Sadly, there’s no quick fix for the effects of aging or the extra pounds that sometimes (and so easily) sneak onto our waistlines. Obesity is a widespread and concerning problem associated with various health issues such as cardiovascular disease and diabetes. Extensive research has focused on the connection between gut health, microbial communities, and obesity. Spermidine, a naturally occurring polyamine, has shown promise in this area due to its crucial role in cellular function. Explore how gut health, Spermidine, and weight loss are interconnected, impacting obesity and overall well-being.
The Role of Fasting and Calorie Restriction
Fasting - abstaining from or restricting food, drink, or both - has been known to have may benefits including weight loss. More importantly though, it improves health (read: waistline impact and beyond) and lifespan in most, if not all, living organisms. As we age, the risk of many diseases increases; this is called an age-associated health effect. For example, the average fifty year old has a higher risk of heart disease than the average five year old. Many of the positive health benefits are realized because calorie restriction activates cellular processes not usually stimulated when food is readily available. One such process, autophagy - a recycling mechanism that “cleans up” the obsolete, damaged, or otherwise unneeded cell contents - via the cell’s very own Marie Kondos - plays a prominent role.
In one study, non-obese, healthy adults who reduced their calorie intake by 15 to 25% for two years reported improved quality of life - including improved general health, sexual drive, and mood and reduced tension. They also lost an average of 7.6 kilograms of mostly body fat. Though the benefits are many and the process is simple, fasting is not without its difficulties (how do you eat 25% less pasta?), discomforts, and risks.
In his talk at the 2021 Future of Autophagy Symposium held by the Oxford Longevity Project, Professor Tamotsu Yoshimori from the University of Osaka, said the following, “Of course we know fasting induces autophagy, but…fasting also has not good effect[s] on [the] body. So, you should think about balance between [the] bad effect[s] of fasting and good effect[s]." If autophagy is beneficial and what we want to induce, but not necessarily via fasting, fasting mimetics, or foods and supplements that mimic or induce similar effects, could be the answer. Although the science is relatively new and most of the evidence available pertains to animals, the initial findings on calorie restriction mimetics (CRM) are promising. Like fasting, some CRMs activate autophagy, prolong life- and healthspan, and ameliorate a diverse array of disease symptoms.
Spermidine: A Calorie Restriction Mimetic
Spermidine is naturally produced by the body, but natural levels decrease as we age. The known benefits of spermidine are many including increasing lifespan, suppressing tumor growth, enhancing your body’s immune response to cancer, and improving the heart’s ability to protect itself from disease; and these are only a few of its known effects. Spermidine is also known to induce mitophagy, a type of autophagy that eliminates damaged or dysfunctional mitochondria, the energy center of the cell, in studies of mice and human cells in culture.
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As the scientific world studies CRMs, and spermidine in particular, the good news keeps coming. In a study published in 2019, scientists assessed the potential of a combination of three CRMs to fight tumor growth in mice with lung cancer. They chose CRMs, including spermidine, that are known to induce autophagy and promote the body’s immune response to cancer. When compared to the control group, scientists found that the CRMs induced autophagy in the tumors and significantly reduced the number of metastases.
In a study published in 2021, researchers explored the ability of spermidine to confer neuroprotective effects on the brains of aging-accelerated rats and naturally aged rats. After six weeks of oral spermidine supplements, the brain tissue of the rats were analyzed. They found that spermidine up-regulated the expression of several autophagy genes (increased autophagy) and down-regulated the expression of an inflammatory gene (decreased inflammation).
In a study published in 2021, thirty healthy Japanese men ate one or two servings of ready-to-eat natto, a known dietary source of spermidine, every day for a year. When compared to a control group, that did not modify their diets, a marker that increases with inflammation, LFA-1, was reduced.
Though calorie restriction is undoubtably effective, it is also difficult and not without risk. Supplementing your diet with CRMs like spermidine can be similarly effective, definitely easier, and probably more satisfying. Spermidine can be found in many foods like the natto eaten in the above study; vegetables like green peas, corn, and pumpkin; and, perhaps easiest, can be taken as a supplement like our premium de-fatted wheatgerm supplement Primeadine®.
Spermidine and Weight Loss: A Promising Approach
Studies have shown that Spermidine has the potential to promote weight loss in obese individuals, as well as reduce their risk of cardiovascular disease and diabetes. In addition, by promoting health cell functioning, spermidine benefits can include improved metabolic function, which can reduce body fat.
