Altered Intracellular Communication: Hallmark of Aging #9

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.

Jun 27, 2023

By Oxford Healthspan

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Altered Intracellular Communication: Hallmark of Aging #9

Altered communication

As he has grown older, my grandfather has progressively lost his hearing. Now sporting a pair of hearing aids, he has the ability to listen when he wants…and not listen when he isn’t in the mood. He is known to simply turn off his hearing aid when he doesn’t want to be bothered or when a book is in his hands. And, he is utterly overwhelmed by too much noise or too many people speaking at once. Needless to say, this has changed how he communicates with people.

Not unlike this change, as people (and their cells) age, the communication between their cells change. Although the cells aren’t deciding not to communicate, the communication becomes deregulated particularly as inflammatory reactions and “noise” increase.

Interconnectedness of the Hallmarks

In the original Hallmarks of Aging (2013), Lopez-Otin et al include inflammation as one of the contributors to their final hallmark of aging, altered intercellular communication. In their update to the Hallmarks (2023), inflammation is a hallmark in its own right. Of course, all the hallmarks are interrelated and contribute to the effects of overall body aging. Inflammation and altered intercellular communication, however, are difficult to tease apart.

Inflammaging

Aging is accompanied by an alternation in intercellular communication Salminen et al termed “inflammaging.” Inflammaging is the result of a combination of causes including, but not limited to, failure of an “ever more dysfunctional immune system to effectively clear pathogens and dysfunctional host cells,” the pro-inflammatory phenotype common in senescent cells (SASP), and a defective autophagic response (more on this in the coming months—it’s another new hallmark!) The inflammaged cell, if you’ll allow the word invention, leads to increased production of IL-1BETA, tumor necrosis factor, and interferons. All of these factors increase the “noise” in the system and compromise regulation of homeostasis.

Contagious Aging

Beyond inflammation, there is some evidence that aging-related changes in one tissue can lead to aging-specific deterioration of other tissues, something Lopez-Otin termed “contagious aging.” As discussed in Hallmark 8, senescent cells can induce senescence in neighboring cells. The microenvironment created by these cells can also contribute to age-related and functional defects in CD4 t-cells, white blood cells that help trigger the immune response to pathogens.

Blood communication

In between publications of the Hallmarks of Aging, a number of studies looked to the blood, another communication pathway in the body, for systemic factors with pro-aging or pro-longevity properties.

As demonstrated by the features of aging induced in young mice simply by the transfusion of old blood, there are circulating factors in the blood that favor the aging process. Among the identified factors are the chemokine CCL11/eotaxim and the inflammation-related protein BETA2-microglobulin which reduce neurogenesis (formation of new neurons, a cell-type in the brain); IL-6 and TGF-BETA that impair hematopoiesis (formation of blood components); and the complement factor C1q that compromises muscle repair. Several of these factors are secreted in the context of SASP.

Conversely, a transfusion of blood from young mice can restore renewal and repair capacity in old mice. Researchers have shown that the blood of young mice can rejuvenate multiple tissues and restore age-associated reduction in general gene expression. They also identified a variety of rejuvenating factors; among them are rejuvenators of the a hematopoietic stem and progenitor cells, a hippocampus rejuvenator, and a factor that improves endurance exercise and whole-body metabolism.

Long-range and short-range communication systems

The central nervous system—which includes the brain and spinal cord—controls may facets of aging that affect the peripheral organs through “long-range” communication. For example, experimentally manipulating the brain to overexpress certain genes like SIRT1 or underexpress other genes like IKBKB have been shown to enhance mouse longevity. These factors, along other extracellular molecules and soluble factors released from tissues like fat tissues, also impact communication within cells and among neighboring cells (“short-range” communication). Again, the system is flooded with noise or messaging that tells cells and systems to age.

Extracellular matrix

In the area between the cells, the extracellular matrix, aging can cause many different types of changes in long-lived protein components like collagen cross-linking and lead to tissue fibrosis. These changes are in response to the excessive release of growth factors among others that trigger the expression of pro-fibrotic genes. Fibrosis can be thought of as stiffness, and this rigidity affects the function of nearby cells and senescent cells, in particular; in response, the senescent cells secrete more factors into the extracellular space and amplify the damage and activate pro-senescent, pro-fibrotic, and pro-inflammatory pathways.

This rigidity has been casually linked with aging; several studies have also suggested several approaches for improving healthy aging including, for example, activation of the YAP gene in mice. Like the long and short-range communication examples, the rigidity of the extracellular matrix offers another avenue to explore in the quest for healthy aging.

Maintaining intercellular communication

Like senescence, intercellular communication is an integrative hallmark of aging. 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. As shown above, the “noise” created by the other hallmarks, particularly senescent cells and inflammation cause the breakdown of communication. As an integrative hallmark, this change leads to further deterioration of cells that are ultimately responsible for aging.

Tips & tricks for good cell communication

In addition to keeping your hearing aids on, we recommend combatting the other hallmarks as the best strategy to prevent and restore altered communication. Chief among the natural ways to combat the hallmarks is dietary restriction and food-derived spermidine, which is a calorie restriction mimetic and inhibits 9 of the 12 hallmarks of aging.

Written by: Katsume Stoneham, BS, Molecular Biology, MA, Public Health

FAQs

See all FAQs or contact us!

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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