Mois : août 2024

A highly anticipated clinical trial was just published by the prestigious Journal of Nutrition with a surprising finding: that C15:0, a trace dietary saturated fat present in butter, can lower liver enzymes in young adults susceptible to fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), also referred to as Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), is a metabolic liver condition involving excess fat deposition in the liver that can progress to extensive liver inflammation, cell damage, and cirrhosis. While the first cases of advanced NAFLD were observed in 1980, today this condition affects 1 in 3 people globally, including 1 in 10 children. Fatty liver disease is a leading cause of liver cancer, liver transplants, and more recently, cardiovascular deaths.

A prior clinical trial had shown that supplementation with pure C15:0, the first essential fatty acid to be discovered in almost 100 years, supported healthy LDL cholesterol levels, improved the gut microbiome, and led to the best improvements in lowered body fat, liver fat, and liver enzymes – above and beyond the benefits of caloric restriction and the Mediterranean diet.

The latest clinical trial adds to mounting evidence that nutritional C15:0 deficiency, called Cellular Fragility Syndrome, accelerates cellular aging and contributes to the onset and progression of chronic conditions, including fatty liver disease. Unfortunately, the past 50 years’ avoidance of dairy fat has led to population-wide decreases in C15:0 levels.

“This study is an important step in confirming that C15:0 supplementation can effectively raise circulating C15:0 levels, potentially leading to improvements in metabolic health,” shared Dr. Jeffrey Schwimmer, senior author of the clinical trial and a global leader in pediatric fatty liver disease research. “While many questions remain, particularly regarding the optimal dosage and application in conditions like fatty liver disease, our findings indicate that C15:0 may have a role in managing the underlying metabolic dysfunction common among some patients with liver disease, diabetes, and cardiovascular disease.”

Previously, Dr. Schwimmer had published a study including 237 children that showed those with higher C15:0 levels had lower fat in their livers.

The most recent randomized, double-blinded and placebo controlled clinical trial included 30 young adults (18 to 24 years old) with overweight or obesity, who actively avoided whole dairy fat. This study population had average baseline liver enzyme levels (ALT and AST) that were elevated, indicative of impaired liver function.

Study participants took a pure C15:0 supplement (fatty15) for 12 weeks. The C15:0 supplemented group demonstrated a significant increase in C15:0 levels and lower gamma glutamyl transferase (GGT) levels, a liver enzyme. Further, study participants who were supplemented with C15:0 and achieved plasma C15:0 levels above the definition of nutritional C15:0 deficiency also had lowered liver enzyme levels (ALT and AST), indicative of improved liver health. These beneficial effects were not observed in the control group.

“Dr. Schwimmer’s clinical trial is an important milestone for the growing movement to fix C15:0 deficiencies and restore global health,” said Dr. Stephanie Venn-Watson, Seraphina Therapeutics’ co-founder and CEO. “There is an increasingly urgent need to revisit current nutritional guidelines around saturated fats, especially odd-chain saturated fats, to help people maintain healthy C15:0 levels and protect their long-term health.”

Dr. Venn-Watson’s initial discoveries on the importance of C15:0, which were made while helping to continually improve the health of aging dolphins with fatty liver disease, is a featured TEDx talk. Seraphina Therapeutics’ scientific advancement of C15:0 has been awarded the 2024 Overall Supplement of the Year by Mindful Awards, is a 2024 Fast Company World Changing Idea in Wellness, and a top 2024 Healthy Aging Ingredient by NutraIngredients.

Press inquiries: Press@fatty15.com

About Seraphina Therapeutics. Inc.

Seraphina Therapeutics, Inc. is a health and wellness company dedicated to advancing global health through the discovery of essential fatty acids and micronutrient therapeutics. Through rigorous breakthrough science, the company develops fatty acid supplements, food fortifiers, and nutritional interventions to strengthen cells, keep mitochondria working and advance cellular homeostasis to counter age-related breakdown. With its team of industry-leading scientists, Seraphina Therapeutics challenges long-held approaches to nutrition, enabling the creation of novel health products designed to support quality of life. For more information, please visit DiscoverC15.com and fatty15.com.

Fecal microbiota transplantation from young mice to older mice improved multiple metabolic parameters and some hallmarks of aging, such as inflammation and telomere shortening [1].

Bringing back the balance

Dysbiosis, an imbalance in the gut microbiome, is a newly recognized hallmark of aging [2]. Dysbiosis elevates the risk of many diseases, including cardiovascular diseases [3]. However, the mechanism behind this association is poorly understood.

The authors of this study discuss that vasculature can be especially susceptible to dysbiosis due to the proximity between the intestine and the blood circulation and reference previous research that, by altering gut microbes, such as through antibiotic treatment, influenced vascular function [4].

In this study, the researchers transplanted fecal microbiota from young to middle-aged and aged mice to test the effects of such intervention on vascular function and metabolism.

