to dive into the research on DNA repair soon and look at how to move the needle there. A new study in mice showed that increasing FOXO3A increased DNA repair activity as well as a 30% increase in median and maximum lifespan.11 In humans, FOXO3A gene variants are linked to increased odds of living to an older age. So… stay tuned for more on this topic!
De Magalhães, João Pedro. “The Evolution of Cancer and Ageing: A History of Constraint.” Nature Reviews Cancer, vol. 25, no. 11, Nov. 2025, pp. 873–80. www.nature.com, https://doi.org/10.1038/s41568-025-00861-4. https://www.nature.com/articles/s41568-025-00861-4
Zhu, Xiaozheng, et al. “Cold-Inducible RNA Binding Protein Alleviates Iron Overload-Induced Neural Ferroptosis under Perinatal Hypoxia Insult.” Cell Death & Differentiation, vol. 31, no. 4, Apr. 2024, pp. 524–39. www.nature.com, https://doi.org/10.1038/s41418-024-01265-x. https://www.nature.com/articles/s41418-024-01265-x
Huntley, Catherine, et al. “Breast Cancer Risk Assessment for Prescription of Menopausal Hormone Therapy in Women with a Family History of Breast Cancer: An Epidemiological Modelling Study.” The British Journal of General Practice: The Journal of the Royal College of General Practitioners, vol. 74, no. 746, Sep. 2024, pp. e610–18. PubMed, https://doi.org/10.3399/BJGP.2023.0327. https://pubmed.ncbi.nlm.nih.gov/38724186/
Simin, Johanna, et al. “Menopausal Hormone Therapy and Cancer Risk: An Overestimated Risk?” European Journal of Cancer (Oxford, England: 1990), vol. 84, Oct. 2017, pp. 60–68. PubMed, https://doi.org/10.1016/j.ejca.2017.07.012.
Inoue-Choi, Maki, et al. “Interaction of Nitrate and Folate on the Risk of Breast Cancer among Postmenopausal Women.” Nutrition and Cancer, vol. 64, no. 5, Jul. 2012, pp. 685–94. PubMed Central, https://doi.org/10.1080/01635581.2012.687427. https://pmc.ncbi.nlm.nih.gov/articles/PMC3403733/
Rees, Judy R, et al. “Unmetabolized Folic Acid, Tetrahydrofolate and Colorectal Adenoma Risk.” Cancer Prevention Research (Philadelphia, Pa.), vol. 10, no. 8, Aug. 2017, pp. 451–58. PubMed Central, https://doi.org/10.1158/1940-6207.CAPR-16-0278. https://pmc.ncbi.nlm.nih.gov/articles/PMC5544920/
Cole, Bernard F., et al. “Folic Acid for the Prevention of Colorectal Adenomas: A Randomized Clinical Trial.” JAMA, vol. 297, no. 21, Jun. 2007, p. 2351. DOI.org (Crossref), https://doi.org/10.1001/jama.297.21.2351. https://jamanetwork.com/journals/jama/fullarticle/207344
Harvie, Michelle. “Nutritional Supplements and Cancer: Potential Benefits and Proven Harms.” American Society of Clinical Oncology Educational Book. American Society of Clinical Oncology. Annual Meeting, 2014, pp. e478-486. PubMed, https://doi.org/10.14694/EdBook_AM.2014.34.e478. https://pubmed.ncbi.nlm.nih.gov/24857143/
Stepień, Tomasz, et al. “Stimulatory Effect of Growth Hormone-Releasing Hormone (GHRH(1-29)NH2) on the Proliferation, VEGF and Chromogranin A Secretion by Human Neuroendocrine Tumor Cell Line NCI-H727 in Vitro.” Neuropeptides, vol. 43, no. 5, Oct. 2009, pp. 397–400. PubMed, https://doi.org/10.1016/j.npep.2009.08.005. https://pubmed.ncbi.nlm.nih.gov/19747727/
Boguszewski, Cesar Luiz, and Margaret Cristina da Silva Boguszewski. “Growth Hormone’s Links to Cancer.” Endocrine Reviews, vol. 40, no. 2, Apr. 2019, pp. 558–74. PubMed, https://doi.org/10.1210/er.2018-00166. https://pubmed.ncbi.nlm.nih.gov/30500870/
Inci, Gozde, et al. “FOXO3a Upregulates DNA Repair Activities by Transcriptional Activation of Target Genes and Provides the Resistance to Gamma Radiation and the Extension of Lifespan in Mouse.” Biogerontology, vol. 26, no. 6, Oct. 2025, p. 196. Springer Link, https://doi.org/10.1007/s10522-025-10341-9. https://link.springer.com/article/10.1007/s10522-025-10341-9
Have you seen these types of findings for fasting? Specifically the 5-day fasting mimicking diet? I just read a book on FMD benefits and cancer, but there’s also research on longevity so I’m wondering if it truly helps with both or if there’s research I’m missing. Thank you!