A new study published in Cell Metabolism has identified S-1-propenyl-L-cysteine (S1PC), a bioactive metabolite derived from aged garlic, as a potential regulator of healthy aging. Researchers found that S1PC activates the LKB1-SIRT1 pathway in adipose tissue, promotes the secretion of eNAMPT, and enhances NAD⁺ synthesis through hypothalamic signaling. In aged mice, long-term S1PC treatment was associated with reduced frailty and improved muscle strength. A preliminary human study involving 44 healthy adults also showed increased circulating eNAMPT after S1PC intake. These findings reveal a potential “adipose tissue–hypothalamus–muscle” signaling pathway, although further clinical research is needed to determine its long-term effects and applications in humans.
Garlic has long been valued as a versatile culinary ingredient, but growing scientific evidence suggests that its biological potential extends far beyond flavor and food preservation. Among the many compounds found in garlic, S-1-propenyl-L-cysteine (S1PC), a metabolite enriched in aged garlic, has recently attracted attention for its potential role in healthy aging. A joint research team from Japan and China reported in Cell Metabolism that S1PC can activate a previously uncharacterized signaling pathway involving adipose tissue, extracellular vesicles, the hypothalamus, and skeletal muscle.
The study found that oral S1PC rapidly increased circulating extracellular nicotinamide phosphoribosyltransferase (eNAMPT), which can contribute to NAD⁺ synthesis in distant tissues. Mechanistically, S1PC promoted the formation of an LKB1-STRAD-MO25 complex in adipose tissue, activated SIRT1, and enhanced the secretion of eNAMPT-containing extracellular vesicles without activating the classical AMPK/lipolysis pathway. In aged mice, long-term S1PC administration was associated with reduced frailty, improved thermoregulation, and greater skeletal muscle strength. Further analysis suggested that these effects were mediated through a systemic “adipose tissue–hypothalamus–sympathetic nervous system–muscle” axis.
A small human study involving 44 healthy Japanese adults also found that S1PC increased circulating eNAMPT in participants with normal body fat levels, while no increase in circulating free fatty acids was observed. Although these findings are promising, the human evidence remains preliminary, and further clinical research is needed to determine the long-term safety, efficacy, appropriate intake levels, and potential applications of S1PC in human nutrition and dietary supplements.
Garlic is undoubtedly a familiar “all-purpose seasoning” in kitchens around the world. But if you still think of garlic simply as an ingredient used to remove unwanted odors and enhance flavor, you may be underestimating its biological potential.
A substantial body of previous research has suggested that regular consumption of garlic extracts may be associated with a reduced risk of mortality from gastric cancer, while also influencing important blood parameters such as hemoglobin, total cholesterol, and low-density lipoprotein (LDL). Positive findings have also been reported in areas related to cardiovascular and cerebrovascular health and cancer prevention.
Recently, garlic has once again attracted scientific attention.
A joint research team from Japan and China published a new study in Cell Metabolism. The researchers isolated a distinctive bioactive compound from aged garlic—S-1-propenyl-L-cysteine, or S1PC—and identified a previously uncharacterized anti-aging signaling pathway. Their findings showed that this garlic-derived metabolite could exert systemic effects and significantly improve the decline in muscle strength associated with aging in mice.
Understanding S1PC
NAD⁺ is a key molecule involved in cellular energy metabolism and repair, and its levels decline with age. It is therefore considered one of the important molecular hallmarks of aging.
In their earlier observations, the researchers found that many of the physiological effects of S1PC resembled those associated with several of the increasingly studied “NAD⁺ boosters,” such as NMN and NR.
In mammals, NAD⁺ synthesis is regulated by both intracellular NAMPT (iNAMPT) and secreted NAMPT (eNAMPT). Of particular interest is eNAMPT, which can be packaged into extracellular vesicles (EVs) by white adipose tissue (WAT) and released into the bloodstream. These extracellular vesicles can travel to distant organs, including the hypothalamus, where eNAMPT can promote local NAD⁺ synthesis.
The researchers therefore proposed the following hypothesis:
Could S1PC increase circulating eNAMPT levels and thereby enhance the availability of NAD⁺ throughout the body?