Metabolic and vascular improvements

The researchers started their investigation by comparing the microbial composition of young and aged mice. Unsurprisingly, they found age-dependent differences in mouse gut microbes. After confirming that gut microbes in the old and young mice differed, they performed fecal microbiota transplants from young (8 weeks old) mice to middle-aged (40-42 weeks old) and aged (over 75 weeks old) mice.

Humans and rodents normally lose weight in advanced age, but in aged mice, fecal microbiota transplantation slowed down this weight loss slightly. This happened despite no changes in food intake, suggesting that the treated mice were absorbing more nutrients from the food.

Fecal microbiota transplantation also altered glucose and lipid metabolism, impacting insulin resistance and cholesterol levels. In middle-aged mice, HDL, the “good” cholesterol, was significantly increased, but LDL, the ”bad” cholesterol, was decreased.

These results suggested the possibility that endothelial function might also be impacted. Previous research had shown that detrimental metabolic changes can damage the endothelium [5], the layer of cells that lines the blood vessels.

The researchers measured endothelium-dependent relaxations as a proxy for endothelial state. They noted that fecal microbiota transplants improved endothelium-dependent relaxations in the aortae and the mesenteric arteries, which distribute blood from the aorta to the gastrointestinal tract, of middle-aged mice.

Aging is associated not only with metabolic changes but also with changes to molecular signaling. In this paper, the researchers observed aging-related downregulation of endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK) phosphorylation, and sirtuin 1 (SIRT1) expression in mouse aortae.

Fecal microbiota transplants helped to alleviate those changes. In middle-aged mice following the procedure, the researchers observed increased levels of eNOS and eNOS upstream regulators, AMPK, and SIRT1, in the aorta. This observation suggested the activation of signaling pathways that can potentially improve endothelial function and reduce vascular aging. They also add that “receiving young microbiota at a younger age might be of higher therapeutic efficacy in vasculature.”

Reversing some hallmarks of aging

Aging is known to be associated with chronic inflammation, which can lead to endothelial dysfunction and vascular damage [6], and age-associated dysbiosis is one of the factors that promote inflammation [7]. A fecal microbiome transplant from young to middle-aged mice helped to alleviate this inflammation, as confirmed by the lower levels of pro-inflammatory cytokines in the serum and aortae of middle-aged mice following the transplant.

Researchers believe that the transplant’s anti-inflammatory effect was achieved by reducing leaky gut. This refers to the aging-associated increase in intestinal permeability, the ability of substances and molecules to get through the protective gut membrane. Following fecal microbiota transplantation, the researchers observed lower levels of fecal and serum endotoxins and intestinal fatty-acid binding protein, a biomarker of increased intestinal permeability, in middle-aged mice.

Fecal microbiome transplants were also successful in helping with telomere attrition. These researchers found that fecal microbiota transplantation in middle-aged mice led to the upregulation of telomerase reverse transcriptase, enhanced telomerase activity, and delayed the shortening of relative telomere length in the aorta.

The researchers note that the positive effect of fecal microbiota transplant on telomeres “was lower in aged mice when compared to middle-aged mice”, suggesting that optimizing the timing of this intervention can enhance its positive effects.

The authors performed similar testing on the intestine, which is in direct contact with the microbiota. They observed that this tissue and the vasculature received similar beneficial effects in middle-aged mice: decreased expression of pro-inflammatory genes, reduced telomere dysfunction, and increased expression of AMPK and SIRT1. Some of the improvements were better in the intestine than in vascular tissues.

Further optimization needed

The researchers believe that further research is needed to investigate the long-term effects, impacts on other organs and tissues, safety, and efficacy of fecal microbiota transplants and whether similar beneficial effects can be observed in humans. The authors believe that a better understanding of the gut-vascular connection can be an avenue for designing therapeutic strategies for age-associated cardiometabolic diseases.

They also point out that the timing of this intervention is essential for optimal results. They believe that since “the pace of aging becomes substantially higher after certain critical timepoints in life [7],” therapeutic effects might be greatly reduced after certain timepoints.

Literature

[1] Cheng, C. K., Gao, J., Kang, L., & Huang, Y. (2024). Fecal Microbiota Transfer from Young Mice Reverts Vascular Aging Hallmarks and Metabolic Impairments in Aged Mice. Aging and disease, 10.14336/AD.2024.0384. Advance online publication.

[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278.

[3] Hou, K., Wu, Z. X., Chen, X. Y., Wang, J. Q., Zhang, D., Xiao, C., Zhu, D., Koya, J. B., Wei, L., Li, J., & Chen, Z. S. (2022). Microbiota in health and diseases. Signal transduction and targeted therapy, 7(1), 135.

[4] Brunt, V. E., Gioscia-Ryan, R. A., Richey, J. J., Zigler, M. C., Cuevas, L. M., Gonzalez, A., Vázquez-Baeza, Y., Battson, M. L., Smithson, A. T., Gilley, A. D., Ackermann, G., Neilson, A. P., Weir, T., Davy, K. P., Knight, R., & Seals, D. R. (2019). Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice. The Journal of physiology, 597(9), 2361–2378.