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Spermidine for weight loss is thought to work in two ways: by promoting gut health and reducing levels of inflammation; and by promoting caloric restriction. Those who struggle with weight loss may find that spermidine supplementation can help in several ways. Spermidine for weight loss has been shown to work by:
Alteration of Gut Bacteria
Researchers have discovered that Spermidine actively influences the functioning and composition of gut microbiota, leading to improved glucose and lipid metabolism. These findings suggest that Spermidine plays a crucial role in promoting weight loss by impacting important metabolic pathways. Moreover, supplementation of Spermidine has demonstrated its ability to protect against diet-induced obesity in both animal and human studies, emphasizing its potential as an effective aid for weight loss.
Autophagy
One of the key ways that Spermidine may contribute to weight loss is through its ability to induce autophagy, the process by which cells recycle and repair damaged components. Autophagy has been linked to improved metabolic function, and Spermidine has been found to act as an autophagy inducer. This suggests Spermidine may help improve cellular and metabolic health, leading to weight loss over time.
Improving Metabolic Function
Studies have also shown that Spermidine benefits those with metabolic dysfunction. For example, one study found that spermidine supplementation improved insulin sensitivity in those who are obese or overweight. This indicates that Spermidine may be particularly beneficial for those with metabolic disorders and may help prevent obesity-related conditions.
Other supplements, such as resveratrol, can assist in weight loss in addition to Spermidine. Resveratrol lowers lipids, restricts calories, and improves glucose metabolism and homeostasis. These findings suggest that resveratrol could be a valuable weight loss aid, and it should be considered alongside Spermidine.
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Research on Spermidine and weight loss is a promising area that shows potential for aiding obesity-related conditions. While more studies are needed, the current evidence suggests that Spermidine may improve metabolic health, induce autophagy, and promote weight loss.
In addition to other supplements such as resveratrol, spermidine warrants further investigation as a potential weight loss aid. However, one should note that no single substance is a miracle cure for obesity, and a holistic approach that includes a health-conscious diet and sustainable lifestyle changes is essential for achieving sustainable weight loss.
Spermidine-Rich Diet for Weight Loss & Longevity
Maintaining a healthy weight is crucial for optimal health and longevity. Achieving successful weight loss requires a combination of caloric restriction and regular exercise. However, finding the right balance can be a challenge for many individuals. That’s where spermidine, a polyamine, comes in. Spermidine not only helps with caloric restriction and weight loss but also offers other health benefits that contribute to longevity.
Spermidine is a naturally occurring compound produced by the microbiota in our gut and can be found in various foods. There is abundant evidence to support that Spermidine can have many of the same healthful effects as caloric restriction. This has led scientists to explore the potential of Spermidine as a supplement that can promote weight loss and longevity.
Spermidine contributes to longevity by protecting against a range of diseases. For instance, it has shown safeguarding effects against metabolic disorders and neurodegeneration. Many of these diseases are associated with inflammation and oxidative stress, both of which spermidine can help combat.
Incorporating Spermidine into Your Diet
One of the best ways to get Spermidine is through food sources. Spermidine is found in many foods, including:
- Wheat germ
- Soybeans
- Nuts
- Mushrooms
- Broccoli
- Mango
Supplements are a great way to increase your spermidine intake. Many companies now offer spermidine supplements in different forms. However, it’s important to be cautious when choosing a supplement, as quality and purity can vary. If you’re considering starting a spermidine regimen, it’s best to consult your healthcare provider beforehand.
Spermidine is a promising compound that can help lose weight and promote longevity. By supporting autophagy, it improves insulin sensitivity and reduces inflammation; the compound contributes to weight loss, healthy aging, and longevity. As such, incorporating spermidine-rich foods into your diet and considering a supplement regimen is a valuable way to support optimal health and wellbeing.
Spermidine and Healthy Weight Loss in Older Populations
As one ages, maintaining a healthy weight becomes increasingly crucial for their overall wellbeing. While diet and exercise are crucial for weight management, incorporating Spermidine can be incredibly effective in promoting healthy weight loss in older populations who also want to maintain their health. So, not only does Spermidine support weight loss, but it has countless other benefits for aging populations.
