Targeting enzyme aging

doi:10.1126/science.abf9566

GSTDTAP > 气候变化

DOI	10.1126/science.abf9566
	Targeting enzyme aging
	Friedrich Becker; K. Lenhard Rudolph
	2021-01-29
发表期刊	Science
出版年	2021
英文摘要	Therapeutic targeting of certain enzyme activities has been exploited to improve health at old age. These approaches have mainly focused on reducing damage-promoting metabolic and growth activities [such as by targeting mammalian target of rapamycin (mTOR)] or on the activation of damage-resolving mechanisms (for example, targeting sirtuins or autophagy). Additionally, however, there is emerging evidence that aging-associated alterations in enzyme activity per se can drive tissue and organism aging. On page 483 of this issue, Palla et al. ([ 1 ][1]) reveal that an aberrant activation of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in aging muscle leads to impaired prostaglandin signaling, resulting in a reduced ratio of protein synthesis versus degradation and in the development of muscle atrophy (sarcopenia). Notably, inhibition of 15-PGDH restores prostaglandin signaling and prevents muscle atrophy in aged mice. These results support the concept that an aging-associated change to enzyme activity by itself represents a druggable, active contributor to tissue aging. During organism aging, profound changes in enzyme activity occur ([ 2 ][2]), including changes in enzyme expression levels ([ 3 ][3]), conformational changes of enzymes through oxidative damage ([ 4 ][4]), decline in essential cofactors, such as nicotinamide adenine dinucleotide (NAD) ([ 3 ][3]), shifts in cellular or tissue pH ([ 5 ][5]), and the accumulation of molecules that inhibit enzyme activity ([ 6 ][6]). Some studies have shown that the reversal of aging-associated alterations in enzyme activities can improve cellular and organismal functions during aging. For example, replenishing aging-associated decrease of NAD, which is an essential cofactor for mitochondrial enzymes and metabolic regulators such as sirtuins, rescues aging-associated decline in stem cell function and organ maintenance in aged mice ([ 7 ][7]). Similar effects were seen after inhibition of aging-associated increases in the expression of the NAD-degrading enzyme CD38 ([ 8 ][8]). Together, these studies provide experimental proof in mice that reversal of aging-associated changes in enzyme activity by repletion of an enzyme cofactor could be a viable strategy to ameliorate aging, which should be tested in further studies, including in humans. Still, it remains poorly understood whether the aging-associated dysregulation of specific enzymes causally contributes to the decline in maintenance and regenerative capacity of distinct tissues during aging. Prostaglandin E2 (PGE2) is an extracellular signaling molecule derived from arachidonic acid in cell membranes. Cyclooxygenases and prostaglandin E synthases (PTGESs) convert arachidonic acid into PGE2, which binds to cell surface receptors and activates intracellular signal transduction. To limit prostaglandin signaling, 15-PGDH degrades PGE2. PGE2-mediated signaling is an important activator of anabolic metabolism, which is essential for regeneration and stem cell function in various tissues, including skeletal muscle ([ 9 ][9]). Palla et al. delineated enzymatic reactions that control prostaglandin signaling in skeletal muscle of old versus young mice, hypothesizing that impairments in prostaglandin signaling could contribute to muscle aging. They found that aging-associated increases in the expression and activity of 15-PGDH are a causative factor for the development of skeletal muscle atrophy with age (see the figure). Specifically, increased 15-PGDH activity reduces local PGE2 availability in aging muscle, which leads to impairment of protein synthesis and induction of muscle atrophy–associated protein degradation by activation of E3-ubiquitin