[5] Bakker, W., Eringa, E. C., Sipkema, P., & van Hinsbergh, V. W. (2009). Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell and tissue research, 335(1), 165–189.

[6] Donato, A. J., Machin, D. R., & Lesniewski, L. A. (2018). Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circulation research, 123(7), 825–848.

[7] Thevaranjan, N., Puchta, A., Schulz, C., Naidoo, A., Szamosi, J. C., Verschoor, C. P., Loukov, D., Schenck, L. P., Jury, J., Foley, K. P., Schertzer, J. D., Larché, M. J., Davidson, D. J., Verdú, E. F., Surette, M. G., & Bowdish, D. M. E. (2017). Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction. Cell host & microbe, 21(4), 455–466.e4.

In a new study, a 12-week protocol of hyperbaric oxygen therapy (HBOT) resulted in marked increases in aerobic capacity and cardiac blood flow [1].

Building pressure

HBOT involves placing patients in a tightly sealed chamber where they breathe pure oxygen under higher-than-normal atmospheric pressure. This treatment has been approved for a small number of conditions, such as gas gangrene and thermal burns.

HBOT can reduce swelling and boost oxygenation in damaged tissues, which is likely to improve mitochondrial metabolism and reduce inflammation. As such, it has been touted as a potential anti-aging intervention. However, not all claims made by HBOT clinics have been confirmed by science.

Dr. Shai Efrati is an HBOT pioneer hellbent on scientifically proving its worth. Previous research by his group has suggested, among other things, that HBOT can alleviate vascular dysfunction and amyloid burden in an Alzheimer’s disease mouse model and in elderly patients and can improve cognition after a stroke [2]. There have also been findings of improved bone health and other benefits.

In this new study, Efrati and his colleagues focused on a different, although not unrelated, aspect of health. To investigate the effects of HBOT on cardiorespiratory fitness in a randomized controlled trial, the researchers recruited 63 elderly patients with a median age of 70 – a respectable sample size.

The primary endpoint of the study was VO2Max, or maximal oxygen uptake. VO2Max is an important marker of cardiorespiratory fitness that has shown strong correlation with all-cause mortality [3]. One study goes as far as to suggest that VO2Max is “a key predictor of longevity” [4]. VO2Max levels markedly decline with age.

Breathe deeper

The participants received 60 sessions of HBOT over a period of 12 weeks. Each session included breathing 100% oxygen at two times normal atmospheric pressure, and lasted 90 minutes, with periodic five-minute breaks. During the trial, no changes in lifestyle, physical training, diet, and medications were allowed for either group.

The treatment resulted in a significant increase in VO2Max and even more significant – in VO2Max/kg, that is, maximal oxygen uptake normalized for body weight. The effect size was moderate but noticeable.

Yet an even more pronounced increase was detected in oxygen consumption measured at the first ventilatory threshold (VO2VT1). This important physiological marker is also called “the aerobic threshold”, because it represents the transition from predominantly aerobic energy production to a mix of aerobic and anaerobic energy production. Simply speaking, people with higher values start becoming out of breath later during exercise.

Let it flow

The researchers also measured cardiac perfusion: the amount of blood the heart receives. Both myocardial blood flow and myocardial blood volume (the total volume of blood within the myocardial tissue at a given moment) showed steep increases in the treatment group. Interestingly, no significant changes were observed in pulmonary function.

The importance of the study stems from the fact that, as the authors note, “while the impact of VO2Max on daily life is generally minimal for young individuals, elderly individuals heavily rely on their VO2Max to perform everyday tasks effectively.” Elevating VO2Max levels in the elderly can theoretically have a strong impact on mortality. People with conditions such as chronic fatigue could also benefit from this treatment. Finally, increased cardiac perfusion can boost brain health. On the downside, HBOT requires complex machinery and is costly, at least for now.

The study findings suggest that the newly used HBOT can enhance physical performance in aging adults. The key enhancements observed include improvements in maximal oxygen consumption, and the first ventilatory threshold. Moreover, the use of cardiac MRI demonstrated increased cardiac perfusion as a significant mechanism underlying the observed improvements induced by HBOT.

Literature

[1] Hadanny, A., Sasson, E., Copel, L., Daniel-Kotovsky, M., Yaakobi, E., Lang, E., … & Efrati, S. (2024). Physical enhancement of older adults using hyperbaric oxygen: a randomized controlled trial. BMC geriatrics, 24(1), 572.

[2] Shapira, R., Gdalyahu, A., Gottfried, I., Sasson, E., Hadanny, A., Efrati, S., … & Ashery, U. (2021). Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer’s disease mouse model and in elderly patients. Aging (Albany NY), 13(17), 20935.

[3] Mandsager, K., Harb, S., Cremer, P., Phelan, D., Nissen, S. E., & Jaber, W. (2018). Association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing. JAMA network open, 1(6), e183605-e183605.

[4] Strasser, B., & Burtscher, M. (2018). Survival of the fittest: VO2max, a key predictor of longevity. Front Biosci (Landmark Ed), 23(8), 1505-1516.