AKG

逆转皮肤和生殖衰老、抗氧化、热量限制,只有你想不到,没有它做不到

AKG,逆转皮肤和生殖衰老、抗氧化、热量限制,只有你想不到,没有它做不到

自上世纪以来,AKGα-酮戊二酸)靠着促进骨骼发育和增加免疫力的功效,成为深受好评的营养补剂[1]。随研究的不断深入,又陆续发现AKG还具降低细胞毒性和治疗胃肠疾病的作用[2]。

直到2014年,”抗衰国师”Brian Kennedy教授于顶级期刊《Nature》发文,披露AKG的新发现——延寿50%[3],自那时起,学界认为AKG或将成为本世纪最值得期待的有效抗衰补剂[4]

那么,AKG究竟有哪些认证的抗衰效用?目前服用的安全性又怎样呢?

1. 自身就能合成的AKG,为什么还需要补充?

AKG,是ATP的前体物质和氨基酸的合成底物,可以产生能量并合成人体必备蛋白质,从而提高线粒体功能,增强细胞修复能力[4]。

随年龄的增长,我们机体的新陈代谢能力逐渐下降,而且AKG在细胞中的作用时间又极其短暂(小于5分钟),因此容易造成AKG水平不足,引发免疫功能下降和代谢失调等问题,并增加老年性相关疾病的患病风险[5]。

此时,就需要通过外源性AKG的补充,提高细胞活性,延长健康寿命[5]。

2. 抗衰不止一条路,AKG:那就统统走一走

经研究证明,AKG可刺激FoxO、DAF-16、SIRT等长寿基因的表达,并且抑制炎症相关NF-κB信号通路的激活,降低促炎因子水平,减缓炎性衰老速率[6]。2014年,《Nature》发表综述再证,AKG还可通过热量限制调节代谢相关通路,体现出抗衰的潜在价值[7]

No.1 :AKG可作为热量限制模拟物

细胞中存在着大量可促进能量代谢的ATP合酶,AKG可与ATP合酶上的β亚基结合,降低ATP的合成速率和数量,减少线粒体中能量的产生,这一过程也正是热量限制的典型标志[6]。

当ATP含量过低时,会激活AMPK信号通路传导,进而抑制mTOR信号通路的表达[7]。AKG通过这一途径,将衰老细胞调节至正常的代谢水平。

AKG的通路调节机制

作为上世纪公认的抗氧化物质,近几年发表的文章进一步证实,AKG可减少与年龄相关的氧化应激,预防衰老[8][9]

No.2 :AKG可以作为外源性抗氧化剂服用,发挥两类抗氧化作用

直接清除自由基

AKG可直接破坏H2O2的分子结构,从根源上降低H2O2产生的氧化毒性,并减弱其形成更高毒性自由基的能力[10]。

增强内源性抗氧化防御系统能力

外源性AKG的补充,可以激活抗氧化防御系统酶的活性,并增加热休克蛋白HSP 60和HSP 90的合成,提高细胞活性和代谢免疫能力,有助于减缓生物体内的衰老进程[11]。

AKG的抗氧化功能及其应用

2020年,AKG相关研究的重点开始转向临床,《Nature》子刊发文表明,AKG对老年人士的结肠癌疗效显著,这一发现也使AKG的抗癌、抗肿瘤能力获得广泛关注[12]。

No.3 :AKG具有抗肿瘤特性

外源性AKG的补充,限制了促进肿瘤细胞分化的HIF-1α亚基的表达,并降低HIF-1α亚基与蛋白连接的能力,从而减少促红细胞生成素的产生,红细胞和血管的生成减少抑制了肿瘤细胞的生长和扩散[13]。

去年11月,Kennedy教授经长达7年的临床试验统计,在《Aging》发文,称平均服用Rejuvant®(AKG膳食补充剂品牌)7个月,可将受试者年龄逆转8岁[14]

No.4 :AKG可调节表观遗传表型

AKG作为去甲基化酶的重要底物,可有效降低DNA和组蛋白的甲基化水平,逆转表观和内部功能的老化[15]。

然而甲基化水平也不宜降得过低,不然反而会干扰染色质功能,不过别担心,AKG同时还具有”防抱死”功能。它在激活去甲基化酶的同时,可通过三羧酸循环产生的代谢产物,把过量的去甲基化酶分解掉,将体内的甲基化程度维持在适当的水平[15]。

AKG调节表观遗传表型

时至今日,AKG的抗衰成果还如雨后春笋般出现。今年4月,来自我国武汉科研团队研制出的AKG面霜仅涂抹56天就能使面部皮肤皱纹显著减少23.64%,同时可修复受损屏障,达到良好保湿效果[16]。

 

绿色部分显示为面部皱纹

而8月的最新临床研究中,研究人员又发现AKG可维持附睾平滑肌细胞内的酸碱平衡,为精子的发育和成熟提供稳定的内部环境,或将成为男性生殖衰老的营养干预补剂[17]

3. 喊话AKG:能吃吗?怎么吃?吃多少?

然而,面对琳琅满目的AKG相关补剂,我们该如何服用?

No.1 :为延寿,到底该怎么做?

根据临床统计,AKG膳食补充剂可以提高肌肉质量,改善骨质疏松,对神经衰退性疾病、心血管疾病、肝病和肾病起到有效治疗[18]。

学界给出的每日安全的服用剂量范围是3.6-6g,当下最有效的给药途径分别为:口服和静脉注射,并且建议最好采用间歇式给药的方式进行补充[19][20]。

而且AKG还被发现可与钙、钠、精氨酸或鸟氨酸类膳食产品联合使用,在提高体内氨基酸合成的同时,降低胰岛素水平,多种补剂的协同可使AKG发挥出更好的抗衰作用[19]。

No.2 :些小副作用,但也不容忽视

然而,在这些临床数据中,也不乏存在一些不容忽视的负面作用。AKG因只能被胃肠道细胞吸收,所以极易造成胃肠道的吸收和代谢压力[21],引发恶心、腹胀、呕吐和腹泻等副作用[22]。对此,目前仍未找到有效手段去缓解,因此学界呼吁应进行更多的AKG临床研究,早日找到人体的最佳服用剂量。

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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