Phytochemicals modulating HSF-1-associated pathways: A systematic review of longevity-extending mechanisms in...

Aging is characterized by progressive loss of proteostasis, and heat shock transcription factor 1 (HSF1) is the master regulator of the cellular stress response, making it an attractive pharmacological target for interventions aimed at extending lifespan. However, a systematic synthesis of phytochemicals that modulate HSF1 has been lacking. Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, Scopus, Embase, and the Cochrane Library from March 2016 to March 2026, identifying 42 original studies that provided clear evidence of HSF-1 activation (nuclear translocation, phosphorylation, or transcriptional activity), together with downstream stress-response markers such as upregulation of heat shock protein genes by phytochemicals with lifespan-extending or health span-improving outcomes. All 42 studies exclusively used Caenorhabditis elegans as the model organism, and the phytochemicals were classified into six categories: plant extracts/mixtures (11 studies), flavonoids (9 studies), carbohydrates/sugars (8 studies), terpenoids (7 studies), phenolic compounds (4 studies), and alkaloids (3 studies). Across all studies, these phytochemicals extended lifespan, enhanced resistance to thermal and oxidative stress, and delayed neurodegenerative pathology (Alzheimer's, Parkinson's, and Huntington's disease models) through activation of HSF-1 and its cooperating transcription factors DAF-16/FOXO and SKN-1/Nrf2. While sharing a common dependency on HSF-1, different classes engaged additional signaling pathways including autophagy, mitochondrial unfolded protein response, insulin/IGF-1 signaling, and lipid metabolism, reflecting class-specific mechanistic signatures. This systematic review provides the first comprehensive evidence base for developing HSF-1-associated longevity strategies using phytochemicals; however, all available evidence is limited to C. elegans models, and urgent validation in mammals and clinical translation are needed before these findings can be applied to human aging.