ligases, called “atrogenes.” Targeting 15-PGDH activity with a selective inhibitor rescued PGE2 signaling, induced protein synthesis, impaired the induction of atrogenes, and improved mitochondrial quality and function, thereby ameliorating muscle atrophy in aging mice. The authors show that the up-regulation of 15-PGDH activity in aging tissues occurs at the messenger RNA (mRNA) level. The transcription of 15-PGDH is induced by c-Jun N-terminal kinases (JNKs) and the transcription factor complex activating protein 1 (AP1) ([ 10 ][10]). Two pathways that lead to JNK activation were implicated in driving the development of aging-associated muscle atrophy: the decline in testosterone signaling ([ 11 ][11]) and the activity of Tribbles homolog 3 (TRB3) ([ 12 ][12]). Of note, the reduction of JNK-AP1 activity either by Trb3 deletion or by testosterone application ameliorates muscle atrophy in aging mice ([ 11 ][11], [ 12 ][12]). It is conceivable that 15-PGDH activity represents a downstream factor of these pathways inducing age-associated muscle atrophy. ![Figure][13] Improving muscle maintenance In aging mice, reduced testosterone concentrations and increased Tribbles homolog 3 ( Trb3 ) expression induce c-Jun N-terminal kinases (JNKs) and activating protein 1 (AP1)–dependent transcription, which could contribute to age-associated up-regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) activity. This leads to degradation of prostaglandin E2 (PGE2) and impairment of muscle homeostasis, involving phosphorylated AKT (pAKT) and forkhead box O (FOXO). GRAPHIC: N. DESAI/ SCIENCE It remains to be delineated whether aging-associated decline of NAD availability affects the activity of 15-PGDH, which is an NAD-dependent enzyme. Thus, aging-associated reduction of NAD may counter-act transcriptionally driven increases in 15-PGDH expression during aging. However, replenishing NAD in aged mice improves muscle stem cell function ([ 7 ][7]), suggesting that the positive effects of NAD repletion on sirtuin 1 and mitochondrial metabolism outweigh possible negative effects of NAD on 15-PGDH activation. Palla et al. provide important evidence that targeting an aging-associated dysregulation of a single enzyme can improve muscle maintenance. Delineating an atlas of aging-associated changes in enzyme activities, with respect to tissue-, cell-, and compartment-specific differences, could generate a basis for the development of future therapies to improve healthy aging across tissues. In this context, it could also be important to delineate aging-associated changes in the capacity of enzymes to react to stress. Early studies on aging-associated changes in enzyme activities documented that the response of enzymes to stress, such as nutrient starvation, is greatly attenuated during aging ([ 2 ][2]). Low levels of stress induce adaptive responses that improve cellular functions and protect the organism from age-associated functional decline. One of the most prominent examples is the increase in life expectancy across species by dietary restriction ([ 13 ][14]), which can also improve health parameters in humans. In nematode worms, dietary restriction requires the induction of stress signaling to mediate health benefits ([ 14 ][15]). Therefore, aging-associated defects in enzymatic stress responses could contribute to the failure of dietary restriction to reduce mortality when applied at old versus young age in mice ([ 13 ][14]). Palla et al. provide a proof of concept that reversing aging-associated dysregulation of a single enzyme can ameliorate aging-associated muscle atrophy in mice. Next-generation inhibitors targeting 15-PGDH have been developed and should now be tested to reverse aging of muscle and other tissues affected by age-associated up-regulation of 15-PGDH activity ([ 1 ][1], [ 15 ][16]). Given that enzyme activities can be targeted at multiple levels, the reversal of enzyme dysregulation in aging may have a high therapeutic potential. It is thus anticipated that an understanding of aging-associated enzyme activity changes will identify drivers of the aging process and will also accelerate the development of therapeutic approaches aiming to improve the maintenance of organ function and ameliorate the induction of aging-associated diseases. 