Resilience in Aging: Salutogenesis

Promoting immune resilience as a core principle for health

Have you noticed when reading about aging research that everything seems to focus on diseases?

Salutogenesis is a framework that looks at health from the point of view of mechanisms that sustain health rather than a disease-focused approach. Salutogenesis comes from the Latin word for health, salus, and the Greek genesis (origin) — so a literal translation would be the origin of health.

Traditional research on longevity and health typically focuses on disease mechanisms. In my articles about personalized health on Genetic Lifehacks, the focus is primarily on disease and prevention, often framed as avoiding the negative effects of a gene variant. Interestingly, many of the common genetic variants that increase susceptibility to certain chronic diseases often also have a tradeoff - a positive benefit in another situation.

A constant focus on the disease side of the picture takes away from what can be learned from research on the positive side of health and resiliency.

Health is more than the absence of disease.

Salutogenesis and longevity:

What does salutogenesis mean in the field of aging? Or, to reframe that question, how can looking at the mechanisms that sustain health help to extend healthspan and lifespan?

The hallmarks of aging include fundamental causes of cellular damage or dysfunction, such as DNA damage, telomere shortening, mitochondrial dysfunction, excess cellular senescence, chronic inflammation, epigenetic changes, misfolded proteins, and stem cell exhaustion.¹ It’s all about the decline of function at the cellular level — working backwards from disease to cause instead of working forwards from health to resiliency pathways.

Salutogenesis instead looks at the underlying systems that give us resilience to the cellular insults thrown at us each day.

Immune resilience as the foundation:

Some researchers posit that immune resilience is the foundation of health, and when it breaks down (often around age 70), we have the downhill slope of old age.

Here’s a graphical abstract from a recent article Aging Cell to illustrate the changes that happen in immune resilience and how it affects salutogenesis:

Salutogenesis- as framed around immune resilience in aging. Screenshot from https://onlinelibrary.wiley.com/doi/10.1111/acel.70089

The core idea here is that immune resilience means having a maximal immune system response to environmental stressors (toxins, pathogens, air pollution, etc.) while minimizing damage from excess inflammation and senescent cell accumulation.

An imbalanced inflammatory response - whether due to a lack of resolution of inflammation or to an overactivation - is what will end up killing most of us. Most chronic diseases, such as heart disease, diabetes, and Alzheimer’s, are rooted in chronic inflammation. Plus, dying of the flu, pneumonia, Covid, or sepsis involves an excessive immune response.

Researchers have tried to quantify and identify the processes that promote immune resilience.

A June 2023 study in Nature Communications² by Ahuja, et al. explored the biomarkers of immune resilience. They looked at metrics in over 48,000 individuals, including centenarians and populations with HIV or autoimmune diseases. They found that the people who resisted the degradation of immune resilience had lower rates of infection (flu, HIV), lower rates of recurrent skin cancer, survival of Covid and sepsis, and extended lifespan.

The authors of the study explain that the lower immune status observed with age can be due to excess cellular senescence and “incomplete/unsuccessful immune allostasis”. Allostasis refers to restoring a stable immune response after a stressor or challenge — e.g., neither an overactive immune system (autoimmune disease, allergies) nor an underactive, immunocompromised response (HIV, chronic infections).

Measuring immune resilience

To understand how immune resilience affects longevity, the researchers looked at specific, measurable markers.

T cell balance:
One measure of immune resilience is the ratio of CD8⁺ to CD4⁺ T cells. CD8⁺ T cells are the killer T cells that eliminate infected cells and cancer cells. CD4⁺ T cells are helper cells that play multiple roles in immune response, including memory of prior infections. Ideal seems to be a 1:1 ratio. A low CD4:CD8 ratio indicates depleted CD4⁺ T cells, such as in AIDS, while a high CD4:CD8 ratio could mean cancer or ongoing infection. There’s more to it than just the simple ratio, which you can dig into in the study if you’re interested.

Essentially, chronic antigenic stimulation causes a decrease in immune resilience. Chronic antigenic stimulation is the prolonged exposure of the immune system to the same antigen, which causes T cell exhaustion. AIDS, organ transplant, persistent infections, autoimmune diseases, chronic Lyme, and possibly long Covid, are examples.³

Gene expression of the immune gene:
Another measure of immune resilience involved gene expression of specific immune system-related genes. The researchers identified CCR7, IL7R, C5AR1, and MYD88 expression as important. CCR7 is involved in how immune cells migrate to the lymph nodes, while IL7R is the receptor for IL-7 found on immune cells and essential to the survival of T cells and B cells, as well as the development of T cells in the thymus. MYD88 is integral to signaling for the response to infections, as well as how the immune system recognizes certain types of cancer.

2025 study: TCF7 as a key
A new study in Aging Cell by Manoharan, et al. identified TCF7 as a key to immune resilience. The researchers (funded by the VA, NIH, and DOD) looked at over 17,000 people of various ages and examined 1380 transcription factors as well as the balance between CD8⁺ and CD4⁺ T cells. They found that optimal TCF7 is the key to maintaining the regeneration of T cells.

