Friday, October 20, 2017

Healthy Aging: Protein Consumption Advice for the Elderly

Protein is essential for your health. In the Mitochondrial Metabolic Therapy diet, Dr Mercola recommends you to target maximum 45 to 55 grams of protein per day for the optimal health. Why?

The reason is: when you consume more protein than your body needs, it may have the following adverse health effects:
  • Excess protein burdens kidneys with removing extra nitrogen waste products from your blood[15]
  • Excess protein stimulates the production of IGF-1 (Insulin-like growth factor one)
    • The more IGF-1 you have in your bloodstream, the higher your risk for developing cancers, such as prostate cancer[45]
  • Excess protein stimulates mTOR
    • More details in this article
However, do consider to increase protein intake when
  • The older you get (e.g., over 65 years old) the more important protein intake becomes to avoid lean muscle loss.[12]
  • On days when you are seeking to increase your muscle mass with strentgh training
In this article, we will focus on the protein's role played in regulating mTOR's activities.

What's mTOR

mTOR is a kinase in your body. It plays a key role in the regulation of protein synthesis , cell proliferation and autophagy.[10,20] It was named as it is the mammalian Target Of Rapamycin which is an antibiotic and immune-suppressor drug that inhibits mTOR's activities.

mTOR forms two multi-protein complexes known as complex 1 (mTORC1) and 2 (mTORC2). Raptor and Rictor are the core proteins for mTORC1 and mTORC2, respectively.

In this article, we will use mTOR in general and mTORC1 in specific, but interchangeably, in the discussion of aging and carcinogenesis. Note that our understanding of the role of mTORC2 in the wider pathway is still evolving and will not be covered here.

Figure 1.  Leucine is predominantly found in animal-based food.

Regulation of Protein Synthesis

In order for cells to grow and proliferate (i.e., manufacturing more proteins), the cells must ensure that they have the resources available for protein production. For example, cells must have
  • Adequate energy resources
  • Availability of amino acid nutrients
  • Oxygen abundance
  • Proper growth factors
in order for mRNA translation to begin (i.e., protein production).

mTORC1 is known to regulate protein synthesis in the following ways:
  • When mTOR is stimulated
    • It cues the cell to grow and proliferate
    • If over-activated,
      • mTOR signaling significantly contributes to the initiation and development of tumors
      • Hence come the benefits of
        • Methionine restriction diets[21,23,27,32,38,41]
        • Leucine restrction diets (video[10,17,37]
    • When mTOR is limited
      • It instructs the cell to turn on the array of repair and maintenance processes at its disposal, including autophagy (cleaning up cellular debris), DNA repair, and activating intracellular antioxidants.
        • Autophagy and mitophagy, which are largely controlled by the mTOR, play an important role in controlling the amount of inflammation in your body and help slow down the aging process
      • Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug
      • Plant-based diets (a better alternative) are associated with lower risk for many cancers because their capability of “down-regulation” of mTOR.

    Figure 2.  Methionine is predominantly found in animal-based food.

    mTOR and Cancer

    There is a growing body of evidence that mTORC1 is upregulated in many types of cancers and plays a role in carcinogenesis[18,19]

    Below we will discuss the relationship of mTOR and two specific cancers:

      Prostate Cancer
      • When mTOR is stimulated
        • mTORC1 is upregulated in nearly 100% of advanced human prostate cancers.[7]
      • When mTOR is limited
        • The potential prostate cancer protective effect of a plant-based diet may be explained by the reduction of dairy- and animal meat-derived leucine intake, and especially lower insulin and IGF-1 signaling of non-dairy plant-based diets attenuating overall mTORC1 activity.[10]

      Breast Cancer
      • When mTOR is stimulated 
        • Higher mTOR expression has been noted in breast cancer tumors, and associated with more aggressive disease, and lower survival rate among breast cancer patients.[8]
      • When mTOR is limited 
        • Compared with the Swedish general population, women hospitalized for anorexia nervosa—one marker of caloric restriction—prior to age 40 years had a 53% lower incidence of breast cancer; nulliparous women with anorexia nervosa had a 23% lower incidence, and parous women with anorexia nervosa had a 76% lower incidence.[9]

      How to Age Gracefully?

