top of page

Resilience in Aging: Lessons from the Immune Systems of Centenarians

Updated: Dec 13, 2023




Netflix specials. New York Times pieces. And of course, numerous podcasts.


Why can’t the world stop talking about centenarians?


Sure, living to 100 years old is an utterly fascinating feat on its own. However, researchers and normal folks alike are more astounded by the fact that most centenarians escape age-related maladies [1]. Unlike most people who start accumulating chronic diseases by their 60s, centenarians exhibit what’s called morbidity compression, in which their bodies and minds serve them well for the vast majority of their lives. Then, a rapid onset of decline in functional status and organ reserve punctuates their well-spent time on this Earth.


That makes them living proof that extreme human longevity — the one where healthspan actually catches up to lifespan — is attainable. So while centenarian studies started almost a century and a half ago (fun fact: one of the subjects was purported to be 152 years old himself, which is unverifiable and highly unlikely) [2], scientists still have a lot more to uncover to bring us all to the centenarian promised land.


From nutrition to mental health, scientists have investigated centenarians’ lives from a myriad of angles. Today, we’ll be focusing on one factor recently theorized to help centenarians achieve exceptional longevity [3]. That would be their immunity; more specifically, their immune resilience.


Basic Immune System Refresher


The immune system, our body's frontline defender, is a complex network working tirelessly to keep us in top shape across three main functions [4]:


Innate Immunity


Picture it as the rapid-response team – always on standby to tackle any threat. White blood cells such as neutrophils and macrophages are the foot soldiers here, patrolling the body, identifying and engulfing foreign intruders.


Adaptive Immunity


The specialized forces – they remember past encounters and tailor responses for specific threats. Lymphocytes, particularly T cells and B cells, are the key players in this arena. T cells orchestrate targeted attacks on infected cells, while B cells produce antibodies, those nimble proteins that mark invaders for destruction. This adaptive system is the reason we don't succumb to the same infection twice.


Barrier Systems


Think of these as security checkpoints. Skin, our outermost layer, acts as a formidable barrier, preventing the entry of pathogens. Mucous membranes, like those in our respiratory and digestive tracts, are additional barriers, trapping intruders before they can cause trouble.


Our immune system doesn't just defend us from infections. It also protects us from cancer, makes sure the body can distinguish its cells from others’, and manages inflammation. Inflammation is the immune system's way of responding to insults. It involves increased blood flow and immune cell activity to eliminate harmful stimuli and promote healing.


Resilience: A Centenarian Miracle?


Credit: ESPN


One of the most remarkable centenarians alive is Fauja Singh, epically nicknamed the Turbaned Tornado, who’s known as the world’s first (and only so far) 100-year-old marathon runner.


Interestingly, when asked after one of those marathons about how he was able to complete the course at his age, he said [5]


"The first 20 miles are not difficult. As for the last six miles, I run while talking to God."

While we don’t know if Singh’s God talks back to him, what he was most likely experiencing during those last six miles is a phenomenon that’s perhaps as miraculous: resilience. 


An elusive biological quality, resilience reflects the body’s intrinsic capacity to bounce back against various stressors [6]. This resilience manifests itself in different systems in our bodies, and scientists recognize centenarians as general exemplars of resilience [7].


Most recently, researchers have started exploring the immune resilience of centenarians. Being immune-resilient means having the power, regardless of age, to manage inflammation and maintain or quickly recover immune activity in states of adversity [8]


During intense physical exertion, like running a marathon, the body undergoes significant stress. This stress triggers an inflammatory response, which in most people might lead to fatigue or illness. However, in individuals with high immune resilience, such as centenarians, the immune system can manage this inflammatory response effectively, preventing it from causing harm to the body. One of the ways it does so is by releasing a protein called Interleukin-13, which temporarily reprograms the metabolism of muscles to provide sustained energy [9]


So when we revisit Singh’s quote, we realize that the first bulk of the marathon might have been handled by his well-conditioned muscles and cardiovascular system as a marathoner. But, the last six miles could be where his immune resilience truly kicked in — championing him all the way to the finish line (and a sweet sponsorship deal with Adidas).


