The impact of dietary protein intake on longevity and metabolic health

Kitada, Munehiro; Ogura, Yoshio; Monno, Itaru; Koya, Daisuke

doi:10.1016/j.ebiom.2019.04.005

Cited by 175Genetics, Aging, and Longevity in Model OrganismsDietary Effects on HealthMuscle metabolism and nutrition

The impact of dietary protein intake on longevity and metabolic health

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Kitada, Munehiro, Ogura, Yoshio, Monno, Itaru, Koya, Daisuke·2019·EBioMedicine

DOI 10.1016/j.ebiom.2019.04.005PMC PMC6562018

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Abstract

Lifespan and metabolic health are influenced by dietary nutrients. Recent studies show that a reduced protein intake or low-protein/high-carbohydrate diet plays a critical role in longevity/metabolic health. Additionally, specific amino acids (AAs), including methionine or branched-chain AAs (BCAAs), are associated with the regulation of lifespan/ageing and metabolism through multiple mechanisms. Therefore, methionine or BCAAs restriction may lead to the benefits on longevity/metabolic health. Moreover, epidemiological studies show that a high intake of animal protein, particularly red meat, which contains high levels of methionine and BCAAs, may be related to the promotion of age-related diseases. Therefore, a low animal protein diet, particularly a diet low in red meat, may provide health benefits. However, malnutrition, including sarcopenia/frailty due to inadequate protein intake, is harmful to longevity/metabolic health. Therefore, further study is necessary to elucidate the specific restriction levels of individual AAs that are most effective for longevity/metabolic health in humans.

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Dietary fibre is associated with cardiovascular and gastrointestinal health.
“Dietary fibre is associated with cardiovascular and gastrointestinal health [87].”
From Challenges for Upcycled Foods: Definition, Inclusion in the Food Waste Management Hierarchy and Public Acceptability (2021) · cites this paper as [87]
The Relationships among protein sources, longevity and metabolic health section discusses cardiovascular risks associated with red and processed meat, not dietary fibre. Searches of our copy for “fibre,” “fiber,” and “gastrointestinal health” found no passage linking dietary fibre to cardiovascular or gastrointestinal health; the copy does not address the attributed claim. (LLM, conf=0.76)
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Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21
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“Moreover, in fruit flies, maximal H2S production capacity was observed in whole-body extracts of flies subjected to varying levels of DR andMetR [54], which are correlated with the maximal lifespan extension [55].”
Background
Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy
Zhang, F., Zhao, S., Yan, W., Xia, Y., Chen, X., Wang, W., Zhang, J., Gao, C., Peng, C. Y., Yan, F., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.10.013 · Cited by 176 · cited 1× · see citing works
“reported that hepatic mTOR activation by BCAAs inhibited lipid-induced hepatic autophagy and caused hepatic lipotoxicity [24].”
Background
The relationship between branched-chain amino acid related metabolomic signature and insulin resistance: A systematic review
Zhao, X., Han, Q., Liu, Y., Sun, C., Gang, X., & Wang, G. (2016) · Journal of Diabetes Research · doi:10.1155/2016/2794591 · Cited by 174 · see citing works
A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
Maida, A., Zota, A., Sjøberg, K. A., Schumacher, J., Sijmonsma, T. P., Pfenninger, A., Christensen, M. M., Gantert, T., Fuhrmeister, J., Rothermel, U., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85946 · Cited by 170 · cited 7× · see citing works
“A LPD also enhances EE by increasing sympathetic flux via β-adrenergic receptor signalling to brown adipose tissue (BAT) with the consequent upregulation of uncoupling protein-1 (UCP-1) expression [38–40] and increased FGF21-mediated thermogenesis [33].”
BackgroundInfluential
Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome.
Plaisance, E., Greenway, F., Boudreau, A., Hill, K., Johnson, W., Krajcik, R., Perrone, C. E., Orentreich, N., Cefalu, W., & Gettys, T. (2011) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2010-2493 · Cited by 161 · cited 3× · see citing works
“Although insulin sensitivity improved and EE was unaffected in both groups, MetR produced a significant increase in fat oxidation and a reduction in intrahepatic lipid content [91].”
BackgroundMethod
Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan
Obata, F., & Miura, M. (2015) · Nature Communications · doi:10.1038/ncomms9332 · Cited by 157 · cited 4× · see citing works
“demonstrated that enhancing SAM catabolism by activating Gnmt extends the lifespan in Drosophila [27].”
BackgroundInfluential
Caloric restriction and human longevity: what can we learn from the Okinawans?
Willcox, D. C., Willcox, B. J., Todoriki, H., Curb, J. D., & Suzuki, M. (2006) · Biogerontology · doi:10.1007/s10522-006-9008-z · Cited by 156 · see citing works
Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation
Zhenyukh, O., González‐Amor, M., Rodrigues-Díez, R. R., Esteban, V., Ruiz‐Ortega, M., Salaíces, M., Mas, S., Briones, A. M., & Egido, J. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13759 · Cited by 155 · cited 1× · see citing works
“BCAAs also cause oxidative stress and inflammation in peripheral blood mononuclear cells [61] and endothelial cells [62] via the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear factor-κB (NF-κB) and mTORC1.”
Background
Evolution of Hydrogen Sulfide Therapeutics to Treat Cardiovascular Disease
Li, Z., Polhemus, D. J., & Lefer, D. J. (2018) · Circulation Research · doi:10.1161/circresaha.118.311134 · Cited by 142 · cited 1× · see citing works
“H2S can readily diffuse through tissues and has pleiotropic and beneficial effects at the cellular, tissue and organismal levels with the potential to contribute to stress resistance by exerting positive effects, including anti-oxidative/anti-inflammatory effects [53].”
Background
Protein Restriction Without Strong Caloric Restriction Decreases Mitochondrial Oxygen Radical Production and Oxidative DNA Damage in Rat Liver
Sanz, A., Caro, P., & Barja, G. (2004) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-004-9001-7 · Cited by 141 · cited 1× · see citing works
“A 40%PR diet for 6–7 weeks without CR also decreases mitochondrial ROS (MtROS) production, specifically in complex I, in the rat liver [56].”
Background
Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization
Bhattacharya, S., Granger, C., Craig, D., Haynes, C., Bain, J., Stevens, R., Hauser, E. R., Newgard, C., Kraus, W. E., Newby, L., et al. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.10.036 · Cited by 138 · see citing works
Methionine Restriction Activates the Retrograde Response and Confers Both Stress Tolerance and Lifespan Extension to Yeast, Mouse and Human Cells
Johnson, J. E., & Johnson, F. B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0097729 · Cited by 138 · see citing works
Towards a synthesis of frameworks in nutritional ecology: interacting effects of protein, carbohydrate and phosphorus on field cricket fitness
Harrison, S. J., Raubenheimer, D., Simpson, S. J., Godin, J. J., & Bertram, S. M. (2014) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2014.0539 · Cited by 136 · see citing works
Remodeling the Integration of Lipid Metabolism Between Liver and Adipose Tissue by Dietary Methionine Restriction in Rats
Hasek, B. E., Boudreau, A., Shin, J., Feng, D., Hulver, M. W., Van, N. T., Laque, A., Stewart, L. K., Stone, K. P., Wanders, D., et al. (2013) · Diabetes · doi:10.2337/db13-0501 · Cited by 136 · cited 1× · see citing works
“Moreover,MetR increasesmetabolicflexibility andoverall insulin sensitivity and improves lipid metabolism while decreasing systemic inflammation [42,88,90].”
