Tissue-specific down-regulation of S-adenosyl-homocysteine via suppression of dAhcyL1/dAhcyL2 extends health span and life span in Drosophila.
Tissue-specific down-regulation of S-adenosyl-homocysteine via suppression of dAhcyL1/dAhcyL2 extends health span and life span in Drosophila.
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DOI：
10.1101/gad.282277.116
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发表时间：
2016-06-15
影响因子：
10.5
通讯作者：
Perrimon N
中科院分区：
文献类型：
--
作者：
Parkhitko AA;Binari R;Zhang N;Asara JM;Demontis F;Perrimon N
甲硫氨酸产生甲基供体SAM，其通过甲基化转化为SAH，SAH在老化过程中积累。Parkhitko等人发现，对SAH水解酶Ahcy的两种非经典果蝇同源物CG 9977/dAhcyL 1和Ahcy 89 E/CG 8956/dAhcyL 2的下调有显著的寿命延长反应，这两种同源物作为经典AHCY的显性负调控因子。大脑和肠道中dAhcyL 1/L2的组织特异性下调可延长健康和寿命。衰老是许多人类病理学的风险因素，其特征在于广泛的代谢变化。使用有针对性的高通量代谢产物分析在果蝇在不同年龄，我们证明，蛋氨酸代谢的变化在衰老过程中显着。甲硫氨酸产生甲基供体S-腺苷甲硫氨酸（SAM），其通过甲基化转化为S-腺苷高半胱氨酸（SAH），其在衰老过程中积累。针对甲硫氨酸途径组分的靶向RNAi筛选显示，对SAH水解酶Ahcy（S-腺苷-L-高半胱氨酸水解酶[SAHH[），CG 9977/dAhcyL 1和Ahcy 89 E/CG 8956/dAhcyL 2）的两种非经典果蝇同源物的下调有显著的寿命延长，这两种同源物作为经典AHCY的显性负调控因子。重要的是，大脑和肠道中dAhcyL 1/L2的组织特异性下调可以延长健康和寿命。此外，dAhcyL 1缺陷果蝇的代谢组学分析揭示了其对年龄依赖性代谢重编程和H3 K4甲基化的影响。总之，重新编程的蛋氨酸代谢在年轻的苍蝇和抑制年龄依赖性SAH积累导致寿命延长。这些研究强调了非经典Ahcy酶作为健康衰老和寿命决定因素的作用。
Methionine generates the methyl donor SAM, which is converted via methylation to SAH, which accumulates during aging. Parkhitko et al. discovered significant life span extension in response to down-regulation of two noncanonical Drosophila homologs of the SAH hydrolase Ahcy, CG9977/dAhcyL1 and Ahcy89E/CG8956/dAhcyL2, which act as dominant-negative regulators of canonical AHCY. Tissue-specific down-regulation of dAhcyL1/L2 in the brain and intestine extends health and life span. Aging is a risk factor for many human pathologies and is characterized by extensive metabolic changes. Using targeted high-throughput metabolite profiling in Drosophila melanogaster at different ages, we demonstrate that methionine metabolism changes strikingly during aging. Methionine generates the methyl donor S-adenosyl-methionine (SAM), which is converted via methylation to S-adenosyl-homocysteine (SAH), which accumulates during aging. A targeted RNAi screen against methionine pathway components revealed significant life span extension in response to down-regulation of two noncanonical Drosophila homologs of the SAH hydrolase Ahcy (S-adenosyl-L-homocysteine hydrolase [SAHH[), CG9977/dAhcyL1 and Ahcy89E/CG8956/dAhcyL2, which act as dominant-negative regulators of canonical AHCY. Importantly, tissue-specific down-regulation of dAhcyL1/L2 in the brain and intestine extends health and life span. Furthermore, metabolomic analysis of dAhcyL1-deficient flies revealed its effect on age-dependent metabolic reprogramming and H3K4 methylation. Altogether, reprogramming of methionine metabolism in young flies and suppression of age-dependent SAH accumulation lead to increased life span. These studies highlight the role of noncanonical Ahcy enzymes as determinants of healthy aging and longevity.