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Trans-Resveratrol

What is Trans-Resveratrol

Trans‑resveratrol (hereafter “resveratrol”) is a naturally occurring polyphenol (stilbene) found in grapes, berries, peanuts, and red wine. It has long attracted interest as a “longevity molecule” because of reported health benefits across multiple organ systems. Resveratrol is known to act as a potent antioxidant and anti-inflammatory agent (Morkovin et al., 2024 ; Cui, Q., & Wang, H., 2025), and it mimics aspects of caloric restriction by activating longevity pathways. In particular, resveratrol strongly activates sirtuin 1 (SIRT1), an NAD⁺‑dependent deacetylase linked to metabolic regulation and stress resistance (Camins et al., 2009 ; Morkovin et al., 2024). By modulating SIRT1 (and other sirtuins such as SIRT6), resveratrol influences numerous downstream targets, including the transcriptional coactivator PGC‑1α, the FOXO family, Akt, and NF-κB (Camins et al., 2009 ; Cui, Q., & Wang, H., 2025). These actions collectively promote cellular stress resistance, reduce inflammation, and support genomic integrity. In animal models, resveratrol supplementation has been reported to extend healthspan and, in some cases, lifespan (Zhou et al., 2021). In human trials, resveratrol is generally well tolerated (up to ~1 g/day) and has shown modest metabolic and anti-inflammatory effects (Brown et al., 2024). Here we review the systemic anti-aging mechanisms of trans-resveratrol, with emphasis on oxidative stress reduction, inflammation modulation, mitochondrial support, genomic stability, sirtuin activation, proteostasis (autophagy), and epigenetic regulation. 

Mechanisms of Action

  1. Oxidative Stress Reduction

Resveratrol is a powerful antioxidant. It directly scavenges reactive oxygen species (ROS) and upregulates endogenous antioxidant defenses (e.g. superoxide dismutase, catalase, glutathione peroxidase)(Morkovin et al., 2024 ; Cui, Q., & Wang, H., 2025). By lowering ROS, resveratrol protects DNA, lipids and proteins from oxidative damage, a major contributor to cellular aging. For example, resveratrol restores mitochondrial membrane potential and reduces lipid peroxidation in stressed cells (Cui, Q., & Wang, H., 2025 ; Pignet et al., 2021). It also indirectly inhibits ROS-producing enzymes: for instance, dietary stilbenes including resveratrol suppress NADPH oxidase and xanthine oxidase (Kasiotis et al., 2013). These combined antioxidant effects help blunt age‑associated oxidative stress (Morkovin et al., 2024).

  1. Inflammation Modulation

Chronic, low‑grade inflammation (inflammaging) drives many age‑related diseases. Resveratrol broadly suppresses inflammatory signaling. It inhibits NF-κB and MAPK pathways, leading to reduced production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) (Cui, Q., & Wang, H., 2025 ; Salehi et al., 2018). This effect is largely SIRT1‑dependent: active SIRT1 deacetylates the NF-κB p65 subunit, dampening its transcriptional activity (Pignet et al 2021 ; Cui, Q., & Wang, H., 2025). Resveratrol also blocks Toll-like receptor 4 (TLR4 - a key innate immune sensor that drives pro-inflammatory response) signaling and NLRP3 (a stress-responsive protein complex that triggers inflammatory cytokine release) inflammasome activation in some models, further curbing inflammation. In vivo, resveratrol reduces systemic inflammatory markers and leukocyte activation in animal models of stress and injury (Cui, Q., & Wang, H., 2025 ; Salehi et al., 2018). Overall, resveratrol’s anti-inflammatory actions help prevent tissue damage and maintain homeostasis during aging.

  1. Mitochondrial Support

Mitochondrial dysfunction is a hallmark of aging. Resveratrol enhances mitochondrial health by activating AMPK and SIRT1/PGC‑1α signaling (Cui, Q., & Wang, H., 2025 ; Camins et al., 2009). SIRT1 deacetylates and activates PGC-1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha), the master regulator of mitochondrial biogenesis. As noted by Cui and Wang, resveratrol “modulates sirtuin activity, particularly SIRT1 and SIRT6, which regulate mitochondrial biogenesis”(Cui, Q., & Wang, H., 2025). In parallel, resveratrol promotes mitophagy (selective removal of damaged mitochondria) by inhibiting mTOR and upregulating autophagy pathways Pignet et al., 2021). These actions restore mitochondrial membrane potential and improve cellular energy metabolism(Brown et al., 2024). Notably, resveratrol combined with exercise in older adults increased skeletal muscle mitochondrial density and improved fatigue resistance (Brown et al., 2024), consistent with enhanced mitochondrial function.