      Life has one imperative which is to reproduce. Once our reproductive peak has passed, nature becomes apathetic to our survival, and we commence the process of programmed degeneration we call aging. To age gracefully, the goal is to
      • Delay aging while simultaneously switch on restorative pathways — activate our internal housecleaning mechanisms (i.e., autophagy).
      As a child, milk is presented as an endocrine signaling system, which activates mTORC1 —promotes cell growth and proliferation. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of human.

       However, as we start aging, we should tip the balance of growth  towards more on the restorative pathways. As an adult, if you still persistently abuse the growth-promoting signaling system of cow milk. The consequences of sustained proliferative signaling is what we have witnessed today—the rising of cancer in the developed countries.

      On the other hand, plant-based diets, especially cruciferous vegetables, not only decrease leucine-dependent mTORC1 activation but also they provide natural plant-derived inhibitors of mTORC1. Increasing studies have demonstrated that
      • 3,3'-Diindolylmethane (DIM)
      • Epigallocatechin gallate (EGCG)
      • Genistein
      • Curcumin
      • Resveratrol
      • Caffeine
      all inhibit mTORC1 signaling directly or indirectly and have been suggested to reduce the risk of prostate cancers and other common cancers.

      Finally, to age gracefully, we should consdier:


      1. Discovery improves understanding of cellular aging and cancer development
        • 1 lentils, 2 hemp seeds, 3 chia seeds 4 quinoa 5 spirulina 6 nutritional yeast 7 seeds 8 nuts 9 beans 10 tempeh/organic tofu/edamame
      3. Increasing Protein Intake After Age 65
      4. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice
      5. X Wang, C G Proud. MTORC1 signaling: What we still don't know. J Mol Cell Biol 2011 3(4):206 – 220.
      6. J D Weber, D H Gutmann. Deconvoluting mTOR biology. Cell Cycle 2012 11(2):236 – 248.
      7. B C Melnik, S M John, P Carrera-Bastos, L Cordain. The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer. Nutr Metab (Lond) 2012 9(1):74.
      8. U Wazir, R F Newbold, W G Jiang, A K Sharma, K Mokbel. Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer. Oncol Rep 2013 29(5):1969 – 1974.
      9. K B Michels, A Ekbom. Caloric restriction and incidence of breast cancer. Jama 2004 291(10):1226 – 1230.
      10. R F Lamb. Amino acid sensing mechanisms: An Achilles heel in cancer? FEBS J. 2012 279(15):2624 – 2631.
      11. Prevent Cancer from Going on TOR
      12. M. E. Levine et al., "Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population," Cell Metabolism, 19, no. 3 (2014): 407-17.
      13. Growth Hormone Receptor Deficiency Is Assoiciated With a Major Reduction in Pro-aging Signaling, Cancer and Diabetes in Humans
      14. Protein—the Good, the Bad, and the Ugly
      15. Risk Factors of Kidney Disease (Travel and Health)
      16. C H Jung, H Kim, J Ahn, T I Jeon, D H Lee, T Y Ha. Fisetin regulates obesity by targeting mTORC1 signaling. J. Nutr. Biochem. 2013 24(8):1547 – 1554.
      17. Sheen JH, Zoncu R, Kim D& Sabatini DM (2011) Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 19, 613–628.
        • Research shows that restriction of the essential amino acid leucine may provoke apoptosis in cancer cells when used in combination with inhibition of autophagy.
      18. Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 12:9–22. 2007.
      19. Xu K, Liu P, Wei W (December 2014). "mTOR signaling in tumorigenesis". Biochimica et Biophysica Acta. 1846 (2): 638–54.
      20. Toschi A, Lee E, Thompson S, et al: Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. Cancer Lett. 299:72–79. 2010.
      21. Starving Cancer with Methionine Restriction
      22. V. Agrawal, S. E. J. Alpini, E. M. Stone, E. P. Frenkel, A. E. Frankel. Targeting methionine auxotrophy in cancer: discovery & exploration. Expert Opin Biol Ther 2012 12(1):53 - 61.
