AKG

逆轉皮膚和生殖衰老、抗氧化、熱量限制,只有你想不到,沒有它做不到

AKG,逆轉皮膚和生殖衰老、抗氧化、熱量限制,只有你想不到,沒有它做不到

自上世紀以來,AKGα-酮戊二酸)靠著促進骨骼發育和增加免疫力的功效,成為深受好評的營養補劑[1]。 隨研究的不斷深入,又陸續發現AKG還具降低細胞毒性和治療胃腸疾病的作用[2]。

直到2014年,「抗衰國師」Brian Kennedy教授於頂級期刊《Nature》發文,披露AKG的新發現——延壽50%[3],自那時起,學界認為AKG或將成為本世紀最值得期待的有效抗衰補劑[4]

那麼,AKG究竟有哪些認證的抗衰效用? 目前服用的安全性又怎樣呢?

1. 自身就能合成的,為什麼還需要補充?

AKG,是ATP的前體物質和氨基酸的合成底物,可以產生能量並合成人體必備蛋白質,從而提高線粒體功能,增強細胞修復能力[4]。

隨年齡的增長,我們機體的新陳代謝能力逐漸下降,而且AKG在細胞中的作用時間又極其短暫(小於5分鐘),因此容易造成AKG水準不足,引發免疫功能下降和代謝失調等問題,並增加老年性相關疾病的患病風險[5]。此時,就需要通過外源性AKG的補充,提高細胞活性,延長健康壽命[5]。

2. 抗衰不止一條路,阿克格:那就統統走一走

經研究證明,AKG可刺激FoxO、DAF-16、SIRT等長壽基因的表達,並且抑制炎症相關NF-κB信號通路的啟動,降低促炎因數水準,減緩炎性衰老速率[6]。

2014年,《Nature》發表綜述再證,AKG還可通過熱量限制調節代謝相關通路,體現出抗衰的潛在價值[7]

No.1 : 阿克格可作為熱量限制類比物

細胞中存在著大量可促進能量代謝的ATP合酶,AKG可與ATP合酶上的β亞基結合,降低ATP的合成速率和數量,減少線粒體中能量的產生,這一過程也正是熱量限制的典型標誌[6]。

啟動AMPK信號通路傳導抑制mTOR信號通路的表達[7]

AKG的通路調節機制

作為上世紀公認的抗氧化物質,近幾年發表的文章進一步證實,阿克格 可減少與年齡相關的氧化應激,預防衰老 [8][9]

No.2 :阿克格可以作為外源性抗氧化劑服用,發揮兩類抗氧化作用

直接清除自由基

阿克格可直接破壞H2O2的分子結構,從根源上降低H2O2產生的氧化毒性,並減弱其形成更高毒性自由基的能力[10]。

增強內源性抗氧化防禦系統能力

外源性阿克格的補充,可以激活抗氧化防禦系統酶的活性,並增加熱休克蛋白HSP 60和HSP 90的合成,提高細胞活性和代謝免疫能力,有助於減緩生物體內的衰老進程[11]。

AKG的抗氧化功能及其應用

2020年,阿克格相關研究的重點開始轉向臨床,《自然界》子刊發文表明,阿克格對老年人士的結腸癌療效顯著,這一發現也使阿克格的抗癌、抗腫瘤能力獲得廣泛關注[12]。

No.3 :阿克格具有抗腫瘤特性

外源性阿克格的補充,限制了促進腫瘤細胞分化的HIF-1α亞基的表達,並降低HIF-1α亞基與蛋白連接的能力,從而減少促紅細胞生成素的產生,紅細胞和血管的生成減少抑制了腫瘤細胞的生長和擴散[13]。

去年11月,Kennedy教授經長達7年的臨床試驗統計,在《Aging平均服用®(阿克格膳食補充劑品牌)7個月,可將受試者年齡逆轉8歲[14]。

No.4 :阿克格可調節表觀遺傳表型

逆轉表觀和內部功能的老化[15]

然而甲基化水平也不宜降得過低,不然反而會幹擾染色質功能,不過別擔心,AKG同時還具有”防抱死”功能。它在激活去甲基化酶的同時,可通過三羧酸循環產生的代謝產物,把過量的去甲基化酶分解掉,將體內的甲基化程度維持在適當的水平[15]。