Background
Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice
Wahl, D., Solon‐Biet, S. M., Wang, Q., Wali, J. A., Pulpitel, T., Clark, X., Raubenheimer, D., Senior, A. M., Sinclair, D. A., Cooney, G. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.070 · Cited by 135 · cited 1× · see citing works
“Additionally, LPHC (5%protein) diets are interestingly associated with increased dendritic spines in dentate gyrus neurons and improved performance in the Barnes maze and novel object recognition test, and the effects are similar to those associated with 20%CR [67].”
Result
Pleiotropic responses to methionine restriction
Ables, G. P., & Johnson, J. E. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.01.012 · Cited by 127 · cited 1× · see citing works
“Food sources of animal protein, such as beef, lamb, fish, pork and eggs, contain higher levels of methionine than plant food sources, including nuts, seeds, legumes, cereals, vegetables and fruits [96].”
Background
Mechanisms of thermogenesis induced by low protein diets
Rothwell, N. J., Stock, M. J., & Tyzbir, R. S. (1983) · Metabolism · doi:10.1016/0026-0495(83)90190-7 · Cited by 124 · see citing works
Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver
Caro, P., Gómez, J., Lopez‐Torres, M., Sánchez-Román, I., Naudí, A., Jové, M., Pamplona, R., & Barja, G. (2008) · Biogerontology · doi:10.1007/s10522-008-9130-1 · Cited by 110 · see citing works
Forty Percent Methionine Restriction Decreases Mitochondrial Oxygen Radical Production and Leak at Complex I During Forward Electron Flow and Lowers Oxidative Damage to Proteins and Mitochondrial DNA in Rat Kidney and Brain Mitochondria
Caro, P., Gómez, J., Sánchez-Román, I., Naudí, A., Ayala, V., Lopez‐Torres, M., Pamplona, R., & Barja, G. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0902 · Cited by 109 · see citing works
Methionine restriction and life‐span control
Lee, B. C., Kaya, A., & Gladyshev, V. N. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12973 · Cited by 108 · see citing works
Implications from and for food cultures for cardiovascular disease: longevity.
Suzuki, M., Wilcox, B. J., & Wilcox, C. (2001) · Asia Pacific Journal of Clinical Nutrition · doi:10.1111/j.1440-6047.2001.00219.x · Cited by 105 · cited 1× · see citing works
“The types of foods included in the traditional Okinawan diet, which includes a high intake of green leafy and yellow root vegetables, sweet potatoes (as a dietary staple), and soy (as the principle protein) supplemented with small amounts of fish and meat, are adequate in most nutrients [72,73].”
Background
Low protein diets produce divergent effects on energy balance
Pezeshki, A., Zapata, R. C., Singh, A., Yee, N. J., & Chelikani, P. K. (2016) · Scientific Reports · doi:10.1038/srep25145 · Cited by 103 · cited 1× · see citing works
“To stabilize protein intake, mice fed a LPD exhibit compensatory increased energy intake; however, the LPD exerted beneficial effects on metabolic health due to increased EE [68].”
Background
Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study
Willcox, D. C., Willcox, B. J., Hsueh, W., & Suzuki, M. (2006) · AGE · doi:10.1007/s11357-006-9020-x · Cited by 102 · cited 1× · see citing works
“Interestingly, on the Japanese island of Okinawa, many people exhibit increased longevity, and the centenarian population is five times larger than that in other developed nations [69].”
Background
A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity
Kitada, M., Ogura, Y., Suzuki, T., Sen, S., Lee, S. M., Kanasaki, K., Kume, S., & Koya, D. (2016) · Diabetologia · doi:10.1007/s00125-016-3925-4 · Cited by 97 · cited 3× · see citing works
“Previously, we also demonstrated that a LPD exerts a reno-protective effect by inducing autophagy via the suppression of mTORC1 in rats with type 2 diabetes mellitus (T2DM)/obesity [25].”
BackgroundSelf-citation
Plasma Branched-Chain Amino Acids and Risk of Incident Type 2 Diabetes: Results from the PREVEND Prospective Cohort Study
Flores-Guerrero, J. L., Osté, M. C. J., Kieneker, L. M., Gruppen, E. G., Wolak, J. E., Otvos, J. D., Connelly, M. A., Bakker, S. J. L., & Dullaart, R. P. F. (2018) · Journal of Clinical Medicine · doi:10.3390/jcm7120513 · Cited by 96 · see citing works
Role of β-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction
Plaisance, E. P., Henagan, T. M., Echlin, H., Boudreau, A., Hill, K. L., Lenard, N. R., Hasek, B. E., Orentreich∥, N., & Gettys, T. W. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00838.2009 · Cited by 95 · cited 1× · see citing works
“Metabolically, MetR also decreases adiposity but acts through a paradoxical increase in both energy intake and EE in rodents [49,88,89].”
Background
The Geometric Framework for Nutrition as a tool in precision medicine
Simpson, S. J., Couteur, D. G. L., James, D. E., George, J., Gunton, J. E., Solon‐Biet, S. M., & Raubenheimer, D. (2017) · Nutrition and Healthy Aging · doi:10.3233/nha-170027 · Cited by 95 · cited 2× · see citing works
“The significance of the macronutrient balance for longevity and metabolic health is shown by the Geometric Framework for Nutrition, which was developed to evaluate the relationship between diet and outcomes such as lifespan across a broad landscape of macronutrient and energy intakes [3].”
Method
Dietary approaches to stop hypertension.
Sacks, F. (1995) · Annals of Epidemiology · doi:10.1016/1047-2797(95)00103-4 · Cited by 85 · cited 1×
“For example, the Mediterranean diet [97] or the Dietary Approaches to Stop Hypertension (DASH) diet [98] may be useful”
Method
Dietary restriction of single essential amino acids reduces plasma insulin-like growth factor-I (IGF-I) but does not affect plasma IGF-binding protein-1 in rats.
Takenaka, A., Oki, N., Takahashi, S.-I., & Noguchi, T. (2000) · Journal of NutriLife · doi:10.1093/jn/130.12.2910 · Cited by 80 · cited 1×
“PR or restriction of particular AAs such as methionine, may explain part of the effects of CR on longevity and disease risk because PR and AA restriction can sufficiently reduce IGF-1 levels and cancer incidence and extend the lifespan in model organisms independently of calorie intake [46].”
Background
New Horizons: Dietary protein, ageing and the Okinawan ratio
Couteur, D. G. L., Solon‐Biet, S. M., Wahl, D., Cogger, V. C., Willcox, B. J., Willcox, D. C., Raubenheimer, D., & Simpson, S. J. (2016) · Age and Ageing · doi:10.1093/ageing/afw069 · Cited by 79 · cited 1× · see citing works
“obtained from theOkinawandiet is derived from9%protein and 85%carbohydrates [74].”
