Inflammation & "Inflammaging": Hallmark of Aging #11

Q: What is spermidine?

Spermidine is a powerful polyamine that promotes autophagy , the body’s cellular “clean-up” process, and inhibits 9 of the 12 scientifically identified root causes of aging, known as the “Hallmarks of Aging.” While two-thirds of the body’s spermidine is produced by the gut and body tissues, the remaining third comes from food. As we age, natural spermidine production declines, so maintaining youthful levels requires external sources, either from spermidine-rich foods or supplements like Primeadine.

Sep 27, 2023

By Georgia Pilling

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Inflammation & "Inflammaging": Hallmark of Aging #11 | Oxford Healthspan

What is Chronic Inflammation?

Inflammation is a recognizable accompaniment to aging. Demonstrably, over one in four American adults between the ages 45 and 64 and nearly half of all Americans over 65 have been diagnosed with osteoarthritis (1). Among the primary symptoms of which is chronically swollen joints.

Normally, inflammation is a vital defense mechanism and the immune system’s response to harmful stimuli like pathogens or toxins. But, when inflammation is sustained and becomes chronic, disease and aging are the result.

Chronic inflammation can happen at both a systemic and a local level. There are many local pathological phenotypes of inflammation including, for example, arteriosclerosis neuroinflammation, intervertebral discal degeneration, and, of course, osteoarthritis.

Accompanied by sustained inflammation are inflammatory cytokines and biomarkers, proteins that respectively promote and indicate inflammation. Immune function decline is associated with this enhanced inflammation.

Links between inflammation and other aging hallmarks

Lopez-Otin et al characterize inflammation or inflammaging as an integrative hallmark (2). The integrative hallmarks arise when the accumulated damage caused by the primary and antagonistic hallmarks cannot be compensated by the cell’s mechanisms to promote homeostasis. It turns out that inflammation is a direct secondary effect of the damage caused by nearly every other hallmark.

The clearest connection between inflammation and another hallmark is with altered intercellular communication. Indeed, even Lopez-Otin et al initially combined their effects into a singular hallmark. You’ll remember from Hallmark 9, altered intercellular communication, that the inflammaged cell leads to increased production of IL-1BETA, tumor necrosis factor, and interferons. All of these factors increase the “noise” in the system and compromise communication.

Overexpression of pro-inflammatory proteins can also be secondary to epigenetic dysregulation (Hallmark 3), deficient proteostasis (Hallmark 4), and disabled autophagy (Hallmark 10).

Anti-inflammatory, anti-aging interventions

Inflammation is a hallmark in its own right because experimentally manipulating the inflammatory and immune system can accelerate or decelerate the aging process across different systems (3). For example, deletion of the DNA repair protein ERCC1 in hematopoietic cells (blood stem cells) in mice induces immunosenecence, aging of non-lymphoid organs, and other types of organ damage that leads to reduced lifespan (4). This phenotype can be rescued with the introduction of fisetin, a plant derivative and known senolytic (5).

There are many examples of how anti-inflammatory treatments increase health and lifespan (decelerating the aging process). For example, knockout of the inflammasome protein NLRP3 in mice has a multitude of health improving effects including improved metabolic biomarkers, glucose tolerance, cognition and motor performance; it also extends longevity (6).

There are, of course, studies looking for interventions safe and suitable for humans. Lopez-Otin et al cite a recent phase 3 clinical trial CANTOS, which evaluated the capacity of canakinumab, a medication currently approved for the treatment of Familial Mediterranean Fever and Active Systemic Juvenile Idiopathic Arthritis, to prevent recurrent cardiovascular disease in patients with a history of heart attack and pronounced inflammation (2). They met the primary endpoint of trial and researchers also found that canakinumab reduced the incidence of diabetes, hypertension, and lung cancer.

What you can do

Like for other integrative hallmarks (stem cell exhaustion, altered intercellular communication, and gut dysbiosis), the best way to combat or prevent inflammation is to address the primary and secondary hallmarks. Chief among the ways to combat the hallmarks is dietary or caloric restriction. Caloric restriction can also improve the immune system directly. For example, Lopez-Otin cite caloric restriction as a known improver of thymopoiesis, a vital t-cell maturation process that helps the body to mount an appropriate immune response to pathogens (2).

