PMC

The figure depicts schematically the current consensus within the biology of aging community as to pathways that are important in order to target aging and indicates at which points metformin has been shown to have effects (see text). Key take-away: outside of the cell (1, top), metformin has been shown to affect the receptors for cytokines, insulin, IGF-1, and adiponectin, all pathways that are activated with aging and, when modulated, are associated with longevity. (1) Intracellular (2, middle) metformin inhibits the inflammatory pathway and activates AMPK, increasing inhibition of mTOR, which seems to be a major target to modulate aging. Through some of these mechanisms, it also modulates oxidative stress and removes senescent cells (the mitochondrial pathways are not shown, and the mechanisms by which metformin induces senescent cell removal remain unclear). (2) These processes jointly (3, bottom) affect inflammation, cellular survival, stress defense, autophagy, and protein synthesis, which are major biological outcomes associated with aging/longevity. Adapted from .

The Biguanide Drugs Phenformin and Metformin Decelerate Aging in C. elegans
(A and B) Metformin (A) and phenformin (B) extend lifespan in a dose-dependent manner. Phenformin alters fecundity and reduces body size (see A–S1D).
(C) Phenformin (4.5 mM) does not increase lifespan in the presence of 50 mM metformin, consistent with similar mechanism of drug action.
(D) Metformin decreases the exponential increase in age-related mortality (for survival curve see E).
(E) Later-life administration (day 8) of metformin increases lifespan at lower concentrations (25, but not 50 or 100 mM).
See also . For statistics, see .

Western blot analysis of the effects of metformin on the AMPK/Foxo3/ERK1/2 signaling pathways [(A-C) AMPK, (D-F) Foxo3 and (G-I) ERK1/2] in aging rats. ^*P<0.05, ^**P<0.01. The data are presented as the means ± SD; n=6 for each subgroup.

Metformin Extending Effects on C. elegans Lifespan Require Live Bacteria
(A) Metformin shortens lifespan of C. elegans cultured axenically (i.e., in the absence of E. coli).
(B) Metformin shortens lifespan of C. elegans cultured on UV-irradiated E. coli (OP50).
(C) Metformin pretreatment of bacteria is sufficient to extend lifespan.
(D) Metformin extends lifespan in the absence of E. coli proliferation (blocked by carbenicillin).
(E) Metformin extends lifespan in the presence of the less pathogenic bacterium Bacillus subtilis.
(F) Retardation of bacterial growth by metformin, monitored over an 18 hr period.
(G) Biguanide drugs cause altered bacterial lawn morphology.
(H) Bacterial viability is reduced by carbenicillin and UV treatment, but not metformin.
(I) Metformin extends lifespan in the presence of multi-antibiotic resistant E. coli OP50-R26.
See also . For statistics, see .