Method
Low protein diet changes the energetic balance and sympathetic activity in brown adipose tissue of growing rats
de França, S. A., dos Santos, M. P., Garófalo, M. A. R., Navegantes, L. C. C., Kettelhut, Í. D. C., Lopes, C. F., & Kawashita, N. H. (2009) · Nutrition · doi:10.1016/j.nut.2009.03.011 · Cited by 79 · see citing works
Influence of carbohydrate and fat intake on diet-induced thermogenesis and brown fat activity in rats fed low protein diets.
Rothwell, N., & Stock, M. J. (1987) · Journal of NutriLife · doi:10.1093/jn/117.10.1721 · Cited by 78 · see citing works
FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1
Kwon, M. M., O’Dwyer, S. M., Baker, R. K., Covey, S. D., & Kieffer, T. J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.021 · Cited by 77 · cited 1× · see citing works
“Moreover, UCP-1 is required for FGF21-mediated improvements in glucose tolerance [41].”
Background
High dietary methionine intake increases the risk of acute coronary events in middle-aged men
Virtanen, J. K., Voutilainen, S., Rissanen, T., Happonen, P., Mursu, J., Laukkanen, J. A., Poulsen, H. E., Lakka, T. A., & Salonen, J. T. (2005) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2005.05.005 · Cited by 74 · see citing works
Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria
Sánchez-Román, I., Gómez, A. G., Pérez-Liébana, I., Sanchez, C., Suárez, H., Naudí, A., Jové, M., Lopez‐Torres, M., Pamplona, R., & Barja, G. (2012) · Biogerontology · doi:10.1007/s10522-012-9384-5 · Cited by 68 · see citing works
Growth hormone alters methionine and glutathione metabolism in Ames dwarf mice
Brown‐Borg, H. M., Rakoczy, S. G., & Uthus, E. O. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.09.005 · Cited by 64 · cited 1× · see citing works
“Moreover, methionine interacts with the GH/IGF-1 pathway to extend the lifespan and improve metabolic health in mice [48,49], and GH/IGF-1 represses Gnmt activity [50,51] (Fig.”
Background
S-Adenosylmethionine Is Associated with Fat Mass and Truncal Adiposity in Older Adults
Elshorbagy, A. K., Nijpels, G., Garcia, M. V., Stehouwer, C. D. A., Marga, O., Refsum, H., & Dekker Jacqueline, M. (2013) · Journal of Nutrition · doi:10.3945/jn.113.179192 · Cited by 60 · cited 1× · see citing works
“Another report demonstrated that plasma SAM, but not methionine, is independently associated with fat mass and truncal adiposity in a cross-sectional study involving 610 elderly people [94], while overfeeding increases serum SAM in proportion to the fat mass gained [95].”
Background
Methionine is a signal of amino acid sufficiency that inhibits autophagy through the methylation of PP2A
Laxman, S., Sutter, B. M., & Tu, B. P. (2014) · Autophagy · doi:10.4161/auto.27485 · Cited by 50 · cited 2×
“Methylated-PP2A can dephosphorylate Npr2, a component of a negative regulatory complex of mTORC1, promoting autophagy [28,29] (Fig.”
Background
Serum S-adenosylmethionine, but not methionine, increases in response to overfeeding in humans
Elshorbagy, A. K., Jernerén, F., Samocha‐Bonet, D., Refsum, H., & Heilbronn, L. K. (2016) · Nutrition and Diabetes · doi:10.1038/nutd.2015.44 · Cited by 50 · cited 1× · see citing works
“Another report demonstrated that plasma SAM, but not methionine, is independently associated with fat mass and truncal adiposity in a cross-sectional study involving 610 elderly people [94], while overfeeding increases serum SAM in proportion to the fat mass gained [95].”
Background
Long-Term Effects of Dietary Protein and Branched-Chain Amino Acids on Metabolism and Inflammation in Mice
Mu, W., Vanhoosier, E., Elks, C. M., & Grant, R. W. (2018) · Nutrients · doi:10.3390/nu10070918 · Cited by 48 · see citing works
Mouse glycine N-methyltransferase is sexually dimorphic and regulated by growth hormone.
Aida, K., Tawata, M., Negishi, M., & Onaya, T. (1997) · Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme · doi:10.1055/s-2007-978982 · Cited by 42 · cited 1×
“Moreover, methionine interacts with the GH/IGF-1 pathway to extend the lifespan and improve metabolic health in mice [48,49], and GH/IGF-1 represses Gnmt activity [50,51] (Fig.”
Background
One-carbon metabolism markers are associated with cardiometabolic risk factors
Lind, M. V., Lauritzen, L., Vestergaard, H., Hansen, T. F., Pedersen, O. B., Kristensen, M., & Ross, A. B. (2018) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2018.01.005 · Cited by 35 · see citing works
A low-protein diet exerts a beneficial effect on diabetic status and prevents diabetic nephropathy in Wistar fatty rats, an animal model of type 2 diabetes and obesity
Kitada, M., Ogura, Y., Suzuki, T., Monno, I., Kanasaki, K., Watanabe, A., & Koya, D. (2018) · Nutrition & Metabolism · doi:10.1186/s12986-018-0255-1 · Cited by 27 · cited 2× · see citing works
“Our previous data indicated that a LPD induced continuous high levels of FGF21, which might be associated with improved glucose/lipid metabolism and body/fat weight in rats with T2DM/obesity [25,36].”
BackgroundSelf-citation

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Sorted by citations

The quest to slow ageing through drug discovery
Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0067-7 · Cited by 468 · see citing works
Branched chain amino acids, aging and age-related health
Couteur, D. G. L., Solon‐Biet, S. M., Cogger, V. C., Ribeiro, R. V., de Cabo, R., Raubenheimer, D., Cooney, G. J., & Simpson, S. J. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101198 · Cited by 233 · see citing works
Challenges for Upcycled Foods: Definition, Inclusion in the Food Waste Management Hierarchy and Public Acceptability
Moshtaghian, H., Bolton, K., & Rousta, K. (2021) · Foods · doi:10.3390/foods10112874 · Cited by 150 · see citing works
“For example, proteins are protective against sarcopenia (loss of muscle mass) and frailty [86].”
Background
Amino acids in the regulation of aging and aging-related diseases
Canfield, C.-A. E., & Bradshaw, P. C. (2019) · Translational Medicine of Aging · doi:10.1016/j.tma.2019.09.001 · Cited by 133 · see citing works
“Many beneficial disease-delaying effects of protein restriction have been found [31].”
