PhD Candidate: Vince Su
Spermidine (SPD) supplementation and methionine restriction (MR) extend lifespan in model organisms, including yeast, worms, flies, and mice. SPD, a polyamine, declines with age and promotes autophagy, a cellular turnover process tied to its lifespan extension. In contrast, MR is proposed to act through methylation inhibition. In Saccharomyces cerevisiae, SPD supplementation extends lifespan but fails to rescue mitochondrial dysfunction in mtDNA-deficient (ρ0) cells. Instead, it shows toxicity linked to mitochondrial complex III dysfunction. This toxicity, observed in S288C-related strains but not in the D273-10B strain, suggests strain-specific genetic variability. Impairing autophagy through ATG8 inactivation, or mitochondrial complex II through SDH2 inactivation, mitigates this toxicity, indicating potential risks for human applications. Conversely, lifespan extension by MR depends on methylation and the retrograde response. MR requires wild-type Sah1p (SAH1 hydrolase), Nop1p (a protein methyltransferase), and RNA methylation, but not HMT1p (a major methyltransferase). A metabolic link between SPD and methionine via 5′-Methylthioadenosine (MTA) suggests it may inhibit methylation by increasing MTA and S-Adenosyl-L-homocysteine (SAH), yet its lifespan extension is independent of methylation. These findings reveal SPD promotes longevity through autophagy, while MR relies on specific methylation pathways and the retrograde response. RNA-seq shows significant differences in up- and downregulated gene sets, suggesting that combining SPD and MR may further extend lifespan. The genetic variability and potential toxicity of SPD highlights the need for caution in applying these interventions to human aging. Further research is needed to confirm their safety and efficacy across diverse genetic backgrounds while minimizing risks.