1. [↵][17]1. A. R. Palla et al ., Science 371, eabc8059 (2021). [OpenUrl][18][Abstract/FREE Full Text][19] 2. [↵][20]1. R. C. Adelman, 2. G. W. Britton , Bioscience 25, 639 (1975). [OpenUrl][21][CrossRef][22] 3. [↵][23]1. C. C. S. Chini et al ., Nat. Metab 2, 1284 (2020). [OpenUrl][24] 4. [↵][25]1. L. J. Yan, 2. R. L. Levine, 3. R. S. Sohal , Proc. Natl. Acad. Sci. U.S.A. 94, 11168 (1997). [OpenUrl][26][Abstract/FREE Full Text][27] 5. [↵][28]1. T. Wilms et al ., PLOS Genet. 13, e1006835 (2017). [OpenUrl][29][CrossRef][30][PubMed][31] 6. [↵][32]1. N. Sitte et al ., FASEB J. 14, 1490 (2000). [OpenUrl][33][CrossRef][34][PubMed][35][Web of Science][36] 7. [↵][37]1. H. Zhang et al ., Science 352, 1436 (2016). [OpenUrl][38][Abstract/FREE Full Text][39] 8. [↵][40]1. M. G. Tarragó et al ., Cell Metab. 27, 1081 (2018). [OpenUrl][41][CrossRef][42] 9. [↵][43]1. Y. Zhang et al ., Science 348, aaa2340 (2015). [OpenUrl][44][Abstract/FREE Full Text][45] 10. [↵][46]1. J.-M. Park, 2. H.-K. Na , J. Cancer Prev. 24, 183 (2019). [OpenUrl][47] 11. [↵][48]1. E. L. Kovacheva et al ., Endocrinology 151, 628 (2010). [OpenUrl][49][CrossRef][50][PubMed][51][Web of Science][52] 12. [↵][53]1. G. K. Shang et al ., J. Cachexia Sarcopenia Muscle 11, 1104 (2020). [OpenUrl][54] 13. [↵][55]1. O. Hahn et al ., Nat. Metab 1, 1059 (2019). [OpenUrl][56] 14. [↵][57]1. T. J. Schulz et al ., Cell Metab. 6, 280 (2007). [OpenUrl][58][CrossRef][59][PubMed][60][Web of Science][61] 15. [↵][62]1. A. Desai et al ., Haematologica 103, 1054 (2018). [OpenUrl][63][Abstract/FREE Full Text][64] Acknowledgments: K.L.R. is funded by the German Research Foundation (DFG, CRC-PolyTarget, project B01). [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9 [10]: #ref-10 [11]: #ref-11 [12]: #ref-12 [13]: pending:yes [14]: #ref-13 [15]: #ref-14 [16]: #ref-15 [17]: #xref-ref-1-1 "View reference 1 in text" [18]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DPalla%26rft.auinit1%253DA.%2BR.%26rft.volume%253D371%26rft.issue%253D6528%26rft.spage%253Deabc8059%26rft.epage%253Deabc8059%26rft.atitle%253DInhibition%2Bof%2Bprostaglandin-degrading%2Benzyme%2B15-PGDH%2Brejuvenates%2Baged%2Bmuscle%2Bmass%2Band%2Bstrength%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.abc8059%26rft_id%253Dinfo%253Apmid%252F33303683%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [19]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjE3OiIzNzEvNjUyOC9lYWJjODA1OSI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3MS82NTI4LzQ2Mi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [20]: #xref-ref-2-1 "View reference 2 in text" [21]: {openurl}?query=rft.jtitle%253DBioscience%26rft_id%253Dinfo%253Adoi%252F10.2307%252F1297031%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [22]: /lookup/external-ref?access_num=10.2307/1297031&link_type=DOI [23]: #xref-ref-3-1 "View reference 3 in text" [24]: {openurl}?query=rft.jtitle%253DNat.%2BMetab%26rft.volume%253D2%26rft.spage%253D1284%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [25]: #xref-ref-4-1 "View reference 4 in text" [26]: {openurl}?query=rft.jtitle%253DPNAS%26rft.stitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BUSA%26rft.aulast%253DYan%26rft.auinit1%253DL.-J.