Low-carbohydrate or ketogenic diets have been extensively studied in animal models and humans for their impact on metabolic health outcomes and longevity. Ketogenic diets are extreme low-carbohydrate diets that induce a state of ketosis, in which the body relies primarily on ketone bodies for energy [52]. Animal studies suggest that a ketogenic diet may enhance longevity and health span through influencing multiple metabolic and aging pathways, including reducing mTOR signaling, AMPK and SIRT1 activation, improving insulin sensitivity, and inhibiting chronic inflammation [53, 54].

In short-term RCTs, low-carbohydrate or ketogenic diets have been shown to be more effective in promoting weight loss compared to conventional low-fat high-carbohydrate diets [55]. In addition, carbohydrate restriction lowers blood glucose levels, reduces postprandial glucose spikes, and improves insulin sensitivity in glycemic control among individuals with type 2 diabetes [56, 57]. However, long-term adherence to very low-carbohydrate or ketogenic diets is often challenging due to their restrictive nature. In addition, very low-carbohydrate intake leads to reduced intake of fiber, vitamins, and minerals, which could have negative health consequences. Although low-carbohydrate diets often decrease triglyceride levels and increase HDL levels, such diets have been associated with increased LDL cholesterol levels [52].

The long-term health effects of low-carbohydrate diets appear to depend on the type of fat and protein in the diets [58]. During up to 20–26 years of follow-up in NHS and HPFS, the overall low-carbohydrate diet score was only weakly associated with all-cause mortality. However, a higher animal low-carbohydrate diet score was associated with higher all-cause and cancer mortality, whereas a higher vegetable low-carbohydrate score (emphasizing plant sources of protein and fat) was associated with lower mortality, particularly CVD mortality. Similarly, among individuals with type 2 diabetes, greater adherence to low-carbohydrate diet patterns that emphasize plant sources of fat and protein was significantly associated with lower total, cardiovascular, and cancer mortality [59]. It should be noted that in real-world epidemiologic studies, the amount of carbohydrates in the low-carbohydrate diet pattern was much higher than that used in controlled intervention studies of ketogenic or very low-carbohydrate diets.

Numerous epidemiologic studies have investigated the role of both quantity and quality of carbohydrates in long-term health outcomes and mortality. Carbohydrate quality is typically defined according to its nutritional value and health effects, including the degree of processing, fiber content, and glycemic index and glycemic load [56]. Overall evidence suggests that carbohydrate quality plays a more important role in chronic disease outcomes than carbohydrate amount. A series of systematic reviews and meta-analyses of data from large cohort studies have shown that high glycemic index or glycemic load diets (often containing higher amounts of refined grains, such as white rice and white bread, starchy foods such as potatoes, and sugar-sweetened beverages [SSBs]), are consistently associated with increased risk of weight gain, obesity, diabetes, CVD, some cancers, and mortality [60-64], whereas minimally processed grains, legumes, whole fruits, and non-starchy vegetables are protective against these conditions [65-68]. In a recent longitudinal analysis of changes in carbohydrate intake and long-term weight gain in the NHS and HPFS, increasing dietary glycemic index, glycemic load, and amounts of starch, added sugars, refined grains, and starchy vegetables was associated with greater midlife weight gain. In contrast, increasing amounts of fiber, whole grains, fruit, and non-starchy vegetables was associated with less weight gain [69].

SSBs are a primary source of added sugars in many diets and have been consistently associated with increased risk of chronic diseases and mortality [70]. In the NHS and HPFS, each serving per day increment in SSBs was associated with a 7% higher risk of total mortality (HR: 1.07; 95% CI: 1.05, 1.09), a 10% higher risk of CVD death (HR: 1.10; 95% CI: 1.06, 1.14), and a 5% higher risk of cancer death (HR 1.05, 95% CI 1.02–1.08) [71]. The association between higher consumption of artificially sweetened beverages (ASBs) and risk of mortality was less clear. Higher consumption of SSBs and ASBs was associated with a significantly increased risk of frailty [72].

SSBs promote weight gain and, consequently, elevate the risk of chronic diseases through multiple mechanisms [70]. These include the body’s incomplete compensation for liquid calorie intake by not sufficiently reducing food intake at subsequent meals, hyperinsulinemia resulting from rapid absorption of large amounts of sugar, increased chronic inflammation, and potential neural pathways linked to food addiction. Although high consumption of these beverages increases type 2 diabetes and cardiometabolic risk primarily through weight gain, it also has direct impact. Specifically, the high amount of glycemic load and fructose in SSBs can lead to accumulation of visceral adipose tissue and ectopic lipid deposition and increased risk of gout and nonalcoholic fatty liver disease [70].