Gut Dysbiosis: Hallmark of Aging #12

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.

Nov 22, 2023

By Kat Stoneham

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Gut Dysbiosis. Image shows gut biome | Oxford Healthspan

What is the Gut Microbiome?

Your gut is populated by a combination of bacteria, archaea, and viruses, often referred to in combination as the gut microbiota. The microbiota of any two people will not be the same. The make-up of a person’s microbiota depends on genetic variants and other factors including ethnicity, dietary factors, lifestyle habits, and environmental conditions. Despite this variation, meta-analyses of thousands of peoples’ microbiota have revealed disease associations across pathologies and countries.

The gut microbiota evolved with humans in a symbiotic relationship. It is an essential part of our biology and supports many physiological functions like nutrient digestion and absorption, protection against pathogens, and production of essential metabolites like vitamins; helps maintain the integrity of our gut lining; and protects us from the diseases like obesity, cancer, and heart attacks.

Gut Dysbiosis, the 12th Hallmark of Aging

The gut microbiota also signal (talk to) to the peripheral and central nervous systems and other organs and strongly impacts the maintenance of whole body (host) health. If the communication between microbiota and host is disrupted due to imbalance in the microbiota, changes in functional composition or metabolic activities, or a shift in distribution, dysbiosis [1] occurs. Dysbiosis contributes to aging and a variety of pathological conditions including those listed above and more. As of 2023, it is now recognized as a key root cause of aging, known as the hallmarks of aging.

Microbiota Alterations in Aging

Bacterial diversity in the gut is established during childhood and remains relatively stable into adulthood. But, the architecture and activity of the bacteria undergoes gradual changes during aging, which eventually lead to a decrease in diversity.

Largescale studies of the gut microbiome and phenotypic data reveal that individual gut microbiomes become increasingly unique to each individual with age. In older age healthy individuals, their microbiome demonstrate this drift toward uniqueness, but this drift is reduced or absent in less healthy individuals.

Despite this uniqueness, when many thousands of peoples’ microbiota are examined, some trends are observed. For example, in healthy aging, there is a reduction of core gut bacteria like Bacteroides and Roseburia and an increase in other types of bacteria like Bifidobacterium and Akkermansia, which appear to have prolongevity effects [2]. Older adults have also been found to exhibit higher abundancies of several health-promoting bacterial species [3].

When the microbiomes of centenarians and supercentenarians are examined, however, they do not always follow the same rules as the general elderly population. For example, their microbiomes have shown enrichment of particular bacteria that generate secondary bile acids. Metabolizing these bile acids produced by the bacteria is hypothesized to reduce the risk of infection and contribute to intestinal homeostasis.

The microbiota have also been shown to produce other metabolites, which have been associated with different phenotypes (visible or observable traits). For example, p-cresol is correlated with increased frailty [4]. Conversely, certain indole metabolites are correlated with improved fitness in older adults and increased health and lifespan in mice [5]; this has been shown to be related, at least in part, through reducing inflammatory responses.

Fecal Microbiota Transplantations

Most health news enthusiasts have heard about fecal microbiota transplants (poop transplants). Whether you are intrigued or horrified at the thought, fecal microbiota transplants (FMT) have proven to be an effective treatment for C.diff in humans [6] and have revealed, at least in animal models, the role the gut microbiota play in aging and the maintenance of many different parts of the body including the brain and the ovaries.

FMT and Aging

Prematurely aged (progeria) mice exhibit intestinal dysbiosis characterized by an increase in the abundance of proteobacteria and cyanobacteria and a decrease in levels of verrucomicrobia [7]. Similarly, human progeria patients also exhibit dysbiosis. Long-lived humans, however, exhibit opposite effects to their gut microbiota with a substantial reduction in proteobacteria, for example, and an increase in verrucomicrobia.

When progeria mice were given FMTs from wildtype mice, the progeroid mice recipients had enhanced health and lifespans. Administering only the bacteria—verrucomrobium Akkermansia muciniphila—was also sufficient to obtain the same effects. FMT from progeroid to wild type mice, however, induced detrimental metabolic alterations. The effects of this FMT can be mitigated by restoring the secondary bile acids and other metabolites of the wildtype gut microbiota. These results suggest that restoring intestinal homeostasis—either by restoring bacteria levels or administering metabolites of those bacteria—can be sufficient to combat (premature) aging [7].