  1. Genomic Stability

Aging is accompanied by DNA damage accumulation and telomere shortening. Resveratrol supports genomic stability through multiple mechanisms. Activation of SIRT1 and SIRT6 promotes DNA repair; for example, Cui and Wang note that “SIRT1 and SIRT6 … regulate DNA repair” (Cui, Q., & Wang, H., 2025). SIRT6 in particular is known to enhance base-excision and double-strand break repair. Resveratrol has also been reported to upregulate telomerase activity and preserve telomeres in some models (Morkovin et al., 2024). By reducing oxidative damage to DNA, resveratrol prevents mutational burden. Additionally, resveratrol can modulate cell‑cycle checkpoints (p53, p21 - key cell-cycle regulators that control DNA damage responses and senescence) via SIRT1, thereby delaying cellular senescence. These genomic actions help maintain stem cell pools and delay aging phenotypes.

  1. Sirtuin Activation

A central mechanism of resveratrol’s anti-aging action is activation of sirtuin proteins, especially SIRT1 (Camins et al., 2009 ; Morkovin et al., 2024). Resveratrol is often described as a SIRT1 “agonist”: it lowers the Michaelis constant of SIRT1 for acetylated substrates, effectively boosting its deacetylase activity in vitro (Pignet et al., 2021). Whether resveratrol directly binds SIRT1 in vivo is debated, but accumulating evidence shows that resveratrol raises cellular NAD⁺ levels via AMPK, leading to indirect SIRT1 activation (Pignet et al., 2021). Once active, SIRT1 deacetylates many transcription factors and histones, orchestrating metabolic and stress responses. For example, SIRT1 deacetylates FOXO3 (stress-responsive transcription factor that promotes antioxidant defense, DNA repair, and longevity pathways) to enhance stress resistance, and deacetylates p53 to modulate senescence. SIRT1 also triggers autophagy and promotes collagen synthesis during tissue repair (Cui, Q., & Wang, H., 2025). Thus, resveratrol-induced SIRT1 signaling is a pleiotropic anti-aging switch.

  1. Proteostasis and  Autophagy

Maintenance of proteostasis (protein homeostasis) is critical for longevity. Resveratrol robustly induces autophagy, the cellular garbage‑disposal system, thereby clearing misfolded proteins and damaged organelles (Pignet et al., 2021 ; Zhou et al., 2021). In cell and animal studies, resveratrol treatment increases autophagosome formation and lysosomal turnover. This effect involves AMPK activation and mTOR inhibition (Pignet et al., 2021). Autophagy induction by resveratrol is functionally important: for example, resveratrol upregulated LC3-II ( membrane-bound, lipidated form of the Microtubule-Associated Protein Light Chain that attaches to autophagosome) and mitophagy vacuoles in stressed cells (Pignet et al., 2021) and genetic blockade of SIRT1 or autophagy genes prevented resveratrol’s benefits in worm lifespan studies (Zhou et al., 2021). By boosting autophagy, resveratrol maintains proteostasis and delays cellular aging and senescence.

  1. Epigenetic Regulation

Resveratrol affects the epigenome via its impact on chromatin regulators. Beyond SIRT1 (a histone deacetylase), resveratrol influences other epigenetic modifiers. It can modulate DNA methyltransferase (DNMT) activity and histone acetylation, altering gene expression patterns associated with aging. For example, resveratrol has been shown to reverse age- or inflammation-induced changes in CpG methylation levels in cultured cells. Resveratrol also enhances circadian clock gene rhythmicity and prevents age-related decline of antioxidant enzyme expression(Cui, Q., & Wang, H., 2025)], indicating broad epigenetic effects on the genome. These epigenetic adjustments help stabilize gene networks against age‑promoting changes. (Ongoing research suggests resveratrol affects microRNAs as well, e.g. upregulating miR-4654(small non-coding RNAs that fine-tune gene expression) to downregulate RHEB (signaling protein that activates mTOR) and induce autophagy (Hecker et al., 2022). 

Taken together, resveratrol’s molecular actions such as antioxidant, anti-inflammatory, mitochondrial, genomic, sirtuin-mediated, proteostatic and epigenetic converge to counter many hallmarks of aging (Cui, Q., & Wang, H., 2025  ; Zhou et al., 2021).

