Glutamine is a conditionally essential amino acid involved in energy production and redox homeostasis. Aging is commonly characterized by energy generation reduction and redox homeostasis dysfunction. Various aging-related diseases have been reported to be accompanied by glutamine exhaustion. Glutamine supplementation has been used as a nutritional therapy for patients and the elderly, although the mechanism by which glutamine availability affects aging remains elusive.
Here, we show that chronic glutamine deprivation induces senescence in fibroblasts and aging in Drosophila melanogaster, while glutamine supplementation protects against oxidative stress-induced cellular senescence and rescues the D-galactose-prompted progeria phenotype in mice. Intriguingly, we found that long-term glutamine deprivation activates the Akt-mTOR pathway, together with the suppression of function. However, the inhibition of the Akt-mTOR pathway effectively rescued the autophagy impairment and cellular senescence caused by glutamine deprivation.
Collectively, our study demonstrates a novel interplay between glutamine availability and the aging process. Mechanistically, long-term glutamine deprivation could evoke mammalian target of rapamycin (mTOR) pathway activation and autophagy impairment. These findings provide new insights into the connection between glutamine availability and the aging process.
https://www.frontiersin.org/articles/10.3389/fphar.2022.924081/full
Inhibitors of mTOR
- Protein restriction [21, 22]
- Calorie restriction [23]
- Ketogenic Diets [24]
- Intermittent Calorie Restriction [23]
- Exercise (inhibits mTOR in the liver and fat cells, but activates it in the brain, muscle, and heart) [25, 26]
- Cortisol/Glucocorticoids [5]
- Metformin [27]
- NAC [28]
- Resveratrol [29]
- Aspirin [30]
- Omega-3 [31]
- Extra Virgin Olive Oil [32]
- EGCG/Tea [33, 1, 34]
- Curcumin [35, 1, 36]
- R-Lipoic Acid [37]
- Caffeine [38, 39, 1]
- Fisetin (in fat cells) [40]
- Apigenin [41]
- Quercetin [42]
- Genistein [1]
- DIM [1]
- Ursolic acid [43]
- Alcohol [44]
- Emodin (found in Fo-Ti, Rhubarb, Aloe) [45]
- Andrographis/Andrographolide [46]
- Pomegranate/Ellagic acid [47]
- Reishi [48]
- Milk thistle/Silymarin [49]
- Oleanolic acid [50]
- Anthocyanins/Grape Seed Extract [51]
- Astragalus [52]
- Rhodiola [53]
- Carnosine [54]
- Plumbagin(black walnut hull) [55]
- Glucagon [56]
- AICAR [27]
Activators of mTOR
The main activators of mTOR are a variety of amino acids and the hormone insulin. Testosterone is also capable of activating mTOR [57, 58].
- Proteins, especially if rich in leucine
- Excess calories
- Excess carbs
- Exercise (in the brain, muscles, and heart, but blocks it in the liver and fat cells) [25, 26]
- Orexin [59]
- IGF-1 [3]
- Insulin
- Testosterone [58]
- Ghrelin (in the hypothalamus) [6]
- Leptin (in the hypothalamus) [60]
- Thyroid hormone (in the hypothalamus) [61]
- Oxygen
- Ketamine (in the brain, producing an antidepressant effect) [62]
- IL-6 (in the muscles and fat) [63]
