Pterostilbene

What is Pterostilbene?

Pterostilbene (often abbreviated PTS or PTE) is a naturally occurring stilbene-type polyphenolic compound and a close structural analog of resveratrol that plants produce as a defence molecule (phytoalexin) against environmental stress (Nagarajan et al., 2022; Liu et al., 2020). It is found most abundantly in blueberries and other Vaccinium berries, but also occurs in grapes, peanuts and the heartwood of certain trees such as Pterocarpus marsupium and Dalbergia species (Nagarajan et al., 2022; Liu et al., 2020). Chemically, pterostilbene is trans-3,5-dimethoxy-4′-hydroxystilbene, meaning it has a stilbene backbone (two benzene rings joined by a carbon–carbon double bond) with one phenolic hydroxyl group (–OH) and two methoxy groups (–OCH₃) attached at defined positions on the rings; this substitution pattern classifies it as a 3,5-dimethoxy analog of resveratrol and gives it the molecular formula C₁₆H₁₆O₃ (Liu et al., 2020; Kim et al., 2020). The presence of methoxy groups reduces the number of free phenolic hydroxyls compared with resveratrol and increases lipophilicity (fat solubility), which in turn improves membrane permeability, metabolic stability and oral bioavailability, that is, the fraction of an ingested dose that reaches the systemic circulation in active form (Kim et al., 2020). Pharmacokinetic studies, which examine absorption, distribution, metabolism and excretion, show that pterostilbene exhibits higher intestinal absorption, a longer plasma half-life and broader tissue distribution, including more efficient penetration of the blood–brain barrier, than resveratrol under comparable dosing conditions (Liu et al., 2020; Dutta et al., 2023). In nature and in industrial production, pterostilbene can be obtained by solvent extraction and purification from rich plant sources, but it can also be generated synthetically or via biotransformation of resveratrol using O-methyltransferase enzymes that transfer methyl groups onto resveratrol’s hydroxyl positions (Liu et al., 2020; Kim et al., 2020). Because of its favourable chemical structure and pharmacokinetic profile, pterostilbene has been extensively investigated as a bioactive small molecule with antioxidant, anti-inflammatory, lipid-modulating, glucose-lowering, neuroprotective and anti-tumour properties across a range of experimental models of chronic metabolic, cardiovascular and neurodegenerative disorders (Nagarajan et al., 2022; Kim et al., 2020; Dutta et al., 2023).

How it influences aging?

A.    Oxidative stress:

Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and the capacity of antioxidant defence systems to neutralise them, is a major driver of ageing because chronic ROS overload damages DNA, proteins and lipids, accelerates mitochondrial dysfunction and promotes the hallmarks of ageing such as cellular senescence and tissue degeneration (Beckman and Ames, 1998; Li et al., 2018). Pterostilbene counters this pressure primarily by strengthening endogenous antioxidant defences and limiting ROS generation. Mechanistic reviews show that pterostilbene directly reduces intracellular ROS levels and upregulates key antioxidant enzymes, including superoxide dismutase (which converts superoxide to hydrogen peroxide), catalase and glutathione peroxidase (which detoxify hydrogen peroxide), thereby lowering markers of oxidative damage across cardiovascular, metabolic and neurological models (McCormack and McFadden, 2013). At the signalling level, pterostilbene activates nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that switches on genes encoding antioxidant and detoxifying enzymes such as heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1, and this NRF2-dependent programme has been shown to reverse arsenic-induced oxidative cytotoxicity in vitro (Zhou et al., 2019). In whole-organism ageing models, dietary pterostilbene supplementation decreases ROS load, boosts antioxidant capacity and is accompanied by improved survival; in fruit flies, for example, pterostilbene both increased mean lifespan and enhanced antioxidant defences, supporting the idea that its lifespan extension is tightly linked to improved oxidative stress resistance (Beghelli et al., 2022). Tissue-specific ageing studies echo this pattern: in ageing laying hens, pterostilbene increased ovarian glutathione, superoxide dismutase, catalase and total antioxidant capacity while reducing oxidative damage and apoptosis, leading to better ovarian function in a model where oxidative stress is recognised as a key cause of ovarian ageing (Wang et al., 2024). Integrative ageing-focused overviews therefore conclude that pterostilbene acts as an anti-ageing molecule largely by restoring redox balance, that is, by lowering chronic oxidative stress at both cellular and tissue levels, which in turn helps preserve cellular integrity, delay functional decline and mitigate age-related pathologies (Dutta et al., 2023).

