Chalcones Emerge as Promising Plant-Derived Anti-Aging Compounds

Aging is the dominant risk factor for cardiovascular disease, neurodegeneration, cancer, and metabolic disorders, yet healthspan has not kept pace with rising life expectancy. Caloric restriction (CR) reliably extends lifespan and healthspan across organisms, but adherence is difficult. Caloric restriction mimetics (CRMs) — compounds that activate the same protective pathways as CR, most critically autophagy — represent a more practical alternative. Chalcones, a structurally distinct subclass of flavonoid polyphenols characterized by two aromatic rings linked by a three-carbon alkenone unit, have recently emerged as a promising CRM category.

The centerpiece of this review is 4,4'-dimethoxychalcone (4,4'-DMC), isolated from the leaves and stems of Angelica keiskei Koidzumi — a plant revered in Japanese and Korean traditional medicine and consumed heavily on the so-called 'island of longevity.' In a screen of 180 flavonoids, 4,4'-DMC was the strongest promoter of chronological lifespan and suppressor of aging-associated ROS in Saccharomyces cerevisiae. Lifespan extension was subsequently validated in C. elegans and Drosophila melanogaster, clonogenic survival was improved in multiple human cell lines, and intraperitoneal administration reduced myocardial infarction area in mice — a clinically meaningful cardioprotective outcome.

Mechanistically, 4,4'-DMC's geroprotective effects are largely autophagy-dependent. Deletion or knockdown of ATG genes abolishes lifespan extension across all tested organisms. The key upstream mechanism is inhibition of specific GATA transcription factors: in yeast, deletion of Gln3 (a GATA TF) extends lifespan and promotes autophagy, while 4,4'-DMC produces a metabolic profile mirroring Gln3-deficient cells. In human cells, GATA-2 knockdown blocks 4,4'-DMC-induced autophagosome formation. Beyond GATA inhibition, 4,4'-DMC also modulates iron homeostasis (via HMOX1, NCOA4) and enhances redox capacity through NRF2 pathway activation and direct radical scavenging. An autophagy-independent hepatoprotective effect against acute ethanol toxicity has also been observed, likely attributable to antioxidant activity.

The review extends beyond 4,4'-DMC to cover other chalcones — including xanthoangelol, 4-hydroxyderricin, isoliquiritigenin, and synthetic derivatives — that demonstrate anti-inflammatory, antidiabetic, neuroprotective, and senolytic properties in various models. The authors note that chalcone synthesis is chemically straightforward, enabling structure-activity relationship studies and medicinal chemistry optimization. The translational potential is further supported by the general rarity of side effects from polyphenol-rich diets in humans, plausibly reflecting co-evolutionary dietary exposure.

Caveats are notable: most longevity data derive from invertebrate models and cell lines; human clinical trial data for chalcones as geroprotectors are absent; mechanistic studies are incomplete for most chalcones beyond 4,4'-DMC; and bioavailability in humans remains to be rigorously characterized. Nevertheless, chalcones represent a compelling, pharmacologically tractable class of compounds warranting controlled human studies.