Not everyone can, of course, tolerate fasting. It can be more problematic for women, especially at the menopausal stage, and those with thyroid conditions like hypothyroidism. There are calorie restriction mimetics, however, that provide the benefits of fasting without the need to fast. Spermidine is one of them, since it boosts autophagy, the body's cellular renewal and clean up process that occurs during fasting.

For more information about safe ways to introduce caloric restriction to your lifestyle, please read more here.

References

(1) Barbour KE, Helmick CG, Boring M, Brady TJ. Vital Signs: Prevalence of Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation - United States, 2013-2015. MMWR Morb Mortal Wkly Rep. 2017 Mar 10;66(9):246-253. doi: 10.15585/mmwr.mm6609e1. PMID: 28278145; PMCID: PMC5687192.

(2) López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349.

(3) Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. 2023 Jun 8;8(1):239. doi: 10.1038/s41392-023-01502-8. PMID: 37291105; PMCID: PMC10248351.

(4) Kim DE, Dollé MET, Vermeij WP, Gyenis A, Vogel K, Hoeijmakers JHJ, Wiley CD, Davalos AR, Hasty P, Desprez PY, Campisi J. Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin. Aging Cell. 2020 Mar;19(3):e13072. doi: 10.1111/acel.13072. Epub 2019 Nov 18. PMID: 31737985; PMCID: PMC7059167.

(5) Robbins PD, Jurk D, Khosla S, Kirkland JL, LeBrasseur NK, Miller JD, Passos JF, Pignolo RJ, Tchkonia T, Niedernhofer LJ. Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span. Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:779-803. doi: 10.1146/annurev-pharmtox-050120-105018. Epub 2020 Sep 30. PMID: 32997601; PMCID: PMC7790861.

(6) Marín-Aguilar F, Lechuga-Vieco AV, Alcocer-Gómez E, Castejón-Vega B, Lucas J, Garrido C, Peralta-Garcia A, Pérez-Pulido AJ, Varela-López A, Quiles JL, Ryffel B, Flores I, Bullón P, Ruiz-Cabello J, Cordero MD. NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice. Aging Cell. 2020 Jan;19(1):e13050. doi: 10.1111/acel.13050. Epub 2019 Oct 18. PMID: 31625260; PMCID: PMC6974709.

Katsume Stoneham, MPH (UCLA), MBA (WHU), BA Molecular Biology (U. Colorado Boulder)

Katsume Stoneham is a writer and marketer passionate about translating hard science for non-scientists. She holds Master's degrees in Public Health (MPH) from UCLA Fielding School of Public Health and Business Administration (MBA) from WHU-Otto Beisheim School of Management and a bachelor's degree in Molecular Biology (BA) from the University of Colorado at Boulder. She previously worked in public health in various capacities including informatics and infectious disease research. She likes to read, ride her bike, and chase after her tiny humans in her free time.

FAQs

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What is spermidine?

Spermidine is a powerful polyamine that promotes autophagy, the body’s cellular “clean-up” process, and inhibits 9 of the 12 scientifically identified root causes of aging, known as the “Hallmarks of Aging.” While two-thirds of the body’s spermidine is produced by the gut and body tissues, the remaining third comes from food. As we age, natural spermidine production declines, so maintaining youthful levels requires external sources, either from spermidine-rich foods or supplements like Primeadine.

What are the benefits of spermidine?

Studies link higher levels of spermidine with longevity. Human trials show that food-derived spermidine supports cognition, heart health, hormonal balance, hair growth, collagen production, and nail strength, with potential benefits for fertility and circadian rhythm. These effects stem from spermidine's ability to trigger autophagy—the body's cell renewal process—and inhibit nine of the twelve "Hallmarks of Aging," including inflammation, stem cell and mitochondrial dysfunction, and gut imbalance. Clients also report deeper sleep, increased energy, gray hair reversal, improved skin, and better gut health. Read this blog post to learn more.

What makes Primeadine superior to other spermidine supplements?

While we can’t speak directly about the formulation of other spermidine products, here are some of the main differentiators of Primeadine®/Oxford Healthspan.