B.    Chronic inflammation (“inflammaging”):

Chronic inflammation in ageing, often termed “inflammaging”, is a state of persistent, low-grade, systemic immune activation in the absence of overt infection. This sterile inflammation is driven by long-term elevation of pro-inflammatory cytokines (small immune signalling proteins such as tumour necrosis factor alpha, interleukin-1 beta and interleukin-6) and sustained activation of inflammatory transcription factors like nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and is recognised as a major risk factor for frailty and most age-related diseases (Franceschi and Campisi, 2014; Ferrucci and Fabbri, 2018). Against this background, pterostilbene appears to act as an “anti-inflammaging” molecule by dampening these chronic inflammatory circuits at multiple levels. Mechanistic ageing reviews report that pterostilbene consistently suppresses NF-κB signalling and reduces expression of classic pro-inflammatory mediators (including cyclooxygenase-2, inducible nitric oxide synthase and the cytokines TNF-α, IL-1β and IL-6) in models of cardiovascular, metabolic and neurodegenerative disease, and they explicitly link these anti-inflammatory shifts to attenuation of the inflammatory hallmark of ageing (Li et al., 2018). At a systems level, long-term dietary pterostilbene in healthy rats remodels the blood transcriptome so that gene sets associated with innate immune activation and cytokine signalling are downregulated, whereas pathways involved in stress resistance and homeostatic regulation are favoured, leading the authors to conclude that pterostilbene targets inflammatory hallmarks of ageing in vivo (Tello-Palencia et al., 2024). In age-linked disease models, pterostilbene also modulates the senescence-associated secretory phenotype (SASP), the pro-inflammatory cocktail released by senescent cells: in osteoarthritic cartilage, pterostilbene acts as a senomorphic agent (a compound that suppresses harmful features of senescent cells without killing them), inhibiting the phosphoinositide 3-kinase/protein kinase B/NF-κB (PI3K/AKT/NF-κB) axis, lowering SASP (Senescence-Associated Secretory Phenotype) factors such as IL-1β, IL-6 and matrix-degrading enzymes, and thereby reducing chronic joint inflammation and structural degeneration in an archetypal age-related inflammatory disorder (Wang et al., 2022). Similarly, in human skin keratinocytes exposed to particulate matter – a model of environmental “skin inflammaging”, pterostilbene reduces reactive oxygen species, suppresses NF-κB-driven inflammatory cytokines and matrix metalloproteinases, and decreases cellular ageing markers, supporting the idea that it protects barrier tissues from chronic inflammatory stress that accumulates with age (Teng et al., 2021). Taken together, these findings support a coherent picture in which pterostilbene mitigates inflammaging by down-tuning NF-κB-centred cytokine networks and SASP output across blood and multiple tissues, thereby reducing the chronic inflammatory burden that accelerates functional decline and age-related pathology.

