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Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin-a biguanide that combats age-related disorders and improves healthspan, is the first drug to be tested for its age-targeting effects in the large clinical trial-TAME (Targeting Aging by MEtformin). This review focuses on metformin's mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrientsensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem-cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make metformin an attractive gerotherapeutic to translate to human trials.

Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two isoforms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. We evaluated the metabolic impact of pharmacological reduction of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively reduced DGAT1 and DGAT2 mRNA levels in liver and fat, but only Dgat2 ASO treatment significantly reduced hepatic lipids (diacylglycerol and triglyceride but not long chain acyl CoAs) and improved hepatic insulin sensitivity. Because Dgat catalyzes triglyceride synthesis from diacylglycerol, and because we have hypothesized that diacylglycerol accumulation triggers fat-induced hepatic insulin resistance through protein kinase C⑀ activation, we next sought to understand the paradoxical reduction in diacylglycerol in Dgat2 ASO-treated rats. Within 3 days of starting Dgat2 ASO therapy in high fat-fed rats, plasma fatty acids increased, whereas hepatic lysophosphatidic acid and diacylglycerol levels were similar to those of control rats. These changes were associated with reduced expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative/thermogenic genes (CPT1 and UCP2). Taken together, these data suggest that knocking down Dgat2 protects against fat-induced hepatic insulin resistance by paradoxically lowering hepatic diacylglycerol content and protein kinase C⑀ activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidation. Nonalcoholic fatty liver disease (NAFLD)5 is the most frequent cause of abnormal liver function tests in the United States (estimated prevalence of 14 -20%) (1, 2). It is caused by triglyceride (TG) accumulation within the liver and is strongly associated with insulin resistance, type 2 diabetes mellitus (T2DM), and the metabolic syndrome (3, 4). Accumulating evidence suggests that hepatic lipid accumulation causes hepatic insulin resistance. For example, increasing hepatic lipid stores in mice by overexpressing lipoprotein lipase in the liver (5) and in rats by short term high fat feeding (6) results in liver-specific fat accumulation and hepatic insulin resistance. Several strategies have been employed to reduce hepatic steatosis in rodents; these include treatment with a mitochondrial uncoupling agent (2,4-dinitrophenol) (6), antisense oligonucleotide inhibition of acetyl-coenzyme A carboxylase I and II (7), adenoviral overexpression of malonyl-CoA decarboxylase (8), and transgenic overexpression of uncoupling protein 1 (9), all of which successfully ameliorated hepatic insulin resistance. We have also shown that moderate weight loss in patients with T2DM lowers liver triglycerides and specifically improves hepatic insulin sensitivity (10). Although the above data strongly suggest that hepatic lipid accumulation causes hepatic insulin r...

Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2 ؊/؊ and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulinstimulated liver and muscle glucose metabolism during a hyperinsulinemic-euglycemic clamp in Acc2 ؊/؊ and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2 ؊/؊ mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2 ؊/؊ mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC activity in muscle and PKC activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2 ؊/؊ mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes. diet-induced obesity prevention ͉ intracellular diacylglycerol ͉ increased fat oxidation ͉ insulin resistance prevention