Spermidine is a natural compound in various foods like fruits, vegetables, and whole grains. However, while it is present in many foods, consuming enough Spermidine to experience its benefits solely through diet can be difficult. That’s why taking spermidine supplements can effectively ensure you’re getting enough of this compound, especially as you age.
Benefits for Older Populations
For older populations, Spermidine helps to promote healthy weight loss and aging in the following ways:
- Cellular Renewal: Spermidine’s ability to promote weight loss and longevity in older populations is partly due to its ability to promote a healthy metabolism and fat-burning processes in the body. In addition, by promoting cellular renewal through autophagy, Spermidine helps to break down damaged and abnormal proteins and other substances into the cell’s cytoplasm. This is crucial for optimal cell functioning and renewal, including healthy weight management.
- Prevention of Heart Failure & Cognitive Decline: This naturally occurring compound promotes the longevity of aging populations by offering numerous benefits. For instance, it improves heart health by preventing cardiac hypertrophy and delaying the progression of heart failure. Additionally, it decreases the risk of cognitive decline and Alzheimer’s disease by triggering the process of amyloid-beta plaque dissolution through autophagy.
- Reducing Cell & Tissue Damage: Spermidine is also rich in antioxidants, protecting against free radicals’ damage. Free radicals are unstable molecules that result in cell and tissue damage by inducing oxidative stress, leading to a range of health problems. As one ages, the body becomes less effective at combating free radicals. Antioxidants aid by neutralizing free radicals and helping to prevent the damage they cause.
- Promotion of Caloric Restriction: Spermidine is a promising tool in combating age-related diseases. By mimicking the effects of life-extending interventions like calorie restriction, Spermidine helps to promote cellular renewal and autophagy. This supports healthy weight management and contributes to overall health and longevity.
It’s important to note that Spermidine is not a magic pill or a substitute for healthy lifestyle choices. Eating a balanced diet of whole foods, staying active, and getting adequate rest are all essential components of healthy aging. However, incorporating spermidine supplements into your routine can be a life-changing addition to your overall health and wellness plan.
Spermidine is a potent tool in promoting healthy weight loss in older populations. Its ability to boost metabolism and fat-burning processes, combined with its numerous other health benefits, makes it an excellent choice for improving overall weight management, health and longevity. By taking spermidine supplements and integrating healthy lifestyle choices, you can support your body’s natural ability to maintain your ideal body weight and promote optimal health and wellbeing.
Incorporating Spermidine Into Your Daily Routine
Incorporating Spermidine into your daily health and wellness routine effectively ensures you are getting enough of this compound. Taking spermidine supplements can help to support weight loss, improve heart health, reduce cognitive decline, and protect against oxidative damage. In addition, by eating a balanced diet and exercising regularly, you can support your body’s natural ability to maintain a healthy weight and promote optimal health and wellbeing.
Incorporating Spermidine into your daily routine is a safe, effective way to boost metabolism, promote autophagy, and protect against oxidative damage. Combined with a healthy lifestyle, it is an excellent tool in ensuring your body can maintain optimal health and longevity throughout aging.
The potential benefits of Spermidine are countless, especially concerning overall wellbeing and longevity. However, everyone’s individual needs are different, so you should highly consider speaking with a healthcare practitioner prior to starting a supplement regimen.
Spermidine and Autophagy-Dependent Geroprotection
MainContinuous caloric restriction (CR) remains the gold standard for extending the lifespan and healthspan of model organisms. Recently, intermittent fasting (IF) interventions, often combined with CR, emerged as alternatives for clinical implementation. However, to date, it remains uncertain whether IF offers health benefits due to the temporary cessation of caloric intake (without CR) or due to a net reduction of total calories de facto resulting in CR. IF, like CR, delays hallmarks of aging in yeast, worms, insects and mice. In humans, intermittent and long-term fasting, as well as continuous CR, are associated with favourable effects on multiple health-relevant parameters that may share a common mechanistic basis. Strong evidence exists that macroautophagy (hereafter referred to as ‘autophagy’) mediates these effects.
In mammals, an age-associated reduction in autophagic flux contributes to the accumulation of protein aggregates and dysfunctional organelles, failing pathogen elimination and exacerbated inflammation. Genetic autophagy inhibition accelerates aging processes in mice and loss-of-function mutations of genes that regulate or execute autophagy have been causally linked to cardiovascular, infectious, neurodegenerative, metabolic, musculoskeletal, ocular and pulmonary diseases, many of which resemble premature aging. Conversely, genetic autophagy stimulation promotes healthspan and lifespan in model organisms, including flies and mice.