Background
Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication
Li, Z., Wang, F., Liang, B., Su, Y., Sun, S., Xia, S., Shao, J., Zhang, Z., Hong, M., Zhang, F., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00349-7 · Cited by 144 · see citing works
“Dietary MR and cysteine restriction have beneficial effects on circulating biomarkers, including FGF21,(149) and MR protects against metabolic diseases and ageing, represses cancer development, and improves cancer therapy.(150,151) However, MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular…”
Background
Dietary Regulation of Immunity
Lee, A. H., & Dixit, V. D. (2020) · Immunity · doi:10.1016/j.immuni.2020.08.013 · Cited by 123 · see citing works
Lesser mealworm (Alphitobius diaperinus) powder as a novel baking ingredient for manufacturing high-protein, mineral-dense snacks
Roncolini, A., Milanović, V., Aquilanti, L., Cardinali, F., Garofalo, C., Sabbatini, R., Clementi, F., Belleggia, L., Pasquini, M., Mozzon, M., et al. (2020) · Food Research International · doi:10.1016/j.foodres.2020.109031 · Cited by 115 · see citing works
Emerging role of aging in the progression of NAFLD to HCC
He, Y., Su, Y., Duan, C., Wang, S., He, W. G., Zhang, Y., An, X., & He, M. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101833 · Cited by 98 · see citing works
The intersection of frailty and metabolism
Mishra, M., Wu, J., Kane, A. E., & Howlett, S. E. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.012 · Cited by 95 · see citing works
The carbon footprint of meat and dairy proteins: a practical perspective to guide low carbon footprint dietary choices
Marbach, S., & Gaillac, R. (2021) · bioRxiv · doi:10.1101/2021.01.31.429047 · Cited by 80
Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress
Kitada, M., Ogura, Y., Monno, I., Xu, J., & Koya, D. (2021) · Biomedicines · doi:10.3390/biomedicines9020130 · Cited by 75 · see citing works
“Therefore, MetR-induced beneficial effects on lifespan extension and metabolic health are mediated partially through a reduction in oxidative stress via multiple mechanisms [11], as described as follows: (1) MetR leads to the induction of autophagy due to the suppression of mechanistic target of rapamycin complex 1 (m…”
BackgroundSelf-citation
Associations of dietary protein intake with all-cause, cardiovascular disease, and cancer mortality: A systematic review and meta-analysis of cohort studies
Qi, X., & Shen, P. (2020) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2020.03.008 · Cited by 78 · see citing works
L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans
Kim, J., Jo, Y., Cho, D., & Ryu, D. (2022) · Nature Communications · doi:10.1038/s41467-022-34265-x · Cited by 65 · see citing works
Methionine restriction alleviates high-fat diet-induced obesity: Involvement of diurnal metabolism of lipids and bile acids
Wang, L., Ren, B., Zhang, Q., Chu, C., Zhao, Z., Wu, J., Zhao, W., Liu, Z., & Liu, X. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165908 · Cited by 57 · see citing works
Molecular mechanisms underlying the lifespan and healthspan benefits of dietary restriction across species
Fan, J., & Xu, Y. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1771707 · Cited by 57 · see citing works
Very-low-protein diets lead to reduced food intake and weight loss, linked to inhibition of hypothalamic mTOR signaling, in mice
Wu, Y., Li, B., Li, L., Mitchell, S. E., Green, C. L., D’Agostino, G., Wang, G., Wang, L., Li, M., Li, J., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.01.017 · Cited by 77 · see citing works
Methionine Restriction Regulates Cognitive Function in High‐Fat Diet‐Fed Mice: Roles of Diurnal Rhythms of SCFAs Producing‐ and Inflammation‐Related Microbes
Wang, L., Ren, B., Yan, H., Chu, C., Zhao, Z., Zhang, Y., Zhao, B., Shi, R., Ren, J., Dai, X., et al. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202000190 · Cited by 57 · see citing works
Nutrients and Pathways that Regulate Health Span and Life Span
Pignatti, C., D’Adamo, S., Stefanelli, C., Flamigni, F., & Cetrullo, S. (2020) · Geriatrics · doi:10.3390/geriatrics5040095 · Cited by 64 · see citing works
“Low levels of animal proteins or methionine or diets with a low protein/CHO ratio are all conditions that are able to decrease the IGF1 pathway, thus reducing mTOR stimulation [38,80,111].”
BackgroundInfluential
Separating the Wheat from the Chaff: Nutritional Value of Plant Proteins and Their Potential Contribution to Human Health
Davies, R. W., & Jakeman, P. M. (2020) · Nutrients · doi:10.3390/nu12082410 · Cited by 53 · see citing works
“In developing regions, protein malnutrition is a major issue [6,7], whereas in developed regions protein intake is generally sufficient and discussions are based on whether higher protein intakes are positively or negatively impact health and fitness outcomes [1,8].”
Background
Alternative dietary protein sources to support healthy and active skeletal muscle aging
van der Heijden, I., Monteyne, A. J., Stephens, F. B., & Wall, B. T. (2023) · Nutrition Reviews · doi:10.1093/nutrit/nuac049 · Cited by 45 · see citing works
The contradictory role of branched-chain amino acids in lifespan and insulin resistance
He, Y., Li, K., Wei, J., Lin, Y., & Liu, Y. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1189982 · Cited by 44 · see citing works
“High intake of red meat containing high levels of BCAAs may be associated with the promotion of age-related diseases (16).”
Background
Mechanism of Activation of Mechanistic Target of Rapamycin Complex 1 by Methionine
Kitada, M., Xu, J., Ogura, Y., Monno, I., & Koya, D. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00715 · Cited by 40 · see citing works
Self-citation
Exploring the underlying mechanisms on NaCl-induced reduction in digestibility of myoglobin.
Liu, H., Li, Q., Jiang, S., Zhang, M., Zhao, D., Shan, K., & Li, C.-B. (2022) · Food Chemistry · doi:10.1016/j.foodchem.2022.132183 · Cited by 38 · see citing works
Global associations between macronutrient supply and age-specific mortality
Senior, A. M., Nakagawa, S., Raubenheimer, D., & Simpson, S. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2015058117 · Cited by 41 · see citing works
“calorie | diet | food security | life span | nutrition D is a powerful determinant of health and life span (1, 2).”
Background
Bioactive Oligopeptides from Ginseng (Panax ginseng Meyer) Suppress Oxidative Stress-Induced Senescence in Fibroblasts via NAD+/SIRT1/PGC-1α Signaling Pathway
Zhu, N., Xu, M., & Li, Y. (2022) · Nutrients · doi:10.3390/nu14245289 · Cited by 33 · see citing works
“Several clinical studies have also shown that branched-chain amino acid supplementation may lessen sarcopenia in the elderly by boosting mitochondrial biosynthesis [2].”
BackgroundInfluential
Low Protein Diets and Energy Balance: Mechanisms of Action on Energy Intake and Expenditure
Pezeshki, A., & Chelikani, P. K. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.655833 · Cited by 35 · see citing works
“Among the macronutrients, the intake of protein is tightly regulated and dietary protein restriction is purported to extend lifespan, improve energy balance and cardiometabolic health (1); however, the underlying mechanisms remain poorly understood.”
Background
Association between polygenetic risk scores related to sarcopenia risk and their interactions with regular exercise in a large cohort of Korean adults
Park, S. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.09.003 · Cited by 31 · see citing works
TNFSF14+ natural killer cells prevent spontaneous abortion by restricting leucine-mediated decidual stromal cell senescence
Shi, J., Lai, Z., Zhou, W., Yang, H., Zhang, T., Sun, J., Zhao, J., & Li, M. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00220-3 · Cited by 24 · see citing works
“BCAA play important roles in regulating the mechanistic target of rapamycin (mTOR), insulin, and insulin-like growth factor (IGF)-1 and further link nutrition and metabolism with health and aging (Kitada et al, 2019; Solon-Biet et al, 2019; Soultoukis and Partridge, 2016).”