C.    Cellular senescence & SASP:

Pterostilbene appears to counter age-related damage partly by acting as a senomorphic compound, that is, a molecule which dampens the harmful secretory profile of senescent cells without necessarily killing them and thereby reduces the senescence-associated secretory phenotype (SASP) burden that drives tissue ageing. In osteoarthritic cartilage, pterostilbene reduces classical senescence markers such as senescence-associated β-galactosidase (SA-β-gal, a lysosomal enzyme used as a senescence stain) and the cell-cycle inhibitors p16 and p21, while simultaneously lowering key SASP factors including interleukin-6 (IL-6), matrix metalloproteinase-13 and ADAMTS5, and this is mechanistically linked to inhibition of the phosphoinositide 3-kinase/protein kinase B/nuclear factor kappa B (PI3K/AKT/NF-κB) signalling axis that drives SASP gene expression in chondrocytes (Wang et al., 2022). In the liver, pterostilbene limits ethanol-triggered hepatocyte senescence and SASP by inducing Sestrin2 (SESN2, a stress-response protein) and promoting p62-dependent selective autophagy, a form of “tag-and-digest” intracellular recycling, that targets the matricellular protein CCN1 for degradation, thereby relieving senescence, inflammatory secretions and steatosis in an ageing-relevant model of alcoholic liver injury (Jiang et al., 2023). Vascular ageing studies show that pterostilbene and a nicotinate derivative suppress endothelial cell senescence (reduced SA-β-gal, p53 and p21) and restore nitric oxide–mediated vasodilation through activation of sirtuin 1 (SIRT1, a nicotinamide adenine dinucleotide-dependent deacetylase that represses senescence transcriptional programmes), supporting a role for pterostilbene in curbing senescence-driven vascular dysfunction (Zhang et al., 2021). At the level of fibroblasts, pterostilbene attenuates human cytomegalovirus-induced cellular senescence by decreasing SA-β-gal positivity, lowering p16, p21 and p53 expression and reducing reactive oxygen species, thereby limiting virus-driven accumulation of senescent cells that would otherwise contribute to systemic senescent burden with age (Wang et al., 2022). Taken together, these findings outline a coherent mechanism in which pterostilbene interferes with pro-senescent signalling nodes such as PI3K/AKT/NF-κB, SIRT1 and SESN2–autophagy pathways, selectively suppresses SASP factor output across joint, liver, vascular and fibroblast systems, and in doing so acts as a senomorphic agent that reduces senescent-cell–mediated inflammatory stress in ageing tissues (Wu et al., 2023).

D.    Mitochondrial function & biogenesis:

Pterostilbene supports healthier ageing in part by preserving and rebuilding mitochondrial networks through nutrient-sensing pathways that are strongly linked to longevity. In high-fat Western-diet models, pterostilbene enhances thermogenesis (heat production from fat) and increases mitochondrial biogenesis in white adipose tissue by activating a sirtuin–coactivator axis: it stimulates sirtuin 1 (SIRT1, a nicotinamide adenine dinucleotide-dependent deacetylase), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α, a master regulator of mitochondrial biogenesis) and the mitochondrial deacetylase sirtuin 3 (SIRT3), leading to higher expression of mitochondrial genes and protection against diet-induced obesity and metabolic decline (Koh et al., 2023). In the heart, pterostilbene similarly boosts the Adenosine Monophosphate-activated protein kinase/sirtuin-1/PGC-1α (AMPK/SIRT1/PGC-1α) cascade, which increases mitochondrial content, maintains mitochondrial membrane potential and Adenosine Triphosphate (ATP) levels and limits structural damage in cardiomyocytes exposed to the chemotherapeutic drug doxorubicin, demonstrating that activating this mitochondrial biogenesis programme can preserve function in an ageing-vulnerable organ (Liu et al., 2019). Drug-screening work in patient-derived fibroblasts with primary mitochondrial respiratory chain defects identifies pterostilbene as a “mitochondrial booster”, particularly when combined in a cocktail (CoC3) with classical mitochondrial cofactors; this mixture increases sirtuin activity, triggers the mitochondrial unfolded protein response (UPRmt, a quality-control pathway that restores protein homeostasis inside mitochondria) and improves basal and maximal respiration as well as spare respiratory capacity, indicating more resilient mitochondrial bioenergetics in cells that model aspects of mitochondrial ageing (Suárez-Rivero et al., 2022). At the whole-animal level, transcriptomic profiling of blood from healthy rats supplemented with pterostilbene shows coordinated upregulation of gene sets associated with oxidative phosphorylation and mitochondrial organisation, and downregulation of signatures linked to the “mitochondrial dysfunction” hallmark of ageing, suggesting that pterostilbene systemically reprogrammes mitochondrial pathways in vivo (Tello-Palencia et al., 2024). Collectively, these findings support a mechanistic narrative in which pterostilbene activates AMPK/SIRT1/PGC-1α/SIRT3 and UPRmt signalling to increase mitochondrial biogenesis, maintain mitochondrial energy production and improve mitochondrial quality control, thereby counteracting mitochondrial decline that would otherwise accelerate metabolic and functional ageing.

  mTOR / Insulin–IGF-1 axis (nutrient sensing):