Individuals with low levels of immune resilience at age 40 were at an equivalent mortality rate to someone at age 56 with high immune resilience. That’s a big difference! Optimal immune resilience reduced cardiovascular disease, Alzheimer's, and serious infections.

The TCF7 gene encodes a transcription regulator, which is involved in T-cell differentiation and stemness. It’s also involved in a lot of other pathways in the body, making it an interesting topic of research on cancer, metabolism, aging, and more.

The authors of the study propose: “a new paradigm in aging research that distinguishes between treating age-related diseases and modifying the aging process itself through IR-associated salutogenic mechanisms.”

OK, so the research focus needs to shift, but how can this be applied today?

Practical applications in middle age to preserve immune resilience

The study in Aging Cell (Manoharan, et al.) went on to identify factors that cause the degradation of immune resilience, with one key being inflammatory stress.

Inflammatory stress included chronic infections (e.g., TB, malaria), autoimmune diseases (lupus), genetic immunodeficiency, and metabolic syndrome. So avoid chronic infections (periodontal disease?), don’t get autoimmune diseases, and stay metabolically healthy (eat well, exercise).

The drug target that the researchers found to have the most potential was TNF-alpha blockers.

Blocking excess TNF with medications, such as Humira or Enbrel, is a foundation of many autoimmune disease treatment plans. However, most of us aren’t going to be prescribed these biologics.

The other option for blocking excess TNF activation is by using natural supplements that research shows can reduce TNF levels.

Natural TNF-alpha inhibitors:

There are a bunch of natural supplements that can reduce excessive TNF levels.

Precautions: If you’re on a prescription medication, be sure to talk with your doctor and check for interactions before taking any supplements. Also, if you have genetic data, be sure to check your COMT function before going all in on luteolin and curcumin.

• Luteolin: Luteolin supplements have been shown to decrease elevated TNF levels significantly.⁴⁵

• Hesperidin: A natural flavonoid from citrus fruits, hesperidin (hesperitin) inhibits the release of TNF-alpha.⁶

• Rosmarinic acid: Found in rosemary, basil, holy basil, Tulsi tea, lemon balm, and perilla oil, rosmarinic acid is a natural TNF-alpha inhibitor.⁷

• Curcumin: A component of the spice turmeric, curcumin is a natural TNF-alpha inhibitor.⁸

• Resveratrol: Another natural flavonoid, resveratrol has also been shown in studies to decrease TNF. ⁹¹⁰

• Probiotics: Probiotics containing Bifidobacteria or Lactobacillus may decrease TNF-alpha levels.¹¹ Specifically: B. adolescentis, Bifidobacterium breve BR03, and Lactobacillus Plantarum ¹²¹³¹⁴

• Aged garlic extract has been shown in a study to decrease TNF-alpha levels by 35%.¹⁵[ref][ref] You can find aged black garlic at grocery stores, and it is available as a supplement online if you don’t like the taste of aged garlic.

While not discussed in the studies on salutogenesis, I wanted to also point out again that the resolution of inflammation is an active process that depends on having sufficient DHA and EPA in order to synthesize pro-resolving mediators when needed.

Conclusion:

The paradigm shift of salutogenesis and a focus on immune resilience seem foundational for longevity research. It resonates with me from both a common-sense point of view and also an evolutionary/systems framework.

Tamping down excessive inflammation by targeting TNF (or NLRP3) is something that is likely beneficial in multiple ways, in multiple situations. It tracks with traditional research on inflammaging and adds more context to it.

What I have a harder time wrapping my brain around is how to balance CD4:CD8 T cells, which neither study addressed. Sounds like a topic that I need to explore more in a future article! Stay tuned.

1. López-Otín, Carlos, et al. “Hallmarks of Aging: An Expanding Universe.” Cell, vol. 186, no. 2, Jan. 2023, pp. 243–78. ScienceDirect, https://doi.org/10.1016/j.cell.2022.11.001. https://www.sciencedirect.com/science/article/pii/S0092867422013770

2. Ahuja, Sunil K., et al. “Immune Resilience despite Inflammatory Stress Promotes Longevity and Favorable Health Outcomes Including Resistance to Infection.” Nature Communications, vol. 14, no. 1, Jun. 2023, p. 3286. www.nature.com, https://doi.org/10.1038/s41467-023-38238-6. https://www.nature.com/articles/s41467-023-38238-6

3. Ahmed, Rafi, et al. “Regulation of T and B Cell Responses to Chronic Antigenic Stimulation during Infection, Autoimmunity and Transplantation.” Immunological Reviews, vol. 292, no. 1, Nov. 2019, pp. 5–8. DOI.org (Crossref), https://doi.org/10.1111/imr.12836. https://onlinelibrary.wiley.com/doi/10.1111/imr.12836