      23. M. F. McCarty, J. Barroso-Aranda, F. Contreras. The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med. Hypotheses 2009 72(2):125 - 128.
      24. M. C. Ruiz, V. Ayala, M. Portero-Otín, J. R. Requena, G. Barja, R. Pamplona. Protein methionine content and MDA-lysine adducts are inversely related to maximum life span in the heart of mammals. Mech. Ageing Dev. 2005 126(10):1106 - 1114.
      25. M. López-Torres, G. Barja. Lowered methionine ingestion as responsible for the decrease in rodent mitochondrial oxidative stress in protein and dietary restriction possible implications for humans. Biochim. Biophys. Acta 2008 1780(11):1337 - 1347.
      26. E. Cohen. Chitin synthesis and degradation as targets for pesticide action. Arch. Insect Biochem. Physiol. 1993 22(1 - 2):245 - 261.
      27. P. Cavuoto, M. F. Fenech. A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. Cancer Treat. Rev. 2012 38(6):726 - 736.
      28. E. Boedeker, G. Friedel, T. Walles. Sniffer dogs as part of a bimodal bionic research approach to develop a lung cancer screening. Interact Cardiovasc Thorac Surg 2012 14(5):511 - 515.
      29. H. Sonoda, S. Kohnoe, T. Yamazato, Y. Satoh, G. Morizono, K. Shikata, M. Morita, A. Watanabe, M. Morita, Y. Kakeji, F. Inoue, Y. Maehara. Colorectal cancer screening with odour material by canine scent detection. Gut 2011 60(6):814 - 819.
      30. K. Yamagishi, K. Onuma, Y. Chiba, S. Yagi, S. Aoki, T. Sato, Y. Sugawara, N. Hosoya, Y. Saeki, M. Takahashi, M. Fuji, T. Ohsaka, T. Okajima, K. Akita, T. Suzuki, P. Senawongse, A. Urushiyama, K. Kawai, H. Shoun, Y. Ishii, H. Ishikawa, S. Sugiyama, M. Nakajima, M. Tsuboi, T. Yamanaka. Generation of gaseous sulfur-containing compounds in tumour tissue and suppression of gas diffusion as an antitumour treatment. Gut 2012 61(4):554 - 561.
      31. H. Y. Guo, H. Herrera, A. Groce, R. M. Hoffman. Expression of the biochemical defect of methionine dependence in fresh patient tumors in primary histoculture. Cancer Res. 1993 53(11):2479 - 2483.
      32. D. E. Epner. Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer? J Am Coll Nutr 2001 20(Suppl 5):443S-449S; discussion 473S-475S.
      33. E. Cellarier, X. Durando, M. P. Vasson, M. C. Farges, A. Demiden, J. C. Maurizis, J. C. Madelmont, P. Chollet. Methionine dependency and cancer treatment. Cancer Treat. Rev. 2003 29(6):489 - 499.
      34. B. C. Halpern, B. R. Clark, D. N. Hardy, R. M. Halpern, R. A. Smith. The effect of replacement of methionine by homocystine on survival of malignant and normal adult mammalian cells in culture. Proc. Natl. Acad. Sci. USA 1974 71(4):1133 - 1136.
      35. C. M. Willis, S. M. Church, C. M. Guest, W. A. Cook, N. McCarthy, A. J. Bransbury, M. R. T. Church, J. C. T. Church. Olfactory detection of human bladder cancer by dogs: Proof of principle study. BMJ 2004 329(7468):712.
      36. D. Pickel, G. P. Manucy, D. B. Walker, S. B. Hall, J. C. Walker. Evidence for canine olfactory detection of melanoma. App Anim Behav Sci 2004 89(1):107-­116.
      37. Living Longer by Reducing Leucine Intake
      38. Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status
      39. Blattler, S. M., Cunningham, J. T., Verdeguer, F., Chim, H., Haas, W., Liu, H., Romanino, K., Ruegg, M. A., Gygi, S. P., Shi, Y. and Puigserver, P. (2012) Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling. Cell Metab. 15, 505-517.
      40. Caloric Restriction vs. Animal Protein Restriction
      41. Methionine Restriction as a Life-Extension Strategy
      42. Heath Effects of Iron Overload and Benefits of Blood Donation (Travel to Health)
      43. Which Food Fights Cancer Better? (Travel to Health)
      44. Plant Proteins that Pack a Punch (Infographic)
      45. Rowlands MA, Gunnell D, Harris R. Vatten L.J, Holly JM, Martin RM. Circulating insulin-like growth factor peptides and prostate cancer risk: a systematic review and meta-analysis.  Int J Cancer. 2009; 124(10):2416-29.
      46. Vegetarians: How to Get Enough Protein? (Travel to Health)
      47. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours

      No comments:

      Post a Comment