Longevity compounds need to be especially safe because they’re intended for generally healthy people who may take them over long periods of time. Unlike treatments for acute or life-threatening conditions, these compounds, also known as geroprotectors, are designed to slow aging and lower the risk of age-related diseases. That makes safety a top priority. Side effects can not only undermine their benefits but may also interfere with other treatments, especially in older adults. Minimizing those risks is thus essential to ensure these interventions truly support long-term health and well-being.
A study published in Biogerontology takes a deep dive into the safety and effectiveness of potential longevity compounds. Researchers examined 124 geroprotectors from the DrugAge database and compared them with side effect predictions from the SEP-L1000 database, which uses gene expression data to estimate risk. Their goal was simple: find compounds that can extend lifespan without putting human health at risk. And among all the candidates, spermidine rose to the top, offering an exceptional balance of efficacy and safety, and outperforming well-known options like D-glucosamine, metformin, and even rapamycin.
Spermidine: The Most Promising and Safest Longevity Molecule So Far
In the study, spermidine emerged as one of the safest and most effective geroprotectors identified. Its standout feature is its ability to stimulate autophagy, the body’s cellular cleanup system. By promoting the removal of damaged components and supporting mitochondrial and metabolic health, spermidine helps preserve cellular function, which is key to slowing the aging process.
Spermidine has been shown to extend lifespan in multiple model organisms, including yeast, worms, flies, and mice. In flies, it boosted lifespan by up to 30%, making it one of the most potent geroprotectors studied so far. In humans, higher dietary intake of spermidine has also been linked to longer life expectancy. But most importantly, spermidine stands out for its exceptional safety profile. According to the study, its most likely side effect is mild dizziness, with no predicted risk of severe outcomes like cardiac failure or death.
Spermidine emerges as the top contender among safe longevity compounds
a. This 3D plot compares how different compounds affect lifespan (y-axis) versus their likelihood and number of side effects (x- and z-axes). Compounds on the left side have fewer and less severe side effects. Spermidine (green dot) stands out in this low-risk group as the top performer, showing the greatest lifespan increase among these safer options.
b. The four most promising low-risk longevity compounds are shown, including spermidine (which promotes autophagy), gallic acid (a natural antioxidant), D-glucosamine (a glycolysis inhibitor), and clofibrate (a lipid-lowering drug). Spermidine has demonstrated lifespan benefits across multiple species and remains one of the safest geroprotectors identified so far. © 2025 Melissa Cano. All rights reserved. Adapted from Janssens et al. (2020).
D-Glucosamine: Another Promising Contender
D-glucosamine, widely used to treat osteoarthritis, was also highlighted in the study as a notable and relatively safe geroprotector. It acts as a calorie restriction mimetic by inhibiting glycolysis, thereby mimicking the metabolic effects of fasting and dietary restriction. This mechanism is linked to its ability to extend lifespan (animal studies have shown lifespan increases of 10–16% in worms and mice). In humans, it has been associated with reduced risk of cardiovascular disease and lower overall mortality rates. It’s naturally derived from shellfish shells or produced synthetically and has a long history of safe use with good tolerance. While it carries a slightly higher chance of mild side effects like rash, it poses no predicted risk of severe adverse events such as cardiac failure or death.
Metformin and Rapamycin: Popular but Not Without Risks
Metformin and rapamycin are probably two of the most talked-about compounds in the longevity world. Metformin, widely used to manage diabetes, shows promise in reducing age-related diseases. However, the study found it’s linked to quite a few side effects, with a high chance of causing nausea or vomiting. Rapamycin works by blocking the mTOR pathway, a major regulator of aging, but it also carries a higher risk of side effects, including some serious ones like cardiovascular issues. While rapamycin has delivered impressive lifespan extensions in animals (including a recent study where combining it with trametinib boosted mouse lifespan by over 30% à check out our blog for details), its risk profile makes it a challenging option for everyday use in otherwise healthy people. So, although these drugs are powerful, their potential side effects mean it’s important to approach them with caution.
The Hormesis Paradox: When More Lifespan Extension Means Greater Side Effects
Interestingly, the study found a clear link between how much a compound can extend lifespan and its likelihood of causing side effects. This may be explained by hormesis, the idea that low doses of potentially harmful substances trigger protective stress responses in the body. Think of it like exercise: a little stress makes your muscles stronger, but too much can cause injury. While this mild stress can be beneficial, it also means that compounds with the strongest lifespan-extending effects often come with higher risks, making them harder to safely translate to humans.
In fact, the paper suggests that focusing solely on maximal lifespan extension might not be the best way to identify promising geroprotectors, since those with extreme effects tend to carry greater side effect burdens. This finding highlights the importance of balancing efficacy with safety when developing anti-aging interventions.
Prioritizing Safety: The Path Forward in Longevity Research
The study concludes that spermidine and D-glucosamine are the top longevity compounds contenders for human trials, combining proven longevity benefits across species with strong safety records, especially spermidine, abundant in everyday foods.
Choosing between them depends on your personal aging goals: spermidine excels at boosting mitochondrial health, autophagy, and cognitive resilience, while D-glucosamine is known for supporting joint health and relieving osteoarthritis pain.
Although combining these compounds could offer complementary benefits due to their different mechanisms of action, the study urges caution. Mixing hormetic geroprotectors that affect the same pathways can raise toxicity risks. More research is needed to confirm the safety and effectiveness of such combinations.
Ultimately, this research highlights a vital truth in the longevity field: it’s not just about what works, but what works safely. While big names like metformin and rapamycin tend to dominate the spotlight, quieter contenders like spermidine may be the real stars of the show, delivering results without the risk. With new clinical trials on the way (and some big revelations likely around the corner, stay tuned!), the race to extend healthy human lifespan is heating up, and spermidine is sprinting ahead.