Animal and vegetable protein intake and malnutrition in older adults: a multicohort study
Carballo‐Casla, A., Sotos‐Prieto, M., García‐Esquinas, E., Struijk, E. A., Caballero, F. F., Calderón‐Larrañaga, A., López‐García, E., Rodríguez‐Artalejo, F., & Ortolá, R. (2024) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2023.100002 · Cited by 32 · see citing works
Long-term silk peptide intake promotes skeletal muscle mass, reduces inflammation, and modulates gut microbiota in middle-aged female rats
Park, S., Yuan, H., Zhang, T., Wu, X., Huang, S. K., & Cho, S. M. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111415 · Cited by 30 · see citing works
Effect of branched-chain amino acid supplementation, dietary intake and circulating levels in cardiometabolic diseases
Víctor de la, O., Zazpe, I., & Ruiz‐Canela, M. (2019) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000614 · Cited by 30 · see citing works
“BCAA supplementation has been recommended in elderly people to reduce sarcopenia [14] and in athletes to improve muscle mass and physical performance [15].”
Background
A low-protein diet exerts a beneficial effect on diabetic status and prevents diabetic nephropathy in Wistar fatty rats, an animal model of type 2 diabetes and obesity
Kitada, M., Ogura, Y., Suzuki, T., Monno, I., Kanasaki, K., Watanabe, A., & Koya, D. (2018) · Nutrition & Metabolism · doi:10.1186/s12986-018-0255-1 · Cited by 27 · see citing works
Self-citation
High dietary protein and fat contents exacerbate hepatic senescence and SASP in mice
Nehme, J., Yang, D., Altulea, A., Varela-Eirín, M., Wang, L., Hu, S., Wu, Y., Togo, J., Niu, C., Speakman, J. R., et al. (2021) · FEBS Journal · doi:10.1111/febs.16292 · Cited by 23 · see citing works
Nutrient Adequacy Is Associated with Reduced Mortality in US Adults
Ha, K., Sakaki, J. R., & Chun, O. K. (2021) · Journal of Nutrition · doi:10.1093/jn/nxab240 · Cited by 27 · see citing works
Methionine Abrogates the Reno-Protective Effect of a Low-Protein Diet Against Diabetic Kidney Disease in Obese Rats with Type 2 Diabetes
Kitada, M., Ogura, Y., Monno, I., Xu, J., & Koya, D. (2019) · Aging · doi:10.18632/aging.102902 · Cited by 20 · see citing works
Self-citation
Dietary Manipulation of Amino Acids for Cancer Therapy
Jiménez‐Alonso, J. J., & López‐Lázaro, M. (2023) · Nutrients · doi:10.3390/nu15132879 · Cited by 24 · see citing works
“Dietary protein restriction can increase life expectancy [28] and reduce the incidence of age-related diseases such as cancer [29].”
Background
Food-Based Dietary Guidelines and Protein Quality Definitions—Time to Move Forward and Encompass Mycoprotein?
Derbyshire, E. J. (2022) · Foods · doi:10.3390/foods11050647 · Cited by 28 · see citing works
“In the 21st century, adequate protein intakes remain essential for longevity, metabolic and muscular health [61,62].”
Background
Evolution of natural lifespan variation and molecular strategies of extended lifespan in yeast
Kaya, A., Phua, C. Z. J., Lee, M. B., Wang, L., Tyshkovskiy, A., Ma, S., Barré, B. P., Liu, W., Harrison, B. R., Zhao, X., et al. (2021) · eLife · doi:10.7554/elife.64860 · Cited by 26 · see citing works
“, 2015), dietary (Alic and Partridge, 2011; Stefana et al., 2017; Kitada et al., 2019), pharmacological (Bitto et al.”
Dietary Restriction and Oxidative Stress: Friends or Enemies?
Mladenović, A., Lončarević‐Vasiljković, N., & Gonos, E. S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7959 · Cited by 27 · see citing works
“Among other factors, SIRTs gained great popularity due to their involvement in DR-mediated beneﬁcial health and antiaging effects (98), including a role in regulating redox homeostasis (65, 131).”
Association of dietary protein intake, inflammation with muscle mass, physical performance and incident sarcopenia in Chinese community-dwelling older adults
Li, S., Lu, Z., Leung, J. C. S., & Kwok, T. C. Y. (2024) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2024.100163 · Cited by 24 · see citing works
Association of dietary intake of branched-chain amino acids with long-term risks of CVD, cancer and all-cause mortality
Xu, B., Wang, M., Pu, L., Shu, C., Li, L., & Han, L.-Y. (2021) · Public Health Nutrition · doi:10.1017/s1368980021004948 · Cited by 19
“Furthermore, BCAA supplementation was recommended to reduce sarcopenia in older adults(26) and to improve muscle mass and physical performance in athletes(27).”
A fifty percent leucine-restricted diet reduces fat mass and improves glucose regulation
Zhou, Z., Yin, H., Guo, Y., Fang, Y., Yuan, F., Chen, S., & Guo, F. (2021) · Nutrition & Metabolism · doi:10.1186/s12986-021-00564-1 · Cited by 22 · see citing works
“Furthermore, many of the effects of dietary restriction on longevity and health span in model organisms have been linked to reduced protein and amino acid (AA) intake and the stimulation of specific nutrient signaling pathways [5, 6].”
Background
Severity of atopic dermatitis is associated with gut-derived metabolites and leaky gut-related biomarkers
Blicharz, L., Samborowska, E., Zagożdżon, R., Bukowska‐Ośko, I., Czuwara, J., Zych, M., Roszczyk, A., Perlejewski, K., Makowska, K., Nowaczyk, J., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-09520-y · Cited by 19 · see citing works
“In addition to providing valuable investigative insights, the results of this study seem to support the importance of common dietary recommendations, such as sufficient fiber consumption 62 and moderation of protein intake 63 .”
Restricted intake of sulfur-containing amino acids reversed the hepatic injury induced by excess Desulfovibrio through gut–liver axis
Zhou, L., Lu, G., Nie, Y., Ren, Y., Shi, J., Xue, Y., Xu, Z., & Geng, Y. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2370634 · Cited by 21 · see citing works
“38 Activation of mTORC1 after feeding increases phosphorylation of ubiquitin-specific peptidase 20 (USP20) which stabilizes HMG-CoA reductase (HMGCR) and therefore promotes cholesterol synthesis.”
Background
Optimal dietary energy and protein levels for breeding pigeons in the winter "2 + 3" lactation pattern
Peng, J., Huang, W., Liang, Y., Zhang, W., Zhang, Y., Yang, M., Zheng, S., Lv, Y., Gou, Z., Cheng, C., et al. (2023) · Poultry Science · doi:10.1016/j.psj.2023.102964 · Cited by 17 · see citing works
“the body and alleviate oxidative stress (Kitada et al., 2019).”
Low‐carbohydrate diets, low‐fat diets, and mortality in middle‐aged and older people: A prospective cohort study
Zhao, Y., Li, Y., Wang, W., Song, Z., Zhuang, Z., Li, D., Qi, L., & Huang, T. (2023) · Journal of Internal Medicine · doi:10.1111/joim.13639 · Cited by 26 · see citing works
Does Diet Have a Role in the Treatment of Alzheimer's Disease?