AKG調節表觀遺傳表型

時至今日,阿克格的抗衰成果還如雨後春筍般出現。 今年4月,來自我國武漢科研團隊研製出的阿克格面霜僅塗抹56天就能使面部皮膚皺紋顯著減少 23.64%,同時可修復受損屏障,達到良好保濕效果[16]。

綠色部分顯示為面部皺紋

而8月的最新臨床研究中,研究人員又發現阿克格可維持附睾平滑肌細胞內的酸鹼平衡或將成為男性生殖衰老的營養干預補劑[17]

3. 喊話AKG:能吃嗎? 怎麼吃? 吃多少?

然而,面對琳琅滿目的阿克格相關補劑,我們該如何服用?

No.1 :為延壽,到底該怎麼做?

根據臨床統計,AKG膳食補充劑可以提高肌肉品質,改善骨質疏鬆,對神經衰退性疾病、心血管疾病、肝病和腎病起到有效治療 [18]。

學界給出的每日安全的服用劑量範圍是3.6-6g,當下最有效的給葯途徑分別為:口服和靜脈注射,並且建議最好採用間歇式給藥的方式進行補充[19][20]。

而且AKG還被發現可與鈣、鈉、精氨酸或鳥氨酸類膳食產品聯合使用,在提高體內氨基酸合成的同時,降低胰島素水準,多種補劑的協同可使AKG發揮出更好的抗衰作用[19]。

No.2 :些小副作用,但也不容忽視

然而,在這些臨床數據中,也不乏存在一些不容忽視的負面作用。AKG因只能被胃腸道細胞吸收,所以極易造成胃腸道的吸收和代謝壓力[21],引發噁心、腹脹、嘔吐和腹瀉等副作用[22]。對此,目前仍未找到有效手段去緩解,因此學界呼籲應進行更多的AKG臨床研究,早日找到人體的最佳服用劑量。

参考文献

[1] Dulaney, M. D., Jr, Brumley, M., Willis, J. T., & Hume, A. S. (1991). Protection against cyanide toxicity by oral alpha-ketoglutaric acid. Veterinary and human toxicology, 33(6), 571–575.

[2] Sheu, K. F., & Blass, J. P. (1999). The alpha-ketoglutarate dehydrogenase complex. Annals of the New York Academy of Sciences, 893, 61–78. https://doi.org/10.1111/j.1749-6632.1999.tb07818.x

[3] Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V. S., Monsalve, G. C., Hu, E., Whelan, S. A., Wang, J. X., Jung, G., Solis, G. M., Fazlollahi, F., Kaweeteerawat, C., Quach, A., Nili, M., Krall, A. S., … Huang, J. (2014). The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature, 510(7505), 397–401.https://doi.org/10.1038/nature13264

[4] Asadi Shahmirzadi, A., Edgar, D., Liao, C. Y., Hsu, Y. M., Lucanic, M., Asadi Shahmirzadi, A., Wiley, C. D., Gan, G., Kim, D. E., Kasler, H. G., Kuehnemann, C., Kaplowitz, B., Bhaumik, D., Riley, R. R., Kennedy, B. K., & Lithgow, G. J. (2020). Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell metabolism, 32(3), 447–456.e6. https://doi.org/10.1016/j.cmet.2020.08.004

[5] Cynober, L., Coudray-Lucas, C., de Bandt, J. P., Guéchot, J., Aussel, C., Salvucci, M., & Giboudeau, J. (1990).
Action of ornithine alpha-ketoglutarate, ornithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects. Journal of the American College of Nutrition, 9(1), 2–12. https://doi.org/10.1080/07315724.1990.10720343

[6] Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V. S., Monsalve, G. C., Hu, E., Whelan, S. A., Wang, J. X., Jung, G., Solis, G. M., Fazlollahi, F., Kaweeteerawat, C., Quach, A., Nili, M., Krall, A. S., … Huang, J. (2014).
The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature, 510(7505), 397–401. https://doi.org/10.1038/nature13264

[7] Filip, R., & Pierzynowski, S. G. (2008).The absorption, tissue distribution and excretion of enteraly administered alpha-ketoglutarate in rats. Journal of animal physiology and animal nutrition, 92(2), 182–189. https://doi.org/10.1111/j.1439-0396.2007.00725.x