FMT and the Health of Systems

FMT has also revealed the role of gut microbiota in chronic systemic inflammation (another hallmark of aging), maintenance of brain health, and ovarian function and fertility: Gut dysbiosis plays a causative role in the chronic systemic inflammation and the decline in adaptive immunity associated with aging and age-related diseases. By transferring the gut mictiobiota of old mice to young mice [8], an inflammatory response is triggered; this response is characterized by enhanced CD4+T-cell differentiation in the spleen, upregulation of inflammatory cytokines, and increased circulation of inflammatory factors of bacterial origin. FMT from young mice donors to older mice reversed aging-associated differences in metabolites in the hippocampus and brain immunity and reduced aging associated impairments in cognitive behavior; this suggests that gut microbiota plays a role in the maintenance of brain health and immunity during aging [9]. FMT from young donor mice also improves ovarian function and fertility in mice [10]; when examined, the immune microenvironment of the aged ovaries is improved and the inflammatory markers are reduced.

Caloric Restriction & Gut Microbiota

Beyond poop implants, there have been a number of other prolongevity interventions on gut microbiota. One that can be taken on without a prescription or a PhD is caloric restriction. Restricting calories, more on this here, induces structural changes to the gut microbiome and increases the bacterial strains like Lactobavillus that influence healthy aging.

The Final Hallmark of Aging

This is the final hallmark set forth by Lopez-Otin et al in their updated 2023 paper on the Hallmarks of Aging [11]. It’s no wonder that gut dysbiosis was included. There are clear causal links between aging and dysbiosis. Interventions aimed at restoring a youthful microbiome, poop transplant and caloric restriction included, may extend lifespan and positively impact the health and functioning of other systems.

Spermidine, a natural polyamine, is believed to play an important role in gut microbiome regulation. Learn more about our premium food-derived spermidine supplement here.

References:

1. "What is Dysbiosis?" WebMD, 06 Dec. 2022, www.webmd.com/skin-problems-and-treatments/tc/athletes-foot-topic-overview.

2. "Gut Microbiota and Extreme Longevity" Current Biology, 12 May 2016, multiple authors.

3. Zhang, X., Zhong, H., Li, Y. et al. Sex- and age-related trajectories of the adult human gut microbiota shared across populations of different ethnicities. Nat Aging 1, 87–100 (2021). https://doi.org/10.1038/s43587-020-00014-2

4.Tarini S GhoshMrinmoy DasIan B JefferyPaul W O'Toole (2020) Adjusting for age improves identification of gut microbiome alterations in multiple diseases eLife 9:e50240.

5. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages, Current Biology,VOLUME 23, ISSUE 4, P1099-1111, APRIL 24, 2018.

6. Fecal Transplant and C.Diff https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/fecal-transplant

7. Bárcena, C., Valdés-Mas, R., Mayoral, P. et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med 25, 1234–1242 (2019). https://doi.org/10.1038/s41591-019-0504-5

8. Aged Gut Microbiota Contributes to Systemical Inflammaging after Transfer to Germ-Free Mice. Front. Immunol., 01 November 2017.Sec. Nutritional Immunology. Volume 8 - 2017

9. Boehme, M., Guzzetta, K.E., Bastiaanssen, T.F.S. et al. Microbiota from young mice counteracts selective age-associated behavioral deficits. Nat Aging 1, 666–676 (2021). https://doi.org/10.1038/s43587-021-00093-9

10. Li Xu, Qiankun Zhang, Xiaowei Dou, Yipeng Wang, Jianwei Wang, Yong Zhou, Xingyin Liu, Jing Li, Fecal microbiota transplantation from young donor mice improves ovarian function in aged mice,Journal of Genetics and Genomics,Volume 49, Issue 11,2022,Pages 1042-1052, ISSN 1673-8527, https://doi.org/10.1016/j.jgg.2022.05.006.

11. 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.

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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