Besides nutritional interventions, administering the natural polyamine spermidine (SPD) to yeast, worms, flies and mice is another strategy to extend the lifespan in an autophagy-dependent fashion. Moreover, SPD restores autophagic flux in circulating lymphocytes from aged humans, coinciding with the observation that increased dietary SPD uptake is associated with reduced overall mortality in human populations.
Hence, fasting, CR and SPD extend the lifespan of model organisms and activate phylogenetically conserved, autophagy-dependent geroprotection. Intrigued by these premises, we investigated whether the geroprotective effects of IF might be connected to, or depend on, SPD.
Fasting and Spermidine Levels
To investigate polyamine metabolism during IF, we subjected four different organisms to acute fasting stimuli. Mass spectrometry (MS)-based quantification of SPD, the primary biologically active polyamine and its precursors ornithine (ORN), putrescine (PUT), as well as its metabolite spermine (SPM) revealed a uniform increase in polyamine content upon fasting across various species.
Starving Saccharomyces cerevisiae (yeast) cells in water increased the levels of SPD and SPM, similar to glucose restriction, while ORN generally decreased. Nitrogen starvation (−N), a classical autophagy-inducing intervention, elicited a fast and transient increase in polyamines, mainly PUT, accompanied by a drastic decrease in the precursor ORN. To shed light on the dynamics under −N, we studied metabolic flux in yeast using 13C6-labelled arginine (ARG). We found that the cellular levels of ARG-derived polyamines after 6 h of nitrogen deprivation were higher than in N-containing control medium. Thus, despite the elimination of extracellular nitrogen, polyamine flux remained active, favouring the utilization of residual ARG molecules for polyamine synthesis.
SPD increased in female and male Drosophila melanogaster (fruit fly) fasted for 24 h, which caused a body weight loss of 10% and 5%, respectively. This SPD increase was reversed by 12 h re-feeding. Similarly, young male and female C57BL6/J mice fasted for 14-16 h, which caused significant weight loss , had higher SPD levels (but not PUT nor SPM) in the serum than their ad libitum-fed controls, whereas ORN content was reduced. Moreover, the abundance of ORN and polyamines changed significantly in several organs of acutely fasted mice in a tissue-specific manner, favouring an increase of SPD in multiple tissues. We next asked whether these alterations in polyamine content would also occur during long-term CR, starting at 9 months of age. We found increased serum SPD at 17 months of age in male, but not female, mice. At later time points (21 months), female CR mice also showed significantly elevated PUT and SPD levels in skeletal muscle.
Furthermore, starvation elevated SPD and SPM levels uniformly in human U2OS osteosarcoma and H4 glioblastoma cells. Accordingly, in nutrient-depleted U2OS cells, the expression of arginase (ARG1), ornithine decarboxylase (ODC1), spermidine/spermine N1-acetyltransferase 1 (SAT1) and glycine N-methyltransferase (GNMT) increased compared with cells cultured in control medium, whereas the polyamine-associated transcription factors MYC and YAP/TAZ, as well as two recently identified polyamine transporters, ATPase cation transporting 13A2/13A3 (ATP13A2/3), were unaffected.
In human volunteers, long-term therapeutic fasting with a daily caloric intake of approximately 250 kcal under clinical supervision for 7-13 days, SPD levels (but not PUT nor SPM) significantly increased in the serum. This increase in SPD content was similarly found in men and women, and was independent of age and body mass index (BMI) before the intervention or body weight loss.
We analysed an independent cohort of volunteers fasting for variable periods. SPD levels increased by ~50% after 4-5 days and remained elevated during long-term fasting. In a third cohort, we analysed plasma SPD of individuals who voluntarily followed an IF routine (12-h eating periods followed by 36-h zero-calorie periods for several months). Again, we observed an elevation in SPD levels. Finally, SPD increased in serum and peripheral blood mononuclear cells (PBMCs) of a separate, fourth cohort of volunteers during fasting and reverted to baseline levels after re-feeding. Notably, in these PBMCs, ODC1 protein levels decreased during fasting, suggesting that elevated SPD levels either caused a feedback repression of ODC1 or, at least in these cells, might stem from increased uptake rather than intracellular synthesis.
