From Longevity Wiki

    Isoleucine, one of the nine essential amino acids, is a branched-chain amino acid (BCAA) that is crucial for protein synthesis and energy production. It is not synthesized by the human body and must be obtained through diet. Sources of isoleucine include meat, fish, poultry, eggs, dairy products, nuts, seeds, and legumes.

    In the human body, isoleucine is involved in muscle metabolism and is heavily concentrated in muscle tissue. It is also significant in hemoglobin synthesis and regulation of blood sugar and energy levels. Isoleucine's role as a BCAA makes it vital for repairing muscle tissue, especially after exercise, and in the maintenance of healthy muscle mass, which tends to decline with age.

    Dietary Sources[edit | edit source]

    Isoleucine is a peptide-bound component of both animal and plant proteins. The following examples refer to 100 g of the food item, with the percentage of isoleucine in the total protein also given.[1]

    Food Protein Isoleucine Percentage
    Beef 21.26 g 967 mg 4.5 %
    Chicken Breast Fillet 23.09 g 1219 mg 5.3 %
    Salmon 20.42 g 968 mg 4.7 %
    Chicken Egg 12.58 g 672 mg 5.3 %
    Cow's Milk, 3.7% Fat 3.28 g 198 mg 6.0 %
    Walnuts 15.23 g 625 mg 4.1 %
    Whole Wheat Flour 13.70 g 508 mg 3.7 %
    Whole Grain Cornmeal 6.93 g 248 mg 3.6 %
    Brown Rice 7.94 g 336 mg 4.2 %
    Dried Peas 24.55 g 1014 mg 4.1 %

    All these foods contain almost exclusively chemically bound L-Isoleucine as a protein component, but in their raw state, they contain no free L-Isoleucine.

    Isoleucine and Longevity[edit | edit source]

    Recent studies have shown that isoleucine plays a significant role in the aging process, particularly in the context of metabolic health and lifespan extension.

    Insulin Resistance[edit | edit source]

    Isoleucine, like other branched-chain amino acids, is associated with insulin resistance: higher levels of isoleucine are observed in the blood of diabetic mice, rats, and humans.[2] In diet-induced obese and insulin resistant mice, a diet with decreased levels of isoleucine (with or without the other branched-chain amino acids) results in reduced adiposity and improved insulin sensitivity.[3][4] Reduced dietary levels of isoleucine are required for the beneficial metabolic effects of a low protein diet.[4] In humans, a protein restricted diet lowers blood levels of isoleucine and decreases fasting blood glucose levels.[5] In humans, higher dietary levels of isoleucine are associated with greater body mass index.[4]

    Isoleucine restriction in UM-HET3 mice
    (Low ILE = Low isoleucine, Low AA = Low amino acid)

    Isoleucine Restriction[edit | edit source]

    Recent research has revealed that dietary isoleucine restriction (IleR) by 67% can have significant effects on metabolic health and lifespan, particularly in genetically heterogeneous UM-HET3 mice. Implemented in 9-week-old mice, IleR has been shown to promote leanness and improve glycemic control across genders. Additionally, it has been noted to cause sex-specific reprogramming of hepatic metabolism.[6][7]

    In male mice, a 33% increase in median lifespan was observed, along with a notable increase in maximum lifespan when compared to control groups. These findings are some of the most significant among interventions tested in rodent models. For female mice, the increase in maximum lifespan was more modest, at 7%. Correspondingly, male mice under IleR also experienced significantly reduced levels of frailty compared to their counterparts. The study also addresses mortality causes, indicating that while cancer accounts for the majority of deaths in HET3 mice, male mice on an IleR diet were considerably less likely to develop cancer, a benefit not as evident in female mice.

    These findings suggest that isoleucine restriction, or pharmacological agents that replicate its effects, may offer a promising geroprotective strategy, potentially enhancing healthspan and longevity. Such findings underscore the significant role of isoleucine in diet and aging and point to its viability as a target for both nutritional and pharmacological interventions in gerontology.

    See Also[edit | edit source]

    References[edit | edit source]

    1. Nutrient Database of the US Department of Agriculture, 21st Edition.
    2. Lynch CJ & Adams SH: Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 2014. (PMID 25287287) [PubMed] [DOI] [Full text] Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.
    3. Cummings NE et al.: Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol 2018. (PMID 29266268) [PubMed] [DOI] [Full text] KEY POINTS: We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets. ABSTRACT: Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.
    4. 4.0 4.1 4.2 Yu D et al.: The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metab 2021. (PMID 33887198) [PubMed] [DOI] [Full text] Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
    5. Fontana L et al.: Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health. Cell Rep 2016. (PMID 27346343) [PubMed] [DOI] [Full text] Protein-restricted (PR), high-carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Furthermore, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderate PR diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet.
    6. Green CL et al.: Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. Cell Metab 2023. (PMID 37939658) [PubMed] [DOI] [Full text] Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.