Centenarian Immune Resilience in Action


The epic of the Turbaned Tornado serves as our prelude to underscore the profound impact of immune resilience on centenarian longevity. Next up, we’ll dive right into the real-world studies

highlighting how the immune system protects centenarians against several age-related complications. 


Centenarians and COVID-19


Old age typically heightens susceptibility to severe COVID-19 outcomes [10]. However, centenarians, characterized by robust immune resilience, appear to be surprising outliers within this equation.


Researchers collected blood samples from centenarians who were residents in a long-term care facility and had been infected with or exposed to SARS-CoV-2, which causes COVID-19. They then tested these samples for the presence of antibodies specific to the SARS-CoV-2 spike protein that the virus uses to enter cells.


Amazingly, the study revealed that centenarians produce potent spike-specific antibodies that prevent the virus from infecting cells and spreading. Plus, these antibodies were still detectable in their blood 60 days after they were first diagnosed with COVID-19 [11].


Immune resilience against infections extends beyond COVID-19 as well, with more research suggesting that immune-resilient individuals show positive health outcomes against influenza, HIV, and sepsis [8].


Centenarians and Cancer 


Centenarian immune resilience seems to provide peculiar resistance to cancers [12]. On their mission to understand the mechanisms underlying this resistance, scientists have identified three main factors: inflammation, a hormone called IGF-1, and a protein called p53 [13].


IGF-1 is similar to insulin and plays a role in growth. However, it can also stimulate the growth of cancer cells. And p53 is a protein that helps prevent the growth of tumors, acting as a kind of security guard against cancer.


Researchers found that centenarians tend to have a unique combination of these factors. They have low responses to IGF-1, high levels of proteins that signal against inflammation, and well-functioning p53 responses. This unique combination could help protect them from cancer.


Centenarians and Inflammaging


Inflammaging, the chronic low-grade inflammation that’s associated with aging, has emerged as a buzzword in mainstream media for good reason. It’s a subtle, persistent condition that can contribute to age-related diseases over time and affect activities of daily living. Centenarians don't fret though.


Researchers have found that centenarians have a unique way of managing inflammaging. They discovered a special balance between two types of immune cells: T Helper 17 and Regulatory T Cells. Normally, T Helper 17 cells can promote inflammation, while Regulatory T Cells help control it.


In centenarians, there’s a higher proportion of Regulatory T Cells and a lower proportion of T Helper 17 cells. This balance helps them fend off inflammaging and is yet another testament to the impressive immune resilience of centenarians [14].


Centenarians and Autoimmune Diseases


Autoimmune diseases, where the body mistakenly attacks its own cells, increase in prevalence with age. But, there’s a twist (and you already get the gist of it by now). This trend isn't seen after the ninth decade of life, and centenarians are often protected from these conditions as well [15].


Scientists found that centenarians have fewer autoantibodies, proteins produced by the immune system that can target the body’s own tissues, including the thyroid and other organs. This suggests that their immune systems are better at distinguishing ‘self’ from ‘non-self’, preventing them from launching these harmful attacks. 


Interesting Implications of Centenarian Immune Resilience 


All that goes to show how pivotal immune resilience is to centenarian longevity. To quantify this effect and compare between different age groups, researchers at the Buck Institute developed the iAge clock. It utilizes deep learning to predict disease state, frailty, and longevity based on immune metrics [16].


Fascinatingly, the senior author of the publication where iAge was revealed said, "On average, centenarians have an immune age that is 40 years younger than what is considered normal.” [17] 


For readers with centenarian parents, great news awaits. Research on Sicilian centenarians suggests that centenarian immune resilience is passed on to offspring [18]


On a different note, scientists have also observed that immune resilience may have evolved more commonly in females [8]. This might be one of the explanations for females’ superior longevity over males.