The study was designed around this hypothesis, with a series of experiments aimed at systematically dissecting the underlying mechanism.
First, young mice were orally administered S1PC at a dose of 5 mg/kg. Blood and tissue samples were collected at different time points—15, 30, 60, 180, and 300 minutes after administration—to measure plasma eNAMPT, hypothalamic NAD⁺, tissue distribution of S1PC, and other parameters.
The results showed that S1PC was rapidly absorbed following oral administration. Its concentration in plasma and epididymal white adipose tissue (eWAT) reached a peak as early as 15 minutes after administration and then declined rapidly. S1PC was also detected in the soleus muscle, mesenteric adipose tissue, and brain.
At the same time, plasma eNAMPT levels showed a distinctive biphasic increase, with the first peak occurring at 15–30 minutes and the second peak appearing at 300 minutes.
Corresponding to the first peak, hypothalamic NAD⁺ levels increased significantly at 15 and 30 minutes after S1PC administration. NAD⁺ levels in the cerebral cortex and liver also increased, although at somewhat later time points.
Taken together, the acute experiments outlined a clear dynamic pathway:
S1PC is rapidly absorbed into the circulation and distributed to adipose tissue, where it promotes the packaging and secretion of eNAMPT into extracellular vesicles. These eNAMPT-containing vesicles enter the circulation and travel to the hypothalamus, where they promote an increase in local NAD⁺ synthesis.
Figure 1. S1PC significantly increases circulating eNAMPT and tissue NAD⁺ levels in mice.
How Does S1PC Activate the Adipose-to-Hypothalamus Signal?
How does S1PC stimulate adipose cells to secrete eNAMPT?
The key appears to be LKB1, one of the important “metabolic master switches” or “longevity switches.”
The researchers found that only 15–30 minutes after oral S1PC administration, LKB1 protein in mouse adipose tissue was rapidly activated and specifically engaged SIRT1, an NAD⁺-dependent deacetylase that is also closely associated with longevity-related biological processes.
Activated SIRT1 promoted the packaging of eNAMPT into extracellular vesicles (EVs) and their release from adipocytes into the circulation. These eNAMPT-containing vesicles could then travel through the bloodstream to the hypothalamus, completing a cross-organ signaling process from peripheral adipose tissue to the central nervous system.
Further investigation revealed that LKB1 must form a ternary complex with STRAD and MO25 in order to become functionally active.
In this process, S1PC appears to act as a kind of “molecular glue,” helping STRAD and MO25 associate more effectively with LKB1.
Importantly, this pathway did not activate the classical AMPK or lipolysis axis. Free fatty acid levels remained unchanged. Instead, S1PC activated a non-classical LKB1→SIRT1 pathway. This finding may help explain why blood lipid levels did not show changes in the human study.
Finally, the research team conducted a combination experiment in aged mice.
Twenty-four- to 27-month-old mice received NMN injections at 300 mg/kg for five consecutive days, followed by oral S1PC administration at 5 mg/kg on the fifth day.
The results showed that circulating eNAMPT levels in the combination-treatment group were significantly higher than those in either the NMN-only or S1PC-only groups, supporting the effect of S1PC on this pathway.
An Eight-Month Study in Aging Mice
The acute experiments provided evidence for the underlying mechanism. But could long-term S1PC administration actually influence age-related decline?
To investigate this question, researchers selected healthy 15-month-old mice, roughly corresponding to humans in their 50s.
Beginning at 15 months of age, the mice received S1PC through feed or drinking water at an approximate dose of 5 mg/kg/day, continuing until 23 months of age—roughly corresponding to humans in their 70s.
The treatment lasted for a total of eight months.
The results were notable.
Long-term S1PC treatment significantly reduced the frailty index of aged mice, indicating an improvement in overall physical condition. Their rectal body temperature returned toward the level observed in younger animals, suggesting improved thermoregulatory capacity.
In assessments of muscle function, S1PC-treated mice generated significantly greater muscle force under high-frequency electrical stimulation than control animals, indicating that muscle function had been protected during the aging process.
