Fig. 8: Aldometanib extends lifespan and healthspan.
From: The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK
a–c,e, Aldometanib extended lifespan in C. elegans via the lysosomal pathway. Wild-type (N2) nematodes or nematodes with AMPKα (aak-2), LAMTOR2 (lmtr-2) or AXIN (axl-1) knocked out were cultured on the agar plates containing aldometanib at indicated concentrations. Lifespan data are shown as Kaplan–Meier curves (a and c; see also statistical analyses on Supplementary Table 2, and the same hereafter for all lifespan data), and AMP:ATP and ADP:ATP ratios (b) and NAD+ (e) levels after 2-d treatment of aldometanib are shown as the mean ± s.e.m. (n = 6 dishes of worms for each treatment, and P values were determined by one-way ANOVA followed by Dunn’s (b; N2 of e) or Dunnet’s (others) test). d, Aldometanib promoted oxidative stress resistance in C. elegans. N2 nematodes were cultured on the agar plates containing aldometanib for 1 d, followed by treatment with 15 mM ferrous sulfate. f,g, Aldometanib promoted mitochondrial functions in C. elegans. The N2 and aak-2 nematodes were cultured on the agar plates containing aldometanib for 1 d, followed by determining the mtDNA:nDNA (f) and OCRs (g). Data are shown as the mean ± s.e.m.; n = 8 (f) or 4 (g) dishes of worms for each treatment, and P values were determined by two-way ANOVA followed by Tukey’s test. h, Aldometanib extended lifespan in mice. Male or female C57BL/6 mice at 52 weeks of age were treated with aldometanib in drinking water. i,j, Aldometanib elevated NAD+ levels and mitochondrial oxidative respiration in aged mouse muscle. Mice were treated as in h, except for 4 months, followed by determination of levels of muscular NAD+ (i), the activities of muscular mitochondrial complex I to IV (j) and the levels of muscular mtDNA:nDNA (j). Data are the mean ± s.e.m., n = 10 (control of i), 8 (aldometanib group of i, and right part of j) or 14 (left part of j) mice, and P values were determined by two-sided Student’s t-test with Welch’s correction (i), two-tailed Mann–Whitney test (resting group of right part of j) or two-sided Student’s t-test (others). k,l, Aldometanib rejuvenates muscle function in aged mice. Mice were treated as in i, followed by determination of running distance (k) and grip strength (both the forelimbs, and the four limbs; l). Data are shown as the mean ± s.e.m. form n = 24 (k), 30 (l; control) or 32 (l; aldometanib-treated) mice for each treatment. P values were determined by two-sided Student’s t-test. Experiments were performed three times, except d and e (four times).
