From Ancient Elixirs to Geroscience: The Full Molecular Map of Anti-Aging Medicine

This 2025 review from the University of Catania provides one of the most thorough integrations of historical and molecular perspectives on anti-aging medicine published to date. The authors begin by tracing humanity's pursuit of longevity from Vedic soma and Greek ambrosia through Taoist elixirs, Ayurvedic rasāyana therapies, and medieval aqua vitae, establishing that the desire to extend healthspan is a universal cross-cultural phenomenon. They argue that the critical conceptual shift came in the late 19th century when Elie Metchnikoff proposed intestinal autointoxication as a driver of aging and advocated fermented milk as a longevity intervention — a hypothesis that presaged modern microbiome research. Serge Voronoff's primate testicular xenotransplantation experiments in the early 20th century are cited as a cautionary tale about enthusiasm outpacing evidence.

The review's scientific core focuses on the molecular architecture of aging. Leonard Hayflick's 1961 discovery of the finite replicative capacity of fibroblasts, combined with subsequent identification of telomeres and telomerase, reframed aging as a cellular process. Denham Harman's 1956 oxidative stress theory inspired decades of antioxidant research, though the authors note that clinical benefits have been inconsistent. The nutrient-sensing triad of mTOR, AMPK, and sirtuins (SIRT1–7) is presented as the central regulatory network: mTOR governs protein synthesis and autophagy via mTORC1 and mTORC2 complexes; AMPK acts as an energy sensor that promotes chromatin remodeling and stabilizes DNA methylation patterns; and sirtuins modulate histone acetylation through NAD+-dependent deacetylation, directly influencing epigenetic clock trajectories.

The preclinical section is unusually comprehensive, covering organisms from Saccharomyces cerevisiae (where TOR and sirtuin pathways were first identified) through C. elegans (over 400 longevity genes identified, ~60% human gene homology), Drosophila melanogaster (Indy gene mutations doubling lifespan via energy metabolism modulation), the African turquoise killifish (4–6 month lifespan enabling rapid drug testing), zebrafish and axolotls (demonstrating that transient senescence actively supports tissue regeneration), rodents (caloric restriction robustly extending lifespan; senescent cell clearance in p16-Ink4a and p21-Cip1 transgenic mice improving frailty and organ function), swine (cardiovascular and metabolic similarity to humans making them translational bridges), and rhesus macaques (decades-long caloric restriction studies showing metabolic and immune improvements, though lifespan effects remain mixed).

On the intervention side, the review synthesizes evidence for rapalogues (mTOR inhibition), metformin (AMPK activation), sirtuin activators such as resveratrol and newer STAC compounds, NAD+ precursors (NMN, NR), senolytic combinations (dasatinib plus quercetin), and GlyNAC (glycine plus N-acetylcysteine). Early human trials of GlyNAC in older adults reported improvements in mitochondrial function, oxidative stress markers, and physical strength. Senolytic trials have shown reductions in circulating senescent cell burden and inflammatory cytokines. The authors note that results across trials are promising but heterogeneous, reflecting differences in dosing, population selection, and outcome measures.

The review concludes by addressing epigenetic clocks (Horvath, GrimAge, DunedinPACE) as biological age biomarkers, multi-omic profiling integrating proteomics and metabolomics, sex-specific physiological responses that demand gender-stratified trial designs, and emerging regenerative and gene-based approaches. Ethical dimensions — including equitable access, commercialization risks, and the medicalization of normal aging — are flagged as unresolved societal challenges. The authors frame the entire arc as a shift from targeting individual diseases to targeting aging itself as a modifiable biological process, with healthspan extension as the primary clinical goal.