Thelen, M., & Brown‐Borg, H. M. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.617071 · Cited by 23 · see citing works
“In short, less dietary intake in methionine leads to decreased mTORC1 signaling and increased health and lifespan (Kitada et al., 2019).”
Background
Association of Quantity and Quality of Protein Intake with Depression and Anxiety Symptoms among Adolescent Boys and Girls (13–15 Years) Studying in Public Schools of Delhi
Khanna, P., & Aeri, B. T. (2020) · Journal of Nutritional Science and Vitaminology · doi:10.3177/jnsv.66.s141 · Cited by 22 · see citing works
Dietary diversity score and the acceleration of biological aging: a population-based study of 88,039 participants
Liu, Y., Kang, M., Wei, W., Hui, J., Gou, Y., Liu, C. Y., Zhou, R., Wang, B., Shi, P., Liu, H., et al. (2024) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2024.100271 · Cited by 14 · see citing works
PGC-1α Methylation, miR-23a, and miR-30e Expression as Biomarkers for Exercise- and Diet-Induced Mitochondrial Biogenesis in Capillary Blood from Healthy Individuals: A Single-Arm Intervention
Krammer, U. D. B., Sommer, A., Tschida, S., Mayer, A., Lilja, S., Switzeny, O. J., Hippe, B., Rust, P., & Haslberger, A. G. (2022) · Sports · doi:10.3390/sports10050073 · Cited by 14 · see citing works
“The consumption of cruciferous vegetables may maintain mtDNA levels via their antioxidant properties by fighting against oxidative stress and thereby affecting athletic performance [40,49].”
BackgroundInfluential
Expression of Multicopy Tandem Recombinant Ginseng Hexapeptide in Bacillus subtilis and the Evaluation of Antiaging Activity
Xiang, Q., Qu, L., Lei, H., Duan, Z., Zhu, C., Yuwen, W., Ma, X., & Fan, D. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c09158 · Cited by 15 · see citing works
Post Hoc Analysis of a Randomized Controlled Trial on Fasting and Plant-Based Diet in Rheumatoid Arthritis (NutriFast): Nutritional Supply and Impact on Dietary Behavior
Hartmann, A. M., D'Urso, M., Dell’Oro, M., Koppold, D. A., Steckhan, N., Michalsen, A., Kandil, F. I., & Keßler, C. S. (2023) · Nutrients · doi:10.3390/nu15040851 · Cited by 16 · see citing works
“This association seems to be abolished or attenuated when proteins are plant-derived [46,47].”
Background
Methionine-Restricted Diet: A Feasible Strategy Against Chronic or Aging-Related Diseases
Wu, G., Xu, J., Wang, Q., Fang, Z., Fang, Y., Jiang, Y., Zhang, X., Cheng, X., Sun, J., & Le, G. (2022) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c05829 · Cited by 17 · see citing works
Drugs, clocks and exercise in ageing: hype and hope, fact and fiction
Furrer, R., & Handschin, C. (2022) · The Journal of Physiology · doi:10.1113/jp282887 · Cited by 25 · see citing works
“…diet balanced in macro-and micronutrients seems to surpass the effects of extreme diet regimens, many of which have been proposed based on experiments in rodents, but with questionable translatability to humans (Lee et al., 2021), for example for low protein-containing diets (Kitada et al., 2019).”
Nicotinamide Riboside Neutralizes Hypothalamic Inflammation and Increases Weight Loss Without Altering Muscle Mass in Obese Rats Under Calorie Restriction: A Preliminary Investigation
de Castro, J. M., Stein, D. J., Medeiros, H. R., de Oliveira, C., & Torres, I. L. D. S. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.648893 · Cited by 15 · see citing works
“Besides that, a low protein intake unintentionally reduces the availability of essential amino acids that are crucial substrates for mTOR signaling and muscle protein synthesis (19).”
Background
Disclosing the Nutritional Quality Diversity of Portuguese Common Beans—The Missing Link for Their Effective Use in Protein Quality Breeding Programs
Mecha, E., Natalello, S., Carbas, B., Bento‐Silva, A., Leitão, S. T., Brites, C. M., Veloso, M. M., Rubiales, D., Costa, J., Cabral, M. F., et al. (2021) · Agronomy · doi:10.3390/agronomy11020221 · Cited by 21 · see citing works
“Although Met has been considered a limiting factor for the beans protein quality, recent studies reviewed by Kitada et al. [47] regarding longevity and animal lifespan, indicate the advantage of restricting methionine on lifespan extension through several mechanisms that involve intracellular suppression of mTORC1 and…”
Background
Red Meat Amino Acids for Beginners: A Narrative Review
Barr, B., Levitt, D. E., & Gollahon, L. (2025) · Nutrients · doi:10.3390/nu17060939 · Cited by 15 · see citing works
“The above issues with HAAs, PAHs and overconsumption, in addition to high fat content of choice red meat cuts, makes it difficult to recommend the use of red meat as the sole protein source for aging individuals [96,97].”
Influential
Exploring alternative sources of protein in food: Trends in nutrient and functional features
Lara-Parra, A. I., Hernández-Hernandez, A. A., Jaguey-Hernández, Y., Jiménez‐Osorio, A. S., Ovando, A. C., Aguilar-Arteaga, K., & Añorve‐Morga, J. (2025) · Food Research International · doi:10.1016/j.foodres.2025.116224 · Cited by 11 · see citing works
Plant-based proteins: clinical and technological importance
Vera, I., Ávila-Nava, A., León-López, L., Solis, A. L. G., Talamantes-Gómez, J. M., & Marquez-Mota, C. C. (2024) · Food Science and Biotechnology · doi:10.1007/s10068-024-01600-5 · Cited by 15 · see citing works
“As previously stated, the amino acid profile has an important role in the activation of the mTORC1 signaling pathway, and it has been well established that after eating animal protein, the serum concentration of EAA rapidly increases, stimulating muscle protein synthesis (Kitada et al., 2019).”
Background
Higher Animal Protein Intake During the Second Trimester of Pregnancy Is Associated With Risk of GDM
Yong, H. Y., Shariff, Z. M., Yusof, B. N. M., Rejali, Z., Tee, Y. Y. S., BINDELS, J. G., & van der Beek, E. M. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.718792 · Cited by 15 · see citing works
“Keywords: egg protein, animal protein, red meat protein, gestational diabetes (GDM), before pregnancy, during pregnancy INTRODUCTION The previous studies have focused on macronutrient intake in relation to the non-communicable diseases (NCDs), such as diabetesmellitus (DM), cardiovascular disease (CVD), chronic respir…”
BackgroundInfluential
Protein Source, Dietary Fibre Intake, and Inflammation in Older Adults: A UK Biobank Study
Jain, M., Celis-Morales, C. A., Ozanne, S. E., Burden, S. T., Gray, S. R., & Morrison, D. J. (2025) · Nutrients · doi:10.3390/nu17091454 · Cited by 13 · see citing works
“…animal protein results in oxidative stress/inflammation, protein/amino acid load, and increased levels of byproducts of protein or AA breakdown by the gut bacteria, such as trimethylamine n -oxide or indoxyl sulphate, which may be linked to an elevated risk of cardiovascular disease mortality [54].”
