Hallmarks of aging: An expanding universe

Sirtuin 6: linking longevity with genome and epigenome stability.

Significance Sirt6 is well known for its role in regulating the aging process, particularly for its ability to extend lifespan in mice when overexpressed. However, the underlying molecular mechanisms responsible for lifespan regulation by Sirt6 are not well understood. Here, we characterized dSirt6 in fruit flies (Drosophila melanogaster). We found that dSirt6 functions very similarly to mammalian Sirt6 at the molecular and biochemical levels. Furthermore, overexpressing dSirt6 increased lifespan in flies. dSirt6 overexpression extends lifespan, in part, by opposing the activity of Myc, a master regulator of protein synthesis, which is associated with decreased protein synthesis. These findings have relevance for the treatment of age-related disease by modulating Sirt6 activity. Sirt6 is a multifunctional enzyme that regulates diverse cellular processes such as metabolism, DNA repair, and aging. Overexpressing Sirt6 extends lifespan in mice, but the underlying cellular mechanisms are unclear. Drosophila melanogaster are an excellent model to study genetic regulation of lifespan; however, despite extensive study in mammals, very little is known about Sirt6 function in flies. Here, we characterized the Drosophila ortholog of Sirt6, dSirt6, and examined its role in regulating longevity; dSirt6 is a nuclear and chromatin-associated protein with NAD+-dependent histone deacetylase activity. dSirt6 overexpression (OE) in flies produces robust lifespan extension in both sexes, while reducing dSirt6 levels shortens lifespan. dSirt6 OE flies have normal food consumption and fertility but increased resistance to oxidative stress and reduced protein synthesis rates. Transcriptomic analyses reveal that dSirt6 OE reduces expression of genes involved in ribosome biogenesis, including many dMyc target genes. dSirt6 OE partially rescues many effects of dMyc OE, including increased nuclear size, up-regulation of ribosome biogenesis genes, and lifespan shortening. Last, dMyc haploinsufficiency does not convey additional lifespan extension to dSirt6 OE flies, suggesting dSirt6 OE is upstream of dMyc in regulating lifespan. Our results provide insight into the mechanisms by which Sirt6 OE leads to longer lifespan.

https://www.pnas.org/content/pnas/119/5/e2111176119.full.pdf

Sirt6 regulates lifespan in Drosophila melanogaster

Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets

Theaflavins (TFs) are the characteristic components of black tea and have been widely acknowledged for their health benefits. The current study aimed to investigate the effects and mechanism of TFs, TF1, TF2a and TF3 on glycolipid metabolism in obese mice induced by a high-fat diet (HFD). Mice were randomly divided into seven groups (n = 8 per group) as follows: low-fat diet (LFD), HFD, HFD + metformin (Met, 100 mg kg-1 d-1), HFD + TFs (TFs, 200 mg kg-1 d-1), HFD + TF1 (TF1, 100 mg kg-1 d-1), HFD + TF2a (TF2a, 100 mg kg-1 d-1), and HFD + TF3 (TF3, 100 mg kg-1 d-1). All groups were studied for 9 weeks continuously. The levels of serum glucose, insulin, TC, TG, LDL and HLD in the plasma, lipid accumulation in the liver, and injury of the liver were investigated. In addition, the effects of TFs and their monomers on the SIRT6/AMPK/SREBP-1/FASN pathway were also evaluated. The results showed that oral administration of TFs, TF1, TF2a and TF3 not only dramatically suppressed weight gain, reduced blood glucose level, and ameliorated insulin resistance but also obviously lowered the levels of serum TC, TG and LDL, suppressed the activities of ALT and AST, and ameliorated hepatic damage in mice fed a HFD when compared to the HFD group. Western blot analysis showed that TFs, TF1, TF2a and TF3 treatments increased the expression of SIRT6 and suppressed the expression levels of SREBP-1 and FASN significantly in mice fed a HFD as compared to the HFD group. The phosphorylation of AMPK in mice fed a HFD was obviously elevated by TF2a and TF3 when compared to the HFD group. These results proved for the first time that TF1, TF2a and TF3 improved the glucolipid metabolism of mice fed a HFD, and activated the SIRT6/AMPK/SREBP-1/FASN signaling pathway to inhibit the synthesis and accumulation of lipids in the liver to ameliorate obesity in mice fed a HFD. These findings indicate that TFs, TF1, TF2a and TF3 as the main functional components of black tea might potentially be used as a food additive for improving glycolipid metabolism and ameliorating obesity, and TF3 may be the best choice.

Hypoglycemic and lipid lowering effects of theaflavins in high-fat diet-induced obese mice.

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.

/pdf/restoration-of-energy-homeostasis-by-sirt6-extends-healthy-2cw88mfvv7.pdf

M. Shurgi

Papers

Restoration of energy homeostasis by SIRT6 extends healthy lifespan.