[8] Salminen, A., & Kaarniranta, K. (2012). AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing research reviews, 11(2), 230–241. https://doi.org/10.1016/j.arr.2011.12.005

[9] Liu, S., He, L., & Yao, K. (2018). The Antioxidative Function of Alpha-Ketoglutarate and Its Applications. BioMed research international, 2018, 3408467. https://doi.org/10.1155/2018/3408467

[10] Zdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M. (2017). Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use. Archivum immunologiae et therapiae experimentalis, 65(1), 21–36. https://doi.org/10.1007/s00005-016-0406-x

[11] Vaiserman, A. M., Lushchak, O. V., & Koliada, A. K. (2016). Anti-aging pharmacology: Promises and pitfalls. Ageing research reviews, 31, 9–35. https://doi.org/10.1016/j.arr.2016.08.004

[12] Bayliak, M. M., Shmihel, H. V., Lylyk, M. P., Storey, K. B., & Lushchak, V. I. (2016). Alpha-ketoglutarate reduces ethanol toxicity in Drosophila melanogaster by enhancing alcohol dehydrogenase activity and antioxidant capacity. Alcohol (Fayetteville, N.Y.), 55, 23–33. https://doi.org/10.1016/j.alcohol.2016.07.009

[13] Krauß, D., & Gottlieb, E. (2020). Restraining colorectal cancer with αKG. Nature cancer, 1(3), 267–269. https://doi.org/10.1038/s43018-020-0044-4

[14] Wu, N., Yang, M., Gaur, U., Xu, H., Yao, Y., & Li, D. (2016). Alpha-Ketoglutarate: Physiological Functions and Applications. Biomolecules & therapeutics, 24(1), 1–8. https://doi.org/10.4062/biomolther.2015.078

[15] Demidenko, O., Barardo, D., Budovskii, V., Finnemore, R., Palmer, F. R., Kennedy, B. K., & Budovskaya, Y. V. (2021). Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test. Aging, 13(22), 24485–24499. https://doi.org/10.18632/aging.203736

[16] Salminen, A., Kaarniranta, K., Hiltunen, M., & Kauppinen, A. (2014). Krebs cycle dysfunction shapes epigenetic landscape of chromatin: novel insights into mitochondrial regulation of aging process. Cellular signalling, 26(7), 1598–1603. https://doi.org/10.1016/j.cellsig.2014.03.030

[17] Yang, F., Zhou, Z., Guo, M., & Zhou, Z. (2022). The study of skin hydration, anti-wrinkles function improvement of anti-aging cream with alpha-ketoglutarate. Journal of cosmetic dermatology, 21(4), 1736–1743. https://doi.org/10.1111/jocd.14635

[18] Fucheng Dong, Wei Li. (2022). α-Ketoglutaric acid: a new chance for male fertility preservation, Life Metabolism, loac015. https://doi.org/10.1093/lifemeta/loac015

[19] Wu, N., Yang, M., Gaur, U., Xu, H., Yao, Y., & Li, D. (2016). Alpha-Ketoglutarate: Physiological Functions and Applications. Biomolecules & therapeutics, 24(1), 1–8. https://doi.org/10.4062/biomolther.2015.078

[20] Cynober, L., Coudray-Lucas, C., de Bandt, J. P., Guéchot, J., Aussel, C., Salvucci, M., & Giboudeau, J. (1990). Action of ornithine alpha-ketoglutarate, ornithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects. Journal of the American College of Nutrition, 9(1), 2–12. https://doi.org/10.1080/07315724.1990.10720343

[21] Filip, R. S., Pierzynowski, S. G., Lindegard, B., Wernerman, J., Haratym-Maj, A., & Podgurniak, M. (2007). Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX) in postmenopausal women with osteopenia: six-month study. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition, 77(2), 89–97. https://doi.org/10.1024/0300-9831.77.2.89

[22] Miedema, H., Felle, H., & Prins, H. B. (1992). Effect of high pH on the plasma membrane potential and conductance in Elodea densa. The Journal of membrane biology, 128(1), 63–69. https://doi.org/10.1007/BF00231871

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