Fungal-Derived Mycoprotein and Health across the Lifespan: A Narrative Review
Derbyshire, E. J. (2022) · Journal of Fungi · doi:10.3390/jof8070653 · Cited by 13 · see citing works
“For example, it has been proposed that shifts away from animal-derived food proteins providing high levels of methionine and movements towards alternative plant sources may benefit longevity and metabolic health [63].”
Background
Tissue‐specific deletion of mouse basolateral uniporter LAT4 (Slc43a2) reveals its crucial role in small intestine and kidney amino acid transport
Rajendran, A., Poncet, N., Oparija-Rogenmozere, L., Herzog, B., & Verrey, F. (2020) · Journal of Physiology · doi:10.1113/jp280234 · Cited by 12
“The optimal quantity and quality of dietary proteins and/or AAs for adult humans is still being debated, with recent evidence pointing towards improved metabolic health under protein and/or specific AA restriction (Green & Lamming 2019; Kitada et al. 2019).”
Background
Gene–Diet Interactions: Dietary Rescue of Metabolic Defects in spen -Depleted Drosophila melanogaster
Gillette, C. M., Hazegh, K. E., Nemkov, T. G., Stefanoni, D., D’Alessandro, A., Taliaferro, J. M., & Reis, T. (2020) · Genetics · doi:10.1534/genetics.119.303015 · Cited by 17 · see citing works
High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice
van Galen, I., Birkisdóttir, M. B., Ozinga, R. A., Brandt, R. M. C., Barnhoorn, S., Imholz, S., van Oostrom, C. T., van der Marel, R. W. G. N., Smit, K., Rijksen, Y., et al. (2025) · npj Metabolic Health and Disease · doi:10.1038/s44324-025-00064-3 · Cited by 8 · see citing works
Low-Protein Diets, Malnutrition, and Bone Metabolism in Chronic Kidney Disease
Pereira, C., Guimarães, C., Ribeiro, V. S., Vaz, D. C., & Martins, M. J. (2024) · Nutrients · doi:10.3390/nu16183098 · Cited by 11 · see citing works
“…adverse effects of long-term high-protein diets (above the recommendations and particularly from animal origin), namely disorders of bone and calcium homeostasis and of renal and liver function, as well as increased cancer risk and accelerated progression of coronary artery disease [22,23].”
Background
Dietary and circulating branched chain amino acids are unfavorably associated with body fat measures among Chinese adults
Zhang, Y., Rao, S., Zhang, X., Peng, Z., Song, W., Xie, S., Cao, H., Zhang, Z., & Yang, W. (2024) · Nutrition Research · doi:10.1016/j.nutres.2024.06.009 · Cited by 12 · see citing works
Methionine restriction diets: Unravelling biological mechanisms and enhancing brain health
Liu, Y., Guo, J., Cheng, H., Wang, J., Tan, Y., Zhang, J., Tao, H., Liu, H., Xiao, J., Qi, D., et al. (2024) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2024.104532 · Cited by 12 · see citing works
Identifying the relation between food groups and biological ageing: a data-driven approach
Biemans, Y., Bach, D., Behrouzi, P., Horvath, S., Kramer, C. S., Liu, S., Manson, J. E., Shadyab, A. H., Stewart, J. D., Whitsel, E. A., et al. (2024) · Age and Ageing · doi:10.1093/ageing/afae038 · Cited by 11 · see citing works
Protein Restriction in Metabolic Health: Lessons from Rodent Models
Na, K., & Park, Y. J. (2024) · Nutrients · doi:10.3390/nu16020229 · Cited by 12 · see citing works
Habitual low carbohydrate high fat diet compared with omnivorous, vegan, and vegetarian diets
Jontez, N. B., Kenig, S., Novak, K. Š., Petelin, A., Pražnikar, Z. J., & Mohorko, N. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1106153 · Cited by 11 · see citing works
“Although our regression model did not reveal animal protein intake as significant predictor of TC, increased animal protein intake was previously associated with decreased longevity (68), contrary to the intake of plant proteins which was associated with decreased risk for cardiovascular and all-cause mortality (69).”
Result
Dietary interventions and molecular mechanisms for healthy musculoskeletal aging
Murphy, A. W., Vyavahare, S. S., Kumar, S., Lee, T. J., Sharma, A. K., Adusumilli, S., Hamrick, M. W., Isales, C. M., & Fulzele, S. (2022) · Biogerontology · doi:10.1007/s10522-022-09970-1 · Cited by 12 · see citing works
Emerging Therapeutic Strategies in Anti‐Aging Medicine: A Comprehensive Review
Peng, Y., Li, R., Li, H., Zhou, J., Liu, X., Valente, G. T., Melo, T. D. C., Chen, S., & 顾镭 (2026) · Medicine Bulletin · doi:10.1002/mdb2.70021 · Cited by 8 · see citing works
Sex-Specific Diet–Microbiota Interactions in Ageing: Implications for Healthy Longevity
Hernández-Acosta, J., Tovar, A. R., & Torres, N. (2025) · Nutrients · doi:10.3390/nu17243833 · Cited by 10 · see citing works
“…fermentable fiber [84], polyphenols [85], omega-3 fatty acids [86], and plant-based protein sources associated with lower all-cause mortality [87], act as functional modulators of the gut microbiota by promoting beneficial taxa, suppressing pro-inflammatory species, and enhancing the…”
Association between dietary patterns and sarcopenia among community-dwelling older adults in five provinces of China: a cross-sectional study
Pu, R., Jia, S., Zhang, X., Man, Q., Yu, D., Cai, S., Song, P., & Zhang, J. (2025) · Frontiers in Public Health · doi:10.3389/fpubh.2025.1556033 · Cited by 7 · see citing works
Protease and Bacillus coagulans Supplementation in a Low-Protein Diet Improves Broiler Growth, Promotes Amino Acid Transport Gene Activity, Strengthens Intestinal Barriers, and Alters the Cecal Microbial Composition
Niu, J., Qiao, Y., Yang, X., Chen, X., Li, H., Guo, Y., Zhang, W., & Wang, Z. (2025) · Animals · doi:10.3390/ani15020170 · Cited by 9 · see citing works
Naturally Occurring Microbiota-Accessible Borates: A Focused Minireview
Biţă, A., Scorei, I. R., Mogoşanu, G. D., Bejenaru, L. E., Biță, C. E., Dinescu, V. C., Rău, G., Ciocîlteu, M. V., Bejenaru, C., & Croitoru, O. (2024) · Inorganics · doi:10.3390/inorganics12120308 · Cited by 10 · see citing works
Dietary intake of branched-chain amino acids (BCAAs), serum BCAAs, and cardiometabolic risk markers among community-dwelling adults
Rao, S., Zhang, Y., Xie, S., Cao, H., Zhang, Z., & Yang, W. (2024) · European Journal of Nutrition · doi:10.1007/s00394-024-03432-9 · Cited by 8 · see citing works
“…size are warranted and need to consider: (1) how to best measure diet, (2) the possible etiological heterogeneity according to BCAA food source, and (3) the interplay with host gut microbiota or genetic variations. and aromatic amino acids, which was inversely associated with the risk of CVD [26].”
