As part of our continued exploration of how spermidine influences the 12 hallmarks of aging, this article focuses on the 7th hallmark: mitochondrial dysfunction.
Aging is a multifaceted biological process marked by several hallmarks, one of which is mitochondrial dysfunction. Mitochondria, the energy-producing organelles of cells, are critical for maintaining cellular health. However, as we age, mitochondrial function deteriorates, leading to reduced energy production, increased oxidative stress, and impaired cellular processes. This decline is closely linked to most age-related diseases, including neurodegenerative disorders and cognitive impairments.
Fortunately, emerging research suggests that spermidine, a naturally occurring polyamine, may help rejuvenate mitochondrial health from the inside out.
What Do Mitochondria Do?
Often called the “powerhouses of the cell,” mitochondria are tiny organelles that generate the energy our cells need to function. But their role goes far beyond energy production.
Mitochondria are central to many key cellular processes that influence health, vitality, and aging. They:
- Produce ATP via oxidative phosphorylation (OXPHOS). ATP is the primary energy currency of the cell and is required for nearly all energy-dependent processes.
- Regulate metabolism by processing carbohydrates, fats, and proteins
- Control programmed cell death (apoptosis), helping eliminate damaged cells
- Balance calcium levels, critical for signaling and muscle function
- Manage oxidative stress by generating and detoxifying reactive oxygen species (ROS)
- Maintain mitochondrial DNA, which supports energy production and longevity
- Contribute to hormone and heme synthesis, including steroid hormones and components of red blood cells
In short, mitochondria are not just energy producers, they are gatekeepers of cellular health, making their maintenance essential for a long and vibrant life.
What Is Mitochondrial Dysfunction?
As we age, mitochondria gradually lose efficiency. They produce less energy and more harmful byproducts like ROS, contributing to fatigue, inflammation, and chronic disease.
Mitochondrial dysfunction refers to a decline in mitochondrial performance, marked by:
- Reduced OXPHOS /ATP production
- Impaired mitochondrial quality control
- Increased production of damaging ROS
These changes disrupt cellular energy metabolism and accelerate aging. One of the body’s key defenses is mitophagy, a specialized form of autophagy that selectively removes damaged mitochondria. Unfortunately, autophagic activity declines with age, allowing dysfunctional mitochondria to accumulate and further impair cellular function.
How Spermidine Prevents Mitochondrial Dysfunction
Two recent studies, Schroeder et al. (2021) and Liang et al. (2021), demonstrate how spermidine helps preserve mitochondrial function through multiple, conserved mechanisms across species. Here are the key findings:
- Promotes autophagy and mitophagy:
Spermidine induces mitophagy/autophagy, to clean up damaged mitochondria and ensure their proper functioning.
- Improves mitochondrial respiration:
Spermidine supplementation boosts mitochondrial respiratory capacity, particularly in neuronal tissues. In aged mice and flies, spermidine supplementation increased mitochondrial oxygen consumption and ATP production.
- Supports eIF5A hypusination and protein synthesis:
Spermidine serves as a precursor for hypusination of eIF5A, a post-translational modification essential for mitochondrial protein synthesis. Hypusinated eIF5A facilitates the translation of mitochondrial proteins and autophagy-related factors, ensuring efficient mitochondrial function and autphagy. In Drosophila, genetic attenuation of eIF5A hypusination led to mitochondrial dysfunction and premature aging.
- Reduces oxidative stress:
By improving mitochondrial function, spermidine reduces the production of ROS. Lower oxidative stress supports overall cellular health and resilience.
Spermidine: A Powerful Ally for Preserving Cognitive Health During Aging
Spermidine’s ability to enhance mitochondrial function plays a vital role in protecting cognitive health as we age. By improving cellular energy production and reducing oxidative stress, spermidine supports brain vitality and resilience. Animal studies show that spermidine supplementation improves memory and learning in aged mice, while human research links higher dietary spermidine intake to a lower risk of cognitive decline. Interestingly, the greatest benefits appear when spermidine is introduced in midlife, when it helps sustain mitochondrial respiration and slow the early signs of cognitive aging. However, its benefits may decrease in advanced age (as shown in Liang et al. study), potentially due to reduced levels of NAD+, a cofactor necessary for the hypusination of eIF5A. That being said, it’s never too late to support your brain. Combining spermidine with NAD+ precursors may help overcome age-related limitations and offer renewed protection for cognitive function. Starting early offers the best chance to stay sharp, but even later in life, this duo could be a powerful ally for a healthier, more vibrant mind.
Conclusion
Mitochondrial dysfunction is a key driver of aging and age-related cognitive decline, but it’s not irreversible. Spermidine offers a promising, natural way to support mitochondrial health by enhancing energy production, reducing oxidative stress, and promoting cellular renewal through autophagy and mitophagy. Whether you're looking to maintain mental sharpness or support healthy aging at the cellular level, spermidine may be a powerful ally, especially when started early and supported with complementary strategies like NAD+ replenishment.