We source our raw materials from Japan, which is known for its Nobel Prize-winning scientific leadership on autophagy, or cell renewal. Japan has the most rigorous quality control and testing policies in the world, meaning our ingredients have the most advanced extraction process and meet the incredibly high standards of the Japan Health Food and Nutrition Food Association. They are tested for heavy metals, mold, fungi, and bacteria at the Japan Food Research Lab (JFRL), a third party independent testing lab.
Every single batch is tested for its amount of food-derived spermidine so we ensure it contains the minimum effective dose of 1mg stated on our labels.
Primeadine® is manufactured in Japan in an FDA-registered and -inspected facility with ISO22000 standards, the highest in food quality control. It is then encapsulated in an FDA cGMP facility in the USA and undergoes purity testing there as well at Eurofins or Delta.
Our capsules and tablets do not contain any synthetic ingredients, whereas other supplements typically contain magnesium stearate (of which circa 80% has hydrogenated fats in it; the supplement industry is not legally required to get rid of hydrogenated oils the way the processed food industry has been mandated by law to), shellac, talc and glycerin. Our products are all suitable for vegans. Learn more about our sourcing, quality, and testing standards.
The Primeadine® Original formulation includes a special type of prebiotic fiber, called FOS (fructooligosaccharide), that selectively feeds the friendly, spermidine-producing bacteria in the gut microbiome. The idea is to increase both supplemental, or 'exogenous' spermidine, as well as encourage your own body's natural ability to produce spermidine in your gut microbiome.
Primeadine® GF comes from a sub-strain of chlorella singled out from over 100 others because it alone contains a high level of spermidine and also contains putrescine, the precursor polyamine to both spermine and spermidine. Our chlorella is grown in the nutrient-abundant longevity islands of Okinawa, Japan, and exposed to sunlight to increase the chlorophyll and other nutrient content, such as vitamins D and K, which together help drive calcium to the bones. We combine the chlorella with two other anti-inflammatories and autophagy inducers, Okinawan turmeric and nobiletin (from Okinawan "Shikuwasa" citrus lime peel).
We do not use liposomes in Primeadine® because this is unnecessary for absorption and would prevent the benefits that happen when spermidine is exposed directly to the gut lining. There is no evidence that spermidine cannot be taken up by the cells on its own. Similar to amino acids, polyamines do not need a liposome to cross into the cell or to be taken up with epithelial cells. The process of creating a liposomal version also creates unnecessary expense.
We do not synthetically enrich our product with synthetic spermidine. Be wary of labels that say "wheat germ with spermidine" as this indicates that the wheat germ has been soaked in synthetic spermidine, thereby increasing the overall amount of spermidine but meaning it is no longer a natural source.
We do not use doses beyond what the European Food Safety Authority (EFSA) has mandated as safe for human consumption, which is 6mg daily. Please note that this is related to food-derived spermidine. Synthetic spermidine and synthetically enriched spermidine have never been tested in humans for safety or efficacy and are being sold without regulatory oversight.
We work closely with our scientific and clinical advisers at the University of Oxford and abroad, all of whom take our product and share it with their loved ones. Learn more about our scientific advisory board here.
We are also the only non-Japanese member of the Japan Autophagy Consortium, whose Senior Adviser is the 2016 Nobel Prize Winner in Medicine or Physiology, Prof Yoshimori Ohsumi, and whose Director is Prof Tamotsu Yoshimori, Osaka University. Prof Yoshimori conducted all of the mammalian research in autophagy that helped underpin Prof Ohsumi's work in yeast cells. Find out more about our story here.

What is the best spermidine dose to take?

The US FDA has not set a safe upper limit for food-derived spermidine, but the European Food Safety Authority considers up to 6 mg safe. Most studies use a daily dose of 1 mg of natural spermidine, along with spermine and putrescine, which are absent in synthetic versions. Synthetic spermidine has not been tested for human safety or efficacy.

Why is your spermidine supplement more expensive compared to other products I see on the internet?

We prioritize the highest quality, avoiding common additives like industrial seed oils, magnesium stearate, and talc often used in supplements. Unlike cheap synthetic spermidine often "cut" into products, we use food-derived spermidine sourced and manufactured in Japan under strict regulatory standards. Our products undergo rigorous third-party testing to ensure purity and effectiveness. This commitment to quality, like choosing the best ingredients for a child’s birthday cake, is our guiding philosophy.

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