Written and Illustrated by Karissa Jade Muñoz, Ph.D.
A healthy immune system: the ultimate balancing act
Our immune system is the foundation of our health. It is the intricate network of cells, tissues, and their secretions that help the body fight illness and infection. The immune system is comprised of two major branches, the innate and the adaptive immune responses, both of which are crucial in maintaining our health. The innate immune response is the first line of defense that immediately works to prevent the spread of pathogens and tumors.1 The adaptive immune response is a more sophisticated, secondary response that is highly specialized for clearance of specific pathogens and can provide long-lasting immunity against these microscopic invaders.2
The efficacy of these two systems depends on a well-balanced inflammatory and anti-inflammatory response. This balance is often referred to as “immunomodulation.” For example, upon injury or infection, macrophages of the innate immune system phagocytose, or engulf, damaged tissue and foreign pathogens while simultaneously secreting molecules that promote inflammation. The pro-inflammatory molecules facilitate the dilation of blood vessels and the migration of other immune cells to the damaged site. While inflammation is initially beneficial, once the infection is cleared, it is important for the immune system to mount an anti-inflammatory reparatory response.
Age-dependent immune dysregulation
As people age, they are more likely to develop a sickness or a life-threatening disease, but why? When people get older, so does their immune system, meaning it doesn’t always function as effectively as it used to. With age, the contrast between inflammatory and anti-inflammatory response is lost, in the favor of low-level, chronic inflammation that is not conducive to repair or regeneration. In fact, immune dysfunction is at the root of many age-related diseases.3
Aging results in a time-dependent accumulation of molecular and cellular damage to our body, including our immune cells. It is identified as immune senescence, in which immune cells no longer respond appropriately to the complex regulatory signals of their environment; thereby causing an imbalance of inflammatory and anti-inflammatory responses.3 A balanced immune system keeps illness at bay, meaning immune dysregulation increases our vulnerability to age-associated disorders.4
The main manifestation of immune senescence is inflammaging, the chronic accumulation of low-grade inflammation from an injury, infection or tumor. Inflammaging results in the production and release of toxic cellular secretions that can affect local and distant organs.4 Due to the persistence of damage signals, additional inflammatory cells are recruited in a positive feedback loop. This hostile extracellular environment contributes to excessive cellular damage throughout the body and contributes to the progressive exhaustion of the immune system.
Age-related muscle atrophy, or sarcopenia, occurs in 100% of individuals and is exacerbated by inflammaging.5 The immune cells that once repaired the everyday wear and tear of muscle tissue no longer maintain these restorative functions later in life. Additionally, almost all age-related diseases such as arthritis, Alzheimer’s, atherosclerosis, diabetes, sarcopenia and cancer have an immune deterministic component, suggesting that preserving immune system function may prevent all age-dependent diseases.6
The secrets of the secretome
The secretome is the total set of substances secreted by a cell and includes proteins, lipids, growth factors, chemokines, cytokines, exosomes and microvesicles.7 The secretome provides the essential stimulation and interaction between cells when resolving an infection. It alleviates cellular damage by sending “danger” and “help” signals. However, defining the specific secretome factors that combat disease remains a challenge.8
The nature and composition of a secretome is highly complex and dependent on the environmental conditions and cell type,9 meaning not all secretomes are the same. Regenerative niches containing stem cells such as mesenchymal stem cells (MSCs) and multi/pluripotent stem cells produce secretomes that demonstrate anti-inflammatory, anti-apoptotic and immunomodulatory properties. Tissues that contain cells that have already become specialized and committed to a particular biological function such as a retinal cell, or in which the regenerative cells are lost, are less likely to provide these same benefits.
As we age, not only do we lose the capacity to efficiently produce new stem cells, but we also lose the benefits of their secretome. One approach is to replenish tissues in need with regenerative stem cells. However, the practical implementation of such therapies faces a long history of challenges such as manufacturing, tumorigenicity and allogeneic incompatibility.10
The secretome is being studied as an alternative therapeutic approach to stem cells because the secretome contains components suggested to be involved in the regeneration, maintenance and differentiation of resident stem cells.11 Thus, it is the secreted bioactive molecules, and not the stem cells themselves, that would yield the immediate therapeutic benefits, and potentially restore the regenerative stem cell niche long-term. In fact, the number of research publications highlighting secretome therapies from partially differentiated stem cells has been on the rise since 2009 because of its advantages over stem cell treatment.12 Secretome-based therapies provide a natural, cell-free method to combating disease, thereby minimizing the risk of immune system rejection and avoiding tumorgenicity. Other advantages are the ease of manufacturing and scalability for mass production, making secretomes off-the-shelf-ready therapies.10Similarly, producing a secretome is more cost-effective than growing large numbers of stem cells for a particular treatment. Lastly, the secretome has multiple methods of administration including (ie injections, topical, inhalation), providing versatile treatment applications.10 The secretome from stem cell derivatives provides incredible therapeutic advantages over traditional stem cell-based therapies and offers another treatment option in the field of biomedicine.
