Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.
A growing number of geroprotectors have demonstrated healthspan extension in young animals, but the effectiveness of these therapies when commenced in midlife or later has been under-studied. We and others have shown that much like calorie restriction (CR), restriction of specific nutrients, including total protein, the three branched-chain amino acids leucine, isoleucine, and valine, or isoleucine alone, can promote lifespan and metabolic health. While CR is less efficacious when starting in late life, the effects of interventions restricting amino acids in late life on healthy aging is unknown. Here, we investigate the metabolic, molecular, and physiological effects of consuming diets with a 67% reduction of either all amino acids (Low AA) or of isoleucine alone (Low Ile) in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diets reduce adiposity in aged mice; however, these diets decreased lean mass, and did not show significant improvements in frailty or fitness. The glucose tolerance of both male and female mice consuming Low Ile and Low AA diets were improved. We also observed a moderate increase in energy expenditure and respiratory exchange ratio induced by the two dietary interventions. In the hearts of aged female mice, Low Ile reversed age-associated changes in heart rate and stroke volume, returning cardiac function to similar levels as observed in young mice. We found that both Low AA and Low Ile diets promoted a more youthful molecular cardiac profile, preventing age-dependent increases in phosphotidylglycerols. These results demonstrate that Low AA and Low Ile diets can improve aspects of metabolic health in aged mice of both sexes, and has positive effects on cardiac health in aged females, suggesting that these dietary interventions are translationally promising for promoting healthy aging even in older people.
Rationale: Cardiovascular disease (CVD) is the leading cause of mortality for women in the USA. Current clinical biomarkers are inadequate to determine CVD risk in women, especially Black women, who disproportionately suffer from CVD.
Methods: Clinical data and LC-MS lipidomics from two independent study cohorts were used to identify novel circulating markers of CVD risk in White and Black women. Machine learning assessed predictive efficacy of identified lipids, and targeted oxylipid analysis provided insight into dysregulated inflammatory pathways.
Results: Select phospholipids and triglycerides containing acyl chains in the arachidonic acid (ARA) pathway were predictive of systolic blood pressure (BP) after adjusting for biological factors including age, obesity, and glycemic status in White and Black women. Oxylipid levels indicated increased conversion of ARA through the COX and LOX enzymes to pro-inflammatory cytokines in Black women.
Conclusion: ARA-containing phospholipid are independent predictors of CVD risk in White and Black women. Predisposition to CVD risk in Black women may further be explained by increased production of pro-inflammatory oxylipids relative to White women, regardless of blood pressure status. Future studies investigating the clinical utility of phospholipid ARA abundance as a marker of CVD risk in White and Black women are warranted.
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