Fig. 7: Enhanced adipose tissue-derived glycerol contributes to maintenance of normoglycemia in aged SIRT6-tg mice.

a Lactate tolerance test in 22–24 months old liver-specific SIRT6-tg and appropriate littermate control male mice. Values are mean ± SEM of n = 6 WT mice, n = 5 lox mice, n = 9 Alb-cre mice and n = 5 liver SIRT6-tg mice. Two-way ANOVA showed no difference between liver SIRT6-tg and controls. Bars represent mean ± SEM. b Heatmap of GNG-related hepatic metabolites in 23–25 months old liver SIRT6-tg male mice and control littermates. Each square represents average metabolite abundance of n = 5 mice per genotype. See Supplementary Table 9 for source data. c Levels of the GNG precursors glycerol, lactate and pyruvate in the plasma of 6 h-fasted young (5–7 months) and old (20–24 months) mice, n = 5, males. Box extends from the 25th to 75th percentiles, line in the middle of the box is the median and whiskers go down to the smallest value and up to the largest. d Western blot and ImageJ quantification of HSL phosphorylation on Ser563 in white adipose tissue of 25 months old WT and SIRT6-tg littermates. n = 4 mice per genotype. Bars represent mean ± SEM, two-tailed Student’s t-test. For (c, d), exact p-values are reported in the Source Data file, *p < 0.05. e Schematic model depicting how SIRT6 improves longevity and healthspan by preserving NAD⁺ metabolism and energy production pathways in old age. Hepatic TCA cycle and GNG deteriorates during aging, leading to perturbed energy homeostasis and fasting glycemia in old age. SIRT6 overexpression increases hepatic energy production from fatty acids and AAs in the liver. This potentially spares GNG substrates, such as lactate and glycerol, whose shuttling during fasting from skeletal muscle and adipose tissue to the liver is increased by SIRT6. This cascade of events leads to preserved hepatic glucose production in old age. TG, triglyceride; HSL, hormone-sensitive lipase; DHAP, dihydroxyacetone phosphate; AAs, amino acids; Oxphos, oxidative phosphorylation.