Immune balance via the secretome
Our immune system is the most critical determinant of our health, affecting our susceptibility to disease and ultimately, quality of life as we age. But how do we regulate our immune system function to circumvent its demise?
Immunomodulation is the use of compounds to either activate or inactivate specific immune cell responses. Believe it or not, immunomodulators exist all around us. Chances are you’ve consumed immunomodulators in your coffee if you added milk. Vitamin D has been shown to increase the phagocytic ability of innate immune cells and produce anti-inflammatory effects.13 Chronic conditions with higher levels of inflammation such as diabetes, asthma, and rheumatoid arthritis are all associated with vitamin D deficiency, suggesting the importance of specific immunomodulators in preventing disease. Ever taken an aspirin? Research suggests that low-dose aspirin can decrease inflammatory markers like NF-kB in the blood. Thus, immunomodulators like aspirin may help lower the risk of inflammatory-associated diseases such as heart disease and type 2 diabetes.14–16
Evidence suggests that the secretome is also involved in immunomodulation, which may make it an effective therapeutic for autoimmune diseases, neurodegenerative diseases and sarcopenia.17,18 As mentioned, all humans develop sarcopenia with age, which significantly impairs mobility and compromises quality of life. Mitigating muscle loss and improving muscle recovery are currently unfulfilled medical needs. Preclinical data using Immunis’ investigational secretome product from partially differentiated stem cells demonstrated immunomodulatory and regenerative capabilities. In aged mouse-models of muscle disuse and atrophy, not only did Immunis’ investigational secretome increase the number of muscle stem cells, enhance muscle size and elevate the frequency of reparatory immune cells, but it also improved muscle strength in aged mouse models for disuse atrophy.19 Immunis is currently conducting an FDA-approved Phase 1/2a clinical trial in aged patients with osteoarthritis-related muscle deterioration to research the safety and tolerability of the investigational treatment.20 Companies like Immunis are paving the way for addressing inevitable, age-related diseases that are currently untreatable.
There is no doubt that the secretome is a powerful tool in biomedicine that has endless potential. Future studies of the secretome will likely attempt to pinpoint the components that are most effective for immune system health and for preventing disease. However, it has become increasingly clear that a single target approach may be insufficient in restoring the complex balance of the immune system. A multi-target secretome has a greater opportunity for success in that there are numerous beneficial factors to address specific needs. Currently, partially differentiated stem cells provide the optimal factory of such multi-target drugs at physiologically relevant concentrations to maintain a healthy immune system and potentially a healthy lifespan.
In understanding that a well-functioning immune system is necessary for our health and that secretomes can refine immune cell responses, the immunomodulatory power of the secretome can drastically reduce susceptibility to disease.
Perhaps the secret to longevity is…the secretome.
(1) Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. Innate Immunity. Mol. Biol. Cell 4th Ed.2002.
(2) Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. The Adaptive Immune System. Mol. Biol. Cell 4th Ed. 2002.
(3) Isobe, K.; Nishio, N.; Hasegawa, T. Immunological Aspects of Age-Related Diseases. World J. Biol. Chem.2017, 8 (2), 129–137. https://doi.org/10.4331/wjbc.v8.i2.129.
(4) Fulop, T.; Larbi, A.; Dupuis, G.; Le Page, A.; Frost, E. H.; Cohen, A. A.; Witkowski, J. M.; Franceschi, C. Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front. Immunol. 2018, 8.
(5) Liang, Z.; Zhang, T.; Liu, H.; Li, Z.; Peng, L.; Wang, C.; Wang, T. Inflammaging: The Ground for Sarcopenia? Exp. Gerontol. 2022, 168, 111931. https://doi.org/10.1016/j.exger.2022.111931.
(6) Kalyani, R. R.; Corriere, M.; Ferrucci, L. Age-Related and Disease-Related Muscle Loss: The Effect of Diabetes, Obesity, and Other Diseases. Lancet Diabetes Endocrinol. 2014, 2 (10), 819–829. https://doi.org/10.1016/S2213-8587(14)70034-8.
(7) Xia, J.; Minamino, S.; Kuwabara, K.; Arai, S. Stem Cell Secretome as a New Booster for Regenerative Medicine. Biosci. Trends 2019, 13 (4), 299–307. https://doi.org/10.5582/bst.2019.01226.