The mechanistic target of rapamycin (mTOR) is a nutrient-sensing serine/threonine kinase that forms two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which integrate amino acid and growth-factor signals to drive protein synthesis, cell growth and inhibition of autophagy. Chronic overactivation of mTORC1 is now recognised as a hallmark of ageing, because it keeps cells locked in an anabolic, growth-focused state and accelerates age-related pathologies in multiple organisms. In parallel, the insulin/insulin-like growth factor-1 (insulin–IGF-1) signalling (IIS) axis senses glucose and energy availability and, when persistently high, activates downstream kinases such as protein kinase B (AKT) and mTORC1, promoting growth at the expense of stress resistance and longevity. Partial attenuation of IIS extends lifespan in worms, flies and mice by shifting signalling towards forkhead box O (FOXO)-driven stress-response and maintenance programmes rather than growth (López-Otín et al., 2013). Within this framework, pterostilbene behaves as a caloric-restriction-like modulator that tilts the AMPK–mTOR–IIS network toward a more longevity-compatible state. In a non-alcoholic fatty liver disease model, pterostilbene activates AMP-activated protein kinase (AMPK, the canonical low-energy sensor) and suppresses mTORC1 activity while enhancing autophagy, a lysosomal self-cleaning process that clears damaged proteins and lipid droplets. This AMPK/mTOR shift is accompanied by reduced steatosis and oxidative stress, suggesting that pterostilbene restores a “low-nutrient” signalling profile that is typically associated with healthier ageing (Shen et al., 2023). Complementary work in high-fat-diet mice shows that pterostilbene and its metabolite 3′-hydroxypterostilbene upregulate the sirtuin-1/AMPK (SIRT1/AMPK) pathway, downregulate sterol regulatory element-binding protein-1 (SREBP-1, a lipogenic transcription factor downstream of insulin/mTOR), boost fatty-acid β-oxidation and improve hepatic insulin signalling, indicating coordinated re-balancing of both mTOR-linked lipid synthesis and the insulin arm of the nutrient-sensing axis (Tsai et al., 2022). In fructose-fed diabetic rats and obesogenic-diet models, pterostilbene lowers the homeostatic model assessment of insulin resistance (HOMA-IR, a composite index of fasting glucose and insulin), improves glycaemic control, increases hepatic glucokinase activity and enhances skeletal-muscle glucose uptake, showing that it restores insulin sensitivity rather than allowing chronic insulin/IGF-1 overdrive that would maintain high mTORC1 signalling and accelerate metabolic ageing (Kosuru and Singh, 2017; Gómez-Zorita et al., 2015). Integrative ageing-focused reviews therefore describe pterostilbene as a small molecule that engages SIRT1/AMPK, dampens mTORC1-driven anabolism and improves insulin/IIS tone, effectively mimicking key molecular features of caloric restriction and helping to correct the deregulated nutrient sensing that is central to mammalian ageing (Li et al., 2018).

Overall, pterostilbene can be viewed as a multi-target, caloric-restriction-like small molecule that acts on several interconnected hallmarks of ageing rather than a single pathway. By virtue of its methoxylated stilbene structure and superior bioavailability compared with resveratrol, it reaches metabolically active and neurologically relevant tissues where it consistently lowers oxidative stress, dampens chronic inflammation, reduces senescent-cell burden and SASP output, supports mitochondrial biogenesis and function and rebalances nutrient-sensing networks such as AMPK–mTOR and insulin/IGF-1 signalling toward a lower-input, stress-resilient state. In whole organisms, these cellular actions translate into improved healthspan phenotypes, including extended lifespan in invertebrate models, protection of ageing-vulnerable organs such as brain, heart, liver, joint cartilage and skin, and transcriptomic signatures in rodents that map onto multiple hallmarks of ageing, including mitochondrial dysfunction, deregulated nutrient sensing, impaired autophagy and altered intercellular communication. Taken together, current preclinical and mechanistic data support a coherent conclusion that pterostilbene is a promising anti-ageing candidate that modulates core ageing biology across oxidative, inflammatory, mitochondrial, senescent and nutrient-sensing axes, although definitive proof of geroprotective efficacy in humans will require well-controlled clinical trials focused specifically on ageing outcomes rather than single diseases.