Evidence from Animal Studies

Animal models offer strong support that resveratrol can extend lifespan and healthspan via the above mechanisms. In diverse species, dietary resveratrol often prolongs life and delays age-related decline (Zhou et al., 2021). For example, a meta-analysis concluded that resveratrol extends lifespan in yeast, nematodes, fruit flies and fish (Zhou et al., 2021). In Caenorhabditis elegans, resveratrol induced autophagy and significantly extended lifespan in a SIRT1-dependent manner (Zhou et al., 2021). Similarly, supplemental resveratrol consistently lengthened adult lifespan in Drosophila melanogaster; this effect was attributed to ROS scavenging and neuroprotection rather than caloric restriction (Zhou et al., 2021). Even honey bees fed resveratrol had longer lifespans (25 days vs. 20-23 days in controls) (Zhou et al., 2021). Transgenic resveratrol-enriched diets (e.g. resveratrol-rich rice) markedly increased median lifespan in flies by up to 50% (Zhou et al., 2021). In killifish (Nothobranchius guentheri), resveratrol supplementation also prolonged longevity and improved cognitive and locomotor behaviors in aged fish (Zhou et al., 2021). In a mutant mouse model lacking the stress-protective protease HtrA2, resveratrol extended median survival by about 10 days (Zhou et al., 2021).

Not all results are uniformly positive, however. Several rodent studies failed to extend natural lifespan with resveratrol. For instance, in healthy rats resveratrol (even at high doses equivalent to red wine intake) delayed vascular aging but did not increase overall lifespan (Zhou et al., 2021). Likewise, a comprehensive analysis found that resveratrol did not significantly prolong life in normal laboratory mouse strains or in wild-type mice fed standard diets (Kasiotis et al., 2013). Nonetheless, resveratrol delayed or attenuated many age-related changes in mammals. Resveratrol treatment reduced age-induced insulin resistance and mitochondrial dysfunction in mice on high-fat diets, and it improved cardiac function and neurovascular coupling in aged rodents(Salehi et al., 2018 ; Zhou et al., 2021). In one study, older rats given resveratrol showed reduced oxidative damage in the brain and enhanced neurogenesis. In summary, in animal models resveratrol often improves healthspan and in many invertebrate models it extends lifespan, primarily by inducing autophagy, reducing oxidative stress, and protecting neurons (Zhou et al., 2021).

Evidence from Human Trials

Translating these findings to humans has been challenging, and evidence is mixed but evolving. To date nearly 200 clinical trials (across cancer, metabolic, cardiovascular and other indications) have tested resveratrol (Brown et al., 2024). Overall, resveratrol appears safe at doses up to ~1 g/day, with few serious adverse effects reported (Brown, et al., 2024). However, clear anti-aging outcomes in humans have not been established.

Several trials have examined metabolic and cardiovascular endpoints. For example, in patients with dyslipidemia, 100 mg/day of resveratrol for two months significantly lowered total cholesterol and triglycerides (Brown et al., 2024). In type 2 diabetes, high-dose resveratrol (2 × 500 mg/day) reduced fasting glucose and modestly raised HDL cholesterol. Other small studies reported improvements in insulin resistance and inflammatory markers (CRP, TNF-α) under resveratrol supplementation. On the other hand, many trials have yielded null results: e.g. one study in overweight men found no change in insulin sensitivity or SIRT1/AMPK signaling after 300 mg acute resveratrol (Brown et al., 2024); another in post-menopausal women saw no effect on glucose metabolism or adipose SIRT1 after 75 mg/day for 12 weeks (Brown et al., 2024).

Evidence for resveratrol’s effects on mitochondrial function in humans comes primarily from exercise trials. In healthy older adults, resveratrol (500 mg/day) combined with an exercise program increased skeletal muscle mitochondrial density and improved muscle fatigue resistance compared to exercise alone. However, resveratrol may also blunt some exercise adaptations: in one trial, high-intensity training raised VO₂max more in placebo than in resveratrol-treated men (Brown et al., 2024).

Clinically, resveratrol has consistently shown anti-inflammatory effects. The systematic review by Brown et al. notes that resveratrol “consistently reduces inflammatory markers” in human studies (Brown et al., 2024). Reductions in IL-6, TNF-α, and CRP have been observed in several trials, suggesting potential to mitigate chronic inflammation. 

Other trials have explored aging biomarkers more directly. For instance, one study in healthy older men found that resveratrol increased circulating levels of lysosomal enzyme protein p16^INK4a (a marker of senescent cells) - suggesting complex effects on senescence pathways. In summary, human evidence suggests resveratrol may favorably modulate metabolism and inflammation. It is generally well tolerated up to gram doses (Brown et al., 2024).