Dietary restriction (DR), also commonly known as caloric restriction, is a strategy to improve health and increase lifespan by limiting the number of calories you eat. When combined with a nutritional diet, DR extends lifespan in a variety of species including yeast, worms, flies, and mice. Currently the effects of DR on lifespan in humans are unknown, however health benefits have been reported in caloric restriction studies in rhesus monkeys. For more background on this subject, read our recent blog post on caloric restriction and aging and our interview with Brian M. Delaney, President of the CR Society International.
The main benefits of DR include increased resistance to stress and extended lifespan, however, the molecular mechanisms behind these benefits are still unknown. One recent study discovered that a low-protein diet can promote health and longevity in middle-aged humans (50-65) but had the opposite effects in the elderly (65+). They found that high protein diets increased activity of the IGF-1 growth hormone receptor, which increased the risk of cancer, diabetes, and mortality in middle-aged individuals.
Protein and amino acid restriction are forms of DR that have beneficial effects on both healthspan and lifespan in mice, and as mentioned above, lower the risk of disease and mortality in humans. Recently, scientists have discovered clues as to why amino acid restriction promotes longevity and health. A recent study at the Harvard School of Health by Hine et al. found that restriction of sulfur-containing amino acids (SAAs) in the diets of mice is essential for maintaining DR-mediated benefits. SAAs methionine and cysteine are metabolized through the transsulfuration (TSP) pathway, which is an important metabolic pathway that is activated upon DR and is required for lifespan extension in flies. Hydrogen sulfide (H2S) gas is a product of the TSP pathway and is known to extend lifespan in worms. At low concentrations, H2S has many beneficial effects including lowering blood pressure and preventing neurodegeneration.
In a nutshell, Hine et al. discovered that mice on DR diets activated the TSP pathway and had more H2S production, which resulted in protection against hepatic ischemia reperfusion injury (IRI). IRI occurs when blood-flow returns to tissue damaged due to decreased blood supply (ischemic tissue). Renewed blood flow causes inflammation and oxidative stress that further damages the tissue. DR is known to improve the outcome of IRI in the liver, brain, and kidneys of mice.
Hine et al. found that mice fed a DR diet for one week before hepatic IRI were protected from extensive liver damage compared to mice fed an ad libitum (AL) diet (meaning they could eat as much as they wanted). This protection was lost when DR mice were fed SAAs (Methionine and Cysteine) before IRI. When they analyzed the livers of DR mice, they found that the levels of H2S were elevated in DR mice compared to AL mice. They also tested the effects of SAA restriction in mice fed a protein free (PR) diet before IRI, and found that PR mice were significantly protected from liver damage while mice fed a complete diet and PR mice fed SAAs were not.
The authors went on to show that treating AL mice with H2S prior to hepatic IRI was protective against liver damage, and that blocking the TSP pathway in DR mice by chemical inhibition or by activation of mTORC1 reduced H2S production and abolished protection. With regards to the mechanisms by which H2S mediates DR benefits, they found that H2S required the mitochondrial protein SQR to protect against IRI, and that it had antioxidant properties that protect liver cells from acute oxidative stress. The study ended with an analysis of H2S production in DR-induced longevity extension models in mice, fruit flies, worms, and yeast. In all four models, they found that DR significantly increased H2S production, and this increase correlated with extended lifespan in flies, worms, and yeast. Thus the authors concluded that H2S is a direct mediator of DR benefits including protection against injury, increased stress resistance, and lifespan extension.
This study sheds new light on how changes in diet can benefit health and promote longevity. It is also one of the first studies to identify a molecular mechanism that explains the beneficial effects of multiple DR regimens (calorie, protein, and SAA restriction). From a clinical perspective, H2S is still a long ways away from becoming a “DR mimetic”. It’s very toxic at high concentrations and also degrades quickly once inside the human body. However, it does seem feasible that H2S, if monitored carefully, could be used to treat patients with ischemic injury in the future. As for extending lifespan, the story of H2S and DR will pave the way for the identification of novel targets and potential therapeutics that can improve health, combat disease, and possibly extend lifespan in humans.