(8) Phelps, J.; Sanati-Nezhad, A.; Ungrin, M.; Duncan, N. A.; Sen, A. Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics. Stem Cells Int. 2018, 2018, e9415367. https://doi.org/10.1155/2018/9415367.
(9) Shin, J.; Rhim, J.; Kwon, Y.; Choi, S. Y.; Shin, S.; Ha, C.-W.; Lee, C. Comparative Analysis of Differentially Secreted Proteins in Serum-Free and Serum-Containing Media by Using BONCAT and Pulsed SILAC. Sci. Rep.2019, 9, 3096. https://doi.org/10.1038/s41598-019-39650-z.
(10) Li, F.; Zhang, J.; Yi, K.; Wang, H.; Wei, H.; Chan, H. F.; Tao, Y.; Li, M. Delivery of Stem Cell Secretome for Therapeutic Applications. ACS Appl. Bio Mater. 2022, 5 (5), 2009–2030. https://doi.org/10.1021/acsabm.1c01312.
(11) Das, M.; Teli, P.; Vaidya, A.; Kale, V. Secretome of Young Mesenchymal Stromal Cells Rejuvenates Aged Mesenchymal Stromal Cells by Normalizing Their Phenotype and Restoring Their Differentiation Profile. Stem Cells Dev. 2023, 32 (1–2), 12–24. https://doi.org/10.1089/scd.2022.0213.
(12) Pinho, A. G.; Cibrão, J. R.; Silva, N. A.; Monteiro, S.; Salgado, A. J. Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders. Pharmaceuticals 2020, 13 (2), 31. https://doi.org/10.3390/ph13020031.
(13) Sassi, F.; Tamone, C.; D’Amelio, P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients 2018, 10(11), 1656. https://doi.org/10.3390/nu10111656.
(14) Kopp, E.; Ghosh, S. Inhibition of NF-Kappa B by Sodium Salicylate and Aspirin. Science 1994, 265 (5174), 956–959. https://doi.org/10.1126/science.8052854.
(15) Grilli, M.; Pizzi, M.; Memo, M.; Spano, P. Neuroprotection by Aspirin and Sodium Salicylate through Blockade of NF- ΚB Activation. Science 1996, 274 (5291), 1383–1385. https://doi.org/10.1126/science.274.5291.1383.
(16) Lin, M.-H.; Lee, C.-H.; Lin, C.; Zou, Y.-F.; Lu, C.-H.; Hsieh, C.-H.; Lee, C.-H. Low-Dose Aspirin for the Primary Prevention of Cardiovascular Disease in Diabetic Individuals: A Meta-Analysis of Randomized Control Trials and Trial Sequential Analysis. J. Clin. Med. 2019, 8 (5), 609. https://doi.org/10.3390/jcm8050609.
(17) Teixeira, F. G.; Carvalho, M. M.; Panchalingam, K. M.; Rodrigues, A. J.; Mendes‐Pinheiro, B.; Anjo, S.; Manadas, B.; Behie, L. A.; Sousa, N.; Salgado, A. J. Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal Behavior in a Rat Model of Parkinson’s Disease. Stem Cells Transl. Med. 2017, 6(2), 634–646. https://doi.org/10.5966/sctm.2016-0071.
(18) Tidball, J. G.; Flores, I.; Welc, S. S.; Wehling-Henricks, M.; Ochi, E. Aging of the Immune System and Impaired Muscle Regeneration: A Failure of Immunomodulation of Adult Myogenesis. Exp. Gerontol. 2021, 145, 111200. https://doi.org/10.1016/j.exger.2020.111200.
(19) Fix, D. K.; Mahmassani, Z. S.; Petrocelli, J. J.; de Hart, N. M. M. P.; Ferrara, P. J.; Painter, J. S.; Nistor, G.; Lane, T. E.; Keirstead, H. S.; Drummond, M. J. Reversal of Deficits in Aged Skeletal Muscle during Disuse and Recovery in Response to Treatment with a Secrotome Product Derived from Partially Differentiated Human Pluripotent Stem Cells. GeroScience 2021, 43 (6), 2635–2652. https://doi.org/10.1007/s11357-021-00423-0.
(20) Immunis, Inc. An Open-Label Dose Escalation Study to Assess the Safety and Tolerability of IMM01-STEM in Participants With Muscle Atrophy Related to Knee Osteoarthritis; Clinical trial registration NCT05211986; clinicaltrials.gov, 2022. https://clinicaltrials.gov/ct2/show/NCT05211986 (accessed 2023-01-30).