Future Directions of Research


With all the crucial discoveries about longevity made possible via centenarian studies, more research is turning to supercentenarians, who live 110 years and above, to discover even more secrets behind extreme longevity.


On this mission, our good friends at LongeviQuest are playing an essential role. They keep track of the world’s supercentenarians, validate their ages, and bring together international researchers to foster collaborative breakthroughs in the field.


The Next Generation of Centenarians and Supercentenarians


All article long, we’ve discussed centenarians’ startling immune resilience which is just one part of their extraordinary longevity.


Now imagine how much longer they would live if they became more conscious about their health profiles. If they had all their health data in one place. And if they knew how to leverage this data to optimize their health. 


That’s exactly what we’re envisioning at Rejuve.AI with our Longevity App. 


The Longevity App empowers users by allowing them to input personal health details sourced from surveys, lab results, and wearables. Utilizing advanced AI, the app provides personalized health recommendations, guiding users and keeping them informed on their journey toward enhanced longevity. As a rewarding feature, users receive RJV tokens upon data submission, which can be redeemed for exclusive discounts on health-related products and services.


In essence, we’re supercharging the longevity of the next generation of centenarians and supercentenarians, very likely including you.



References:


[1] Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health Span Approximates Life Span Among Many Supercentenarians: Compression of Morbidity at the Approximate Limit of Life Span. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 67A(4), 395–405. https://doi.org/10.1093/gerona/glr223


[2] Humphry, G. M. (1887). Post-Mortem Examinations of Centenarians: With Remarks. BMJ, 1(1367), 564–565. https://doi.org/10.1136/bmj.1.1367.564


[3] Karagiannis, T. T., Dowrey, T. W., Villacorta-Martin, C., Montano, M., Reed, E., Belkina, A. C., Andersen, S. L., Perls, T. T., Monti, S., Murphy, G. J., & Sebastiani, P. (2023). Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity. EBioMedicine, 104514. https://doi.org/10.1016/j.ebiom.2023.104514


[4] Marshall, J. S., Warrington, R., Watson, W., & Kim, H. L. (2018). An Introduction to Immunology and Immunopathology. Allergy, Asthma & Clinical Immunology, 14(S2). https://doi.org/10.1186/s13223-018-0278-1


[5] Rana, V. (2004, April 19). At 93, Adidas Marathon man Fauja runs with god as partner. The Indian Express. http://www.indianexpress.com/oldStory/45350


[6] Windle, G. (2011). What Is Resilience? A Review and Concept Analysis. Reviews in Clinical Gerontology, 21(02), 152–169. https://doi.org/10.1017/s0959259810000420


[7] Borras, C., Ingles, M., Mas-Bargues, C., Dromant, M., Sanz-Ros, J., Román-Domínguez, A., Gimeno-Mallench, L., Gambini, J., & Viña, J. (2020). Centenarians: An excellent example of resilience for successful ageing. Mechanisms of Ageing and Development, 186, 111199. https://doi.org/10.1016/j.mad.2019.111199


[8] Ahuja, S. K., Manoharan, M. S., Lee, G. C., McKinnon, L. R., Meunier, J. A., Steri, M., Harper, N., Fiorillo, E., Smith, A. M., Restrepo, M. I., Branum, A. P., Bottomley, M. J., Orrù, V., Jimenez, F., Carrillo, A., Pandranki, L., Winter, C. A., Winter, L. A., Gaitan, A. A., & Moreira, A. G. (2023). Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Nature Communications, 14(1), 3286. https://doi.org/10.1038/s41467-023-38238-6