Mechanistic analysis revealed that S1PC treatment increased the expression of β2-adrenergic receptors (β2AR) in the soleus muscle of aged mice and significantly enhanced CREB phosphorylation. At the same time, mitochondrial proteins associated with oxidative phosphorylation were also increased.
Together, these molecular changes point toward a functional chain in which:
increased sympathetic nervous system activity → enhanced β-adrenergic signaling → improved muscle oxidative metabolism → increased muscle strength.
These findings suggest that the improvement in muscle function was not necessarily the result of a direct action of S1PC on skeletal muscle.
Instead, the researchers proposed a systemic signaling axis:
“Adipose tissue → hypothalamus → sympathetic nervous system → skeletal muscle.”
In this model, S1PC initiates regulatory signals at the level of the hypothalamus, which then enhance neural signaling and ultimately contribute to improved muscle function.
Figure 3. Long-term S1PC treatment reduces frailty and enhances skeletal muscle strength in aged mice.
A 44-Participant Human Study
The study also included a small-scale human clinical trial.
A total of 44 healthy Japanese adults aged 20–49 years were enrolled and divided into a placebo group and an S1PC group.
Participants in the S1PC group received a single oral tablet containing 25 mg of S1PC in high-concentration garlic powder, with an S1PC purity of 17%.
Blood samples were collected at 30, 60, and 120 minutes after administration for analysis.
The results were broadly consistent with the mouse experiments.
Among participants with normal body fat percentages and healthy levels of adipose tissue, S1PC intake resulted in a significant increase in circulating eNAMPT levels after 120 minutes. This finding suggests that S1PC may also stimulate eNAMPT secretion in humans.
However, individuals with a BMI below 18.5 and lower body fat levels showed little change in their baseline eNAMPT response and exhibited almost no response to S1PC.
Furthermore, consistent with the findings from the cellular experiments, S1PC administration did not increase circulating free fatty acid levels in the participants. This suggests that S1PC did not trigger unnecessary fat breakdown and provides further support for the specificity of the proposed signaling pathway.
Figure 4. S1PC increases circulating eNAMPT levels in healthy human participants.
Conclusion
There is an old saying in China: “Eating garlic gives you strength.”
In ancient Egyptian and Greek civilizations, garlic was also regarded as a food associated with restoring physical strength and improving endurance. Laborers and soldiers were reportedly encouraged to consume garlic before demanding physical activities or military campaigns.
For thousands of years, however, these observations remained largely within the realm of traditional experience.
Today, researchers have begun to provide a biological explanation through animal experiments and preliminary human clinical research.
The study suggests that the garlic-derived metabolite S1PC may influence a sophisticated cross-organ signaling network involving the “adipose tissue → hypothalamus → sympathetic nervous system → skeletal muscle” axis, potentially helping counter some aspects of age-related muscle weakness and physical frailty in experimental models.
In this sense, modern science may be beginning to provide a biological interpretation for the long-standing traditional observation that garlic may be associated with physical strength.
Nevertheless, it is important to interpret these findings cautiously. The strongest evidence in this study comes from experimental work in mice, while the human study was small, involved healthy adults, and evaluated short-term changes in circulating eNAMPT rather than long-term anti-aging or muscle-function outcomes. Whether S1PC supplementation can produce meaningful long-term benefits in humans remains to be determined through larger and longer clinical trials.
For now, maintaining a balanced diet, keeping a healthy level of body fat, and engaging in regular resistance exercise remain practical strategies for supporting healthy aging and preserving muscle function.
As for whether higher-concentration S1PC derived from garlic extracts will eventually become a component of everyday dietary supplements, further research will be needed to establish its safety, appropriate dosage, efficacy, and potential applications.
References
Suzuki JI, Yoshioka K, Kurita M et al. Garlic-derived metabolite activates LKB1, promotes adipose eNAMPT secretion, and improves age-related muscle function via hypothalamic signaling. Cell Metab. 2026 Jun 2;38(6):1218-1228.e10. doi: 10.1016/j.cmet.2026.04.006. Epub 2026 May 7. PMID: 42102814.