Aging is a complex biological process characterized by the progressive decline in physiological functions, leading to increased vulnerability to diseases. Scientists have identified twelve hallmarks of aging, interconnected processes that drive aging and its associated pathologies. Among these hallmarks, dysbiosis, or to the imbalance in gut microbiota, has emerged as the 12th hallmark, highlighting the critical role of gut health in aging. Recent research has revealed that spermidine, a naturally occurring polyamine, holds promise in addressing dysbiosis and promoting healthy aging.
Understanding Dysbiosis: The 12th Hallmark of Aging
Dysbiosis refers to the disruption of the gut microbiota's balance, which can lead to chronic inflammation, metabolic dysfunction, and increased susceptibility to age-related diseases. As we age, the diversity and composition of gut microbiota change, often resulting in a decline in beneficial bacteria and an increase in harmful ones. This imbalance can exacerbate systemic inflammation, impair nutrient absorption, and contribute to conditions such as inflammatory bowel disease (IBD), obesity, and neurodegenerative disorders.
How Spermidine Fights Dysbiosis
Spermidine is a polyamine found in all living organisms, synthesized endogenously, obtained from dietary sources, or produced by the gut microbiota. It plays a vital role in cellular processes including autophagy, DNA stabilization, protein synthesis, and oxidative stress regulation. However, spermidine levels naturally decline with age, correlating with dysbiosis and the onset of age-related diseases. Research has shown that spermidine supplementation can counteract dysbiosis by:
- Promoting autophagy: Autophagy is a cellular process that removes damaged organelles and proteins, maintaining cellular homeostasis. Autophagic activity naturally declines with age, and dysbiosis further impairs this process, leading to a weakened intestinal barrier and increased inflammation. Spermidine has been shown to activate autophagy and support cellular renewal, thereby restoring the intestinal epithelial barrier and reducing inflammation. This mechanism is particularly beneficial in conditions like ulcerative colitis, where mucosal repair is critical.
- Restoring gut microbiota balance: Spermidine has been shown to enhance the growth of beneficial gut bacteria, such as Bifidobacterium and Lactobacillus. These bacteria play a crucial role in maintaining gut health by producing metabolites, such as short-chain fatty acids and polyamines including spermidine, that support intestinal barrier function and suppress inflammation. For example, studies have demonstrated that supplementation with Bifidobacterium lactis LKM512 yogurt increases gut polyamine levels, reduces gut mutagenic activity, and improves mucosal integrity.
- Strengthening the intestinal barrier: A strong intestinal barrier is critical for preventing dysbiosis. Spermidine enhances gut barrier function by preserving tight junction proteins, including occludin, claudins, and ZO-1. This helps prevent increased intestinal permeability, commonly known as leaky gut, a hallmark of aging linked to chronic inflammation and microbiome imbalance. By reducing microbial translocation and limiting exposure to bacterial toxins, spermidine creates a stable intestinal environment that favors beneficial microbes.
- Reducing chronic inflammation: Dysbiosis often triggers chronic inflammation, a key driver of aging and age-related diseases. Spermidine has potent anti-inflammatory properties, as it induces the production of anti-inflammatory macrophages and suppresses pro-inflammatory markers such as TNF-α, IL-1β, and IL-6. These effects help mitigate the harmful consequences of dysbiosis and promote gut health.
Spermidine, Gut Health & Longevity
The benefits of spermidine extend beyond gut health, positioning it as a central molecular link between the microbiome and the biology of aging. Aging reflects the progressive breakdown of cellular maintenance systems, and mounting evidence shows that age-related shifts in gut microbiota play a pivotal role in this decline. Dysbiosis reduces microbial diversity, diminishes beneficial bacteria, and lowers the production of key metabolites including spermidine itself.
By restoring microbial balance and replenishing spermidine levels, a powerful virtuous cycle emerges: a healthier gut microbiome produces more spermidine, and spermidine, in turn, supports the growth and function of beneficial microbes while strengthening the intestinal barrier. This self-reinforcing loop reduces chronic low-grade inflammation (inflammaging), enhances metabolic resilience, and sustains cellular repair mechanisms such as autophagy and mitochondrial quality control.
Through this gut–cellular feedback loop, spermidine influences multiple hallmarks of aging which helps explain why higher spermidine exposure has been linked to improved cardiovascular health, neuroprotection, and extended healthspan. Notably, centenarians often display gut microbiota profiles resembling those of much younger individuals, alongside preserved polyamine metabolism, reinforcing the idea that maintaining this virtuous gut–spermidine cycle may be a foundational driver of longevity.
Conclusion: Targeting the Gut for Healthy Aging
Dysbiosis places gut health at the center of longevity science. Spermidine stands out as a powerful modulator of this process, activating autophagy, restoring microbial balance, strengthening the intestinal barrier, and reducing chronic inflammation.
Through diet, targeted probiotics and prebiotics, or direct supplementation, supporting spermidine levels helps reestablish a virtuous cycle between a healthy gut microbiome and cellular resilience. As longevity research advances, spermidine-based strategies are emerging as practical, science-backed tools to protect healthspan and support healthier aging from the inside out.
(Adapted from López-Otín et al., 2022)
Curious about the other hallmarks of aging and how spermidine can help combat them? Read more here.