[9] Knudsen, N. H., Stanya, K. J., Hyde, A. L., Chalom, M. M., Alexander, R. S., Liou, Y.-H., Starost, K. A., Gangl, M. R., Jacobi, D., Liu, S., Sopariwala, D. H., Diogo Fonseca-Pereira, Li, J., Hu, F. B., Garrett, W. S., Narkar, V. A., Ortlund, E. A., Kim, J. H., Paton, C. M., & Cooper, J. A. (2020). Interleukin-13 drives metabolic conditioning of muscle to endurance exercise. Science, 368(6490). https://doi.org/10.1126/science.aat3987


[10] Chen, Y., Klein, S. L., Garibaldi, B. T., Li, H., Wu, C., Osevala, N. M., Li, T., Margolick, J. B., Pawelec, G., & Leng, S. X. (2021). Aging in COVID-19: Vulnerability, immunity and intervention. Ageing Research Reviews, 65, 101205. https://doi.org/10.1016/j.arr.2020.101205


[11] Foley, M. K., Searle, S. D., Toloue, A., Booth, R., Falkenham, A., Falzarano, D., Rubino, S., Francis, M. E., McNeil, M., Richardson, C., LeBlanc, J., Oldford, S., Gerdts, V., Andrew, M. K., McNeil, S. A., Clarke, B., Rockwood, K., Kelvin, D. J., & Kelvin, A. A. (2021). Centenarians and extremely old people living with frailty can elicit durable SARS-CoV-2 spike specific IgG antibodies with virus neutralization functions following virus infection as determined by serological study. EClinicalMedicine, 37, 100975. https://doi.org/10.1016/j.eclinm.2021.100975


[12] CARUSO, C. (2004). Aging, Longevity, Inflammation, and Cancer. Annals of the New York Academy of Sciences, 1028(1), 1–13. https://doi.org/10.1196/annals.1322.001


[13] Salvioli, S., Capri, M., Bucci, L., Lanni, C., Racchi, M., Uberti, D., Memo, M., Mari, D., Govoni, S., & Franceschi, C. (2009). Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunology, Immunotherapy, 58(12), 1909–1917. https://doi.org/10.1007/s00262-008-0639-6


[14] Zhou, L., Ge, M., Zhang, Y., Wu, X., Leng, M., Gan, C., Mou, Y., Zhou, J., Valencia, C. A., Hao, Q., Zhu, B., Dong, B., & Dong, B. (2022). Centenarians Alleviate Inflammaging by Changing the Ratio and Secretory Phenotypes of T Helper 17 and Regulatory T Cells. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.877709


[15] Mariotti, S., Barbesino, G., Caturegli, P., Giacomelli, T., Pinchera, A., Monti, D., Cossarizza, A., Franceschi, C., Sansoni, P., Passeri, G., & Fagiolo, U. (1992). Thyroid and other organ-specific autoantibodies in healthy ceritenarians. The Lancet, 339(8808), 1506–1508. https://doi.org/10.1016/0140-6736(92)91265-a


[16] Sayed, N., Huang, Y., Nguyen, K., Krejciova-Rajaniemi, Z., Grawe, A. P., Gao, T., Tibshirani, R., Hastie, T., Alpert, A., Cui, L., Kuznetsova, T., Rosenberg-Hasson, Y., Ostan, R., Monti, D., Lehallier, B., Shen-Orr, S. S., Maecker, H. T., Dekker, C. L., Wyss-Coray, T., & Franceschi, C. (2021). An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nature Aging, 1(7), 598–615. https://doi.org/10.1038/s43587-021-00082-y


[17] BUCK INSTITUTE FOR RESEARCH ON AGING. (2021, July 12). First actionable clock that predicts immunological health and chronic diseases of aging. EurekAlert! https://www.eurekalert.org/news-releases/556749


[18] Rubino, G., Bulati, M., Aiello, A., Aprile, S., Gambino, C. M., Gervasi, F., Caruso, C., & Accardi, G. (2018). Sicilian centenarian offspring are more resistant to immune ageing. Aging Clinical and Experimental Research, 31(1), 125–133. https://doi.org/10.1007/s40520-018-0936-7




Comments


bottom of page