A new synthesis in Nature Communications positions chalcones—a simple, naturally occurring class of flavonoids—as increasingly credible candidates in geroscience. While still early-stage, they appear to intersect with three of the most therapeutically important pillars of aging biology: autophagy, senescent-cell clearance, and iron/redox homeostasis. The review draws together nearly a decade of work across multiple species and highlights the chalcone scaffold as a promising—but not yet clinically validated—platform for future geroprotective drug development.
At the center of the story is 4,4′-dimethoxychalcone (4,4′-DMC), a compound originally identified in Angelica keiskei(ashitaba). Across yeast, nematodes, and flies, 4,4′-DMC extends lifespan. In human cells and mouse models, it activates autophagy, protects the heart from ischemia, suppresses senescent phenotypes, and decreases inflammatory signaling. Mechanistically, 4,4′-DMC inhibits GATA transcription factors, which normally repress autophagy genes. Removing this brake creates a metabolic state resembling caloric restriction—a well-established lever for extending healthy lifespan across species.
Recent studies add a second mechanism: senescent-cell elimination via ferritinophagy-driven ferroptosis. Senescent cells accumulate iron, resist apoptosis, and secrete inflammatory SASP factors that damage tissue-wide microenvironments. In aged mice, 4,4′-DMC reduces senescent hepatocytes, lowers SASP cytokines (IL-6, IL-1β, CXCL10), improves motor function, and even prevents age-related hair loss. The compound accelerates selective ferritin degradation (via NCOA4), increasing labile iron enough to trigger ferroptosis in senescent—but not young—cells. This positions chalcones as a potential dual-action class: pro-autophagy CRM and selective senolytic.
A structurally related molecule, 3,4-dimethoxychalcone (3,4-DMC), activates TFEB and TFE3, the master regulators of lysosomal biogenesis. In rodent cardiovascular models, 3,4-DMC reduces arterial thickening and protects cardiac tissue. These data reinforce a unifying theme: different chalcones may converge on nutrient sensing, lysosomal function, and stress resilience—core pathways spanning nearly all hallmarks of aging.
Other chalcones reviewed include xanthohumol (from hops), which shows anti-inflammatory and metabolic benefits in early human studies; hesperidin methylchalcone, clinically used for venous insufficiency; and licochalcone A, a dermatological anti-inflammatory. These have partial human translation, but none yet meet the standard for geroprotective claims. Most mechanistic data remain preclinical, and the authors are explicit about the lack of mammalian lifespan studies for DMCs—an important limitation given the complexity of aging circuits in long-lived species.
For longevity-focused readers, the most immediate implications are conceptual. Chalcones reinforce the centrality of autophagy, iron metabolism, mitochondrial turnover, and controlled cellular clearance as tractable levers for extending healthspan. They also highlight the importance of polyphenol diversity in diet, which may provide low-dose, multi-targeted stimulation of these pathways with strong safety margins. Yet the review is clear: chalcones are not yet ready for clinical use as lifespan-extending agents. Their oral bioavailability, long-term safety, dosing windows, and interaction with cancer-immune surveillance remain unresolved.
Still, this body of work underscores an emerging principle in geroscience: simple molecular scaffolds can produce multi-pathway interventions that mimic the cellular consequences of caloric restriction and selective senescent-cell removal. Chalcones may represent the early blueprint for future autophagy-centric therapeutics—pointing toward a new generation of small molecules engineered for human healthspan extension.
Paper: The geroprotective potential of chalcones - PMC