Gcn4 impacts metabolic fluxes to promote yeast chronological lifespan
Gulías, J. F., Niesi, F., Arán, M., Correa-García, S., & Moretti, M. B. (2023) · PLoS ONE · doi:10.1371/journal.pone.0292949 · Cited by 9 · see citing works
Recent advances of bioactive proteins/polypeptides in the treatment of breast cancer
Li, Q., Zhou, Z., Hu, C., Li, X., Chang, Y., Liu, Y., Wang, Y., & Zhou, X. (2023) · Food Science and Biotechnology · doi:10.1007/s10068-022-01233-6 · Cited by 8 · see citing works
Dietary protein restriction throughout intrauterine and postnatal life results in potentially beneficial myocardial tissue remodeling in the adult mouse heart
Hennig, M., Ewering, L., Pyschny, S., Shimoyama, S., Olecka, M., Ewald, D., Magarin, M., Uebing, A. S., Thierfelder, L., Jux, C., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-51654-3 · Cited by 11 · see citing works
The role of branched chain aminotransferase in the interrelated pathways of type 2 diabetes mellitus and Alzheimer’s disease
Majid, H., Kohli, S., Islam, S. U., & Nidhi (2025) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-025-01597-6 · Cited by 13 · see citing works
The effects of macronutrients metabolism on cellular and organismal aging
Nehme, J., Altulea, A., Gheorghe, T., & Demaria, M. (2023) · Biomedical Journal · doi:10.1016/j.bj.2023.02.005 · Cited by 12 · see citing works
“Mammalian cells produce H2S through the reverse trans-sulfuration pathway, where sulfur is transferred from homocysteine to cysteine, producing several sulfur metabolites in the process, including H2S [97].”
BackgroundInfluential
Decreased Hyocholic Acid and Lysophosphatidylcholine Induce Elevated Blood Glucose in a Transgenic Porcine Model of Metabolic Disease
Xu, J., Zhang, K., Qiu, B., Liu, J., Liu, X., Yang, S., & Xiao, X. (2022) · Metabolites · doi:10.3390/metabo12121164 · Cited by 10 · see citing works
Association of Energy and Macronutrients Intake with S-Klotho Plasma Levels in Middle-Aged Sedentary Adults: A Cross-Sectional Study
De‐la‐O, A., Jurado‐Fasoli, L., Gracia‐Marco, L., Henriksson, P., Castillo, M. J., & Amaro‐Gahete, F. J. (2022) · The journal of nutrition health & aging · doi:10.1007/s12603-022-1763-2 · Cited by 8 · see citing works
“Protein and carbohydrate restriction could decrease the growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling in reducing oxidative stress and inflammation (53), which may modulate α-Klotho expression and S-Klotho plasma levels (47, 54).”
Zone-specific damage of the olfactory epithelium under protein restriction
Tuerdi, A., Kikuta, S., Kinoshita, M., Kamogashira, T., Kondo, K., & Yamasoba, T. (2020) · Scientific Reports · doi:10.1038/s41598-020-79249-3 · Cited by 9 · see citing works
Dietary diversity contributes to delay biological aging
Liao, W., & Li, M.-Y. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1463569 · Cited by 7
“A diet high in animal protein, especially red meat with elevated levels of methionine and branched-chain amino acids, may promote age-related diseases (13).”
Background
Nutrient Composition of Four Dietary Patterns in Italy: Results from an Online Survey (the INVITA Study)
Baroni, L., Bonetto, C., Rizzo, G., Galchenko, A. V., Guidi, G., Visaggi, P., Savarino, E. V., Zavoli, M., & de Bortoli, N. (2024) · Foods · doi:10.3390/foods13132103 · Cited by 8 · see citing works
“Of note, a lower but still adequate intake of protein has been positively associated with longevity and metabolic health, and it is suggested that the protein source can represent a more important factor for mortality risk than the level of protein intake, through multiple mechanisms [41].”
Background
The Dietary Branched-Chain Amino Acids Transition and Risk of Type 2 Diabetes Among Chinese Adults From 1997 to 2015: Based on Seven Cross-Sectional Studies and a Prospective Cohort Study
Yu, L., Song, P., Zhu, Q., Li, Y., Jia, S., Zhang, S., Wang, Z., & Zhang, J. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.881847 · Cited by 9 · see citing works
Insulin resistance and cognitive decline: the metabolic mechanisms linking type 2 diabetes to Alzheimer’s disease
Majid, H., Dahalia, M., Hussain, S., Saini, S., & Nidhi, N. (2025) · Diabetology International · doi:10.1007/s13340-025-00830-0 · Cited by 7 · see citing works
“2 Mechanism of glucose uptake and signaling of insulin reducing autophagic activity, potentially accelerating age-related conditions like cognitive decline [96].”
The L-shaped link between total antioxidant capacity and phenotypic age acceleration: evidence from NHANES 2003–2010
Wu, Y.-K., Xiang, M., Zhao, Y., Zhang, Y., Cheng, W.-J., & Deng, J. (2025) · Biogerontology (Dordrecht) · doi:10.1007/s10522-025-10223-0 · Cited by 6 · see citing works
“Diets rich in animal protein, particularly red meat, have been associated with an increased risk of age-related diseases (Kitada 2019).”
The protein paradox, carnivore diet & hypertrophy versus longevity. Short term nutrition and hypertrophy versus longevity
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“Emerging evidence indicates that DPR influences mitochondrial function and quality con-trol, which may contribute to reduced cardiovascular risk and ultimately promote longevity (Zhang, Ye, et al. 2023; Kitada et al. 2019).”
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Authors: Kitada, M., Ogura, Y., Monno, I., & Koya, D.
Affiliations: Kanazawa Medical University (JP)
Corresponding author: Kitada, Munehiro
Koya, Daisuke
ORCID: Kitada, Munehiro
Koya, Daisuke
Venue: EBioMedicine
Publisher: Elsevier BV
Published: 2019-05
Volume: 43
Pages: 632-640
ISSN: 2352-3964 (ISSN-L)
DOI: 10.1016/j.ebiom.2019.04.005
PMC: PMC6562018
OpenAlex: W2939866782
Cited by: 175
References: 99
Citations by year: 2026: 19 · 2025: 35 · 2024: 28 · 2023: 16 · 2022: 25 · 2021: 22 · 2020: 24 · 2019: 6
FWCI: 1.67
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: EBioMedicine (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Japan Society for the Promotion of Science
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Health Sciences › Medicine › Physiology › Dietary Effects on Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
Keywords: protein intake, longevity, metabolic health, lifespan, methionine restriction, branched-chain amino acids, amino acid restriction, red meat, animal protein, age-related diseases, sarcopenia, frailty, malnutrition, low-protein diet
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Animals, Diet, Dietary Proteins, Disease Susceptibility, Energy Metabolism, Health Status, Humans, Longevity, Signal Transduction, Biomarkers, Oxidative Stress

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The impact of dietary protein intake on longevity and metabolic health

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