In conclusion, nutrient starvation (yeast and human cell lines), overnight fasting (flies, mice and humans), long-term CR (mice) or long-term fasting (humans) induced SPD elevation.
Polyamine Synthesis and Metabolic Remodelling
Next, we investigated the cellular consequences of impaired polyamine anabolism on acute fasting responses. We generated yeast lacking the rate-limiting enzyme ornithine decarboxylase (ODC1; yeast Spe1), which are characterized by polyamine depletion . This strain (∆spe1) showed no elevation of polyamines upon starvation, and SPD supplementation (100 µM) fully replenished the intracellular SPD pool. We subjected ∆spe1 cells with and without SPD to proteomic analyses after 6 h nitrogen starvation. Principal-component analysis (PCA) of the proteome revealed a clear distinction between the genotypes and that SPD could revert ∆spe1-associated global differences, whereas it did not affect the wild-type (WT) proteome. Mapping the identified proteins to Kyoto Encyclopedia of Genes and Genomes (KEGG) terms, we found several pathways that have been implicated in the starvation response dysregulated in ∆spe1 . This included, for example, the metabolism of several amino acids (including ARG), lipids and fatty acids, as well as energy-relevant pathways (tricarboxylic acid (TCA) cycle and oxidative phosphorylation). Notably, we also found a disturbed starvation response of the proteostasis-associated pathways autophagy and TORC1/2, the yeast homologues of mechanistic target of rapamycin complex 1/2 (mTORC1/2), in ∆spe1 versus WT cells.
The prominent dysregulation in metabolic pathways was supported by unbiased metabolomic profiling by nuclear magnetic resonance (NMR) spectroscopy, revealing substantial differences in the intracellular metabolomes after nitrogen deprivation . The metabolic disturbances affecting starved ∆spe1 cells confirmed findings from the proteome analysis, including increased citric acid and reduced levels of nicotinamide adenine dinucleotide (NAD+) and adenosine/guanosine-X-phosphate (AXP/GXP; where X stands for mono-, di- or triphosphate), suggesting a disrupted energy metabolism secondary to the loss of intracellular polyamine synthesis . Our analysis also indicated dysregulated amino acid homoeostasis, which is normally maintained by autophagy in starving yeast.
Notably, exogenously supplemented SPD reversed the metabolic dysregulations in ∆spe1 cells, both in control and nitrogen-starvation medium, whereas it hardly affected the general WT metabolomes .
Spermidine's Impact on Gut Health and Obesity
Obesity is associated with impaired intestinal barrier function and dysbiosis of the gut microbiota. Spermidine, a polyamine that acts as an autophagy inducer, has important benefits in patients with aging-associated diseases and metabolic dysfunction. However, the mechanism of spermidine on obesity remains unclear. Here, we show that spermidine intake is negatively correlated with obesity in both humans and mice.
Spermidine supplementation causes a significant loss of weight and improves insulin resistance in diet-induced obese (DIO) mice. These effects are associated with the alleviation of metabolic endotoxemia and enhancement of intestinal barrier function, which might be mediated through autophagy pathway and TLR4-mediated microbial signaling transduction. Moreover, spermidine causes the significant alteration of microbiota composition and function. Microbiota depletion compromises function, while transplantation of spermidine-altered microbiota confers protection against obesity. These changes might partly be driven by an SCFA-producing bacterium, Lachnospiraceae NK4A136 group, which was decreased in obese subjects and subsequently increased by spermidine. Notably, the change of Lachnospiraceae NK4A136 group is significantly correlated with enhanced gut barrier function induced by spermidine.
Spermidine intake is negatively correlated with the obesity index in both humans and mice.
Spermidine and Gut Barrier Integrity
Beneficial effects of spermidine are associated with enhanced gut barrier integrity. Spermidine preserves the integrity of gut barrier associated with autophagy induction. Spermidine alters the composition and function of the gut microbiota. Gut microbiota is required for spermidine-mediated alleviation of metabolic syndrome in DIO mice. Inhibition of TLR4 signaling contributed to anti-obesity effect spermidine. The beneficial effects of spermidine were attributable in part to the enhancement of gut barrier integrity and the alteration of the gut microbiota.
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