4. Gendrisch, Fabian, et al. “Luteolin as a Modulator of Skin Aging and Inflammation.” BioFactors (Oxford, England), vol. 47, no. 2, Mar. 2021, pp. 170–80. PubMed, https://doi.org/10.1002/biof.1699. https://pubmed.ncbi.nlm.nih.gov/33368702/

5. Tsilioni, I., et al. “Children with Autism Spectrum Disorders, Who Improved with a Luteolin-Containing Dietary Formulation, Show Reduced Serum Levels of TNF and IL-6.” Translational Psychiatry, vol. 5, no. 9, Sep. 2015, p. e647. PubMed Central, https://doi.org/10.1038/tp.2015.142. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545641/

6. Yari, Zahra, et al. “The Effect of Hesperidin Supplementation on Metabolic Profiles in Patients with Metabolic Syndrome: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.” European Journal of Nutrition, vol. 59, no. 6, Sep. 2020, pp. 2569–77. PubMed, https://doi.org/10.1007/s00394-019-02105-2. https://pubmed.ncbi.nlm.nih.gov/31844967/

7. Rui, Yehua, et al. “Rosmarinic Acid Suppresses Adipogenesis, Lipolysis in 3T3-L1 Adipocytes, Lipopolysaccharide-Stimulated Tumor Necrosis Factor-α Secretion in Macrophages, and Inflammatory Mediators in 3T3-L1 Adipocytes.” Food & Nutrition Research, vol. 61, no. 1, 2017, p. 1330096. PubMed, https://doi.org/10.1080/16546628.2017.1330096. https://www.ncbi.nlm.nih.gov/pubmed/28659738

8. Shao, Nan, et al. “Curcumin Improves Treatment Outcome of Takayasu Arteritis Patients by Reducing TNF-α: A Randomized Placebo-Controlled Double-Blind Clinical Trial.” Immunologic Research, vol. 65, no. 4, Aug. 2017, pp. 969–74. PubMed, https://doi.org/10.1007/s12026-017-8917-z. https://www.ncbi.nlm.nih.gov/pubmed/28349250

9. Csiszar, Anna, et al. “Vasoprotective Effects of Resveratrol and SIRT1: Attenuation of Cigarette Smoke-Induced Oxidative Stress and Proinflammatory Phenotypic Alterations.” American Journal of Physiology. Heart and Circulatory Physiology, vol. 294, no. 6, Jun. 2008, pp. H2721–35. PubMed Central, https://doi.org/10.1152/ajpheart.00235.2008. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2551743/

10. Csiszar, Anna, et al. “Resveratrol Attenuates TNF-Alpha-Induced Activation of Coronary Arterial Endothelial Cells: Role of NF-kappaB Inhibition.” American Journal of Physiology. Heart and Circulatory Physiology, vol. 291, no. 4, Oct. 2006, pp. H1694-1699. PubMed, https://doi.org/10.1152/ajpheart.00340.2006. https://pubmed.ncbi.nlm.nih.gov/16973825/

11. Zaharuddin, Liyana, et al. “A Randomized Double-Blind Placebo-Controlled Trial of Probiotics in Post-Surgical Colorectal Cancer.” BMC Gastroenterology, vol. 19, no. 1, Jul. 2019, p. 131. PubMed, https://doi.org/10.1186/s12876-019-1047-4. https://www.ncbi.nlm.nih.gov/pubmed/31340751

12. Guo, Ying, et al. “Prophylactic Effects of Bifidobacterium Adolescentis on Anxiety and Depression-Like Phenotypes After Chronic Stress: A Role of the Gut Microbiota-Inflammation Axis.” Frontiers in Behavioral Neuroscience, vol. 13, 2019, p. 126. PubMed, https://doi.org/10.3389/fnbeh.2019.00126. https://www.ncbi.nlm.nih.gov/pubmed/31275120

13. Klemenak, Martina, et al. “Administration of Bifidobacterium Breve Decreases the Production of TNF-α in Children with Celiac Disease.” Digestive Diseases and Sciences, vol. 60, no. 11, Nov. 2015, pp. 3386–92. PubMed, https://doi.org/10.1007/s10620-015-3769-7. https://www.ncbi.nlm.nih.gov/pubmed/26134988

14. Nam, Bora, et al. “Lactobacillus Plantarum HY7714 Restores TNF-α Induced Defects on Tight Junctions.” Preventive Nutrition and Food Science, vol. 24, no. 1, Mar. 2019, pp. 64–69. PubMed, https://doi.org/10.3746/pnf.2019.24.1.64. https://www.ncbi.nlm.nih.gov/pubmed/31008098

15. Morihara, Naoaki, et al. “Aged Garlic Extract Suppresses the Development of Atherosclerosis in Apolipoprotein E-Knockout Mice.” The Journal of Nutrition, vol. 146, no. 2, Feb. 2016, pp. 460S-463S. PubMed, https://doi.org/10.3945/jn.114.206953. https://www.ncbi.nlm.nih.gov/pubmed/26764329