%26rft.volume%253D94%26rft.issue%253D21%26rft.spage%253D11168%26rft.epage%253D11172%26rft.atitle%253DOxidative%2Bdamage%2Bduring%2Baging%2Btargets%2Bmitochondrial%2Baconitase%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.94.21.11168%26rft_id%253Dinfo%253Apmid%252F9326580%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [27]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMToiOTQvMjEvMTExNjgiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzEvNjUyOC80NjIuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [28]: #xref-ref-5-1 "View reference 5 in text" [29]: {openurl}?query=rft.jtitle%253DPLOS%2BGenet.%26rft.volume%253D13%26rft.spage%253De1006835%26rft_id%253Dinfo%253Adoi%252F10.1371%252Fjournal.pgen.1006835%26rft_id%253Dinfo%253Apmid%252F28604780%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [30]: /lookup/external-ref?access_num=10.1371/journal.pgen.1006835&link_type=DOI [31]: /lookup/external-ref?access_num=28604780&link_type=MED&atom=%2Fsci%2F371%2F6528%2F462.atom [32]: #xref-ref-6-1 "View reference 6 in text" [33]: {openurl}?query=rft.jtitle%253DThe%2BFASEB%2BJournal%26rft.stitle%253DFASEB%2BJ.%26rft.aulast%253DSITTE%26rft.auinit1%253DN.%26rft.volume%253D14%26rft.issue%253D11%26rft.spage%253D1490%26rft.epage%253D1498%26rft.atitle%253DProteasome%2Binhibition%2Bby%2Blipofuscin%252Fceroid%2Bduring%2Bpostmitotic%2Baging%2Bof%2Bfibroblasts%26rft_id%253Dinfo%253Adoi%252F10.1096%252Ffj.14.11.1490%26rft_id%253Dinfo%253Apmid%252F10928983%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [34]: /lookup/external-ref?access_num=10.1096/fj.14.11.1490&link_type=DOI [35]: /lookup/external-ref?access_num=10928983&link_type=MED&atom=%2Fsci%2F371%2F6528%2F462.atom [36]: /lookup/external-ref?access_num=000088627800003&link_type=ISI [37]: #xref-ref-7-1 "View reference 7 in text" [38]: 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{openurl}?query=rft.jtitle%253DCell%2BMetab.%26rft.volume%253D27%26rft.spage%253D1081%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cmet.2018.03.016%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [42]: /lookup/external-ref?access_num=10.1016/j.cmet.2018.03.016&link_type=DOI [43]: #xref-ref-9-1 "View reference 9 in text" [44]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DZhang%26rft.auinit1%253DY.%26rft.volume%253D348%26rft.issue%253D6240%26rft.spage%253Daaa2340%26rft.epage%253Daaa2340%26rft.atitle%253DInhibition%2Bof%2Bthe%2Bprostaglandin-degrading%2Benzyme%2B15-PGDH%2Bpotentiates%2Btissue%2Bregeneration%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaa2340%26rft_id%253Dinfo%253Apmid%252F26068857%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [45]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjE2OiIzNDgvNjI0MC9hYWEyMzQwIjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzcxLzY1MjgvNDYyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [46]: #xref-ref-10-1 "View reference 10 in text" [47]: {openurl}?query=rft.jtitle%253DJ.%2BCancer%2BPrev.%26rft.volume%253D24%26rft.spage%253D183%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [48]: #xref-ref-11-1 "View reference 11 in text" [49]: {openurl}?query=rft.jtitle%253DEndocrinology%26rft_id%253Dinfo%253Adoi%252F10.1210%252Fen.2009-1177%26rft_id%253Dinfo%253Apmid%252F20022929%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [50]: /lookup/external-ref?access_num=10.1210/en.2009-1177&link_type=DOI [51]: /lookup/external-ref?access_num=20022929&link_type=MED&atom=%2Fsci%2F371%2F6528%2F462.atom [52]: /lookup/external-ref?access_num=000273948600022&link_type=ISI [53]: #xref-ref-12-1 "View reference 12 in text" [54]: {openurl}?query=rft.jtitle%253DJ.%2BCachexia%2BSarcopenia%2BMuscle%26rft.volume%253D11%26rft.spage%253D1104%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [55]: #xref-ref-13-1 "View reference 13 in text" [56]: {openurl}?query=rft.jtitle%253DNat.%2BMetab%26rft.volume%253D1%26rft.spage%253D1059%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [57]: #xref-ref-14-1 "View reference 14 in text" [58]: {openurl}?query=rft.stitle%253DCell%2BMetab%26rft.aulast%253DSchulz%26rft.auinit1%253DT.%2BJ.%26rft.volume%253D6%26rft.issue%253D4%26rft.spage%253D280%26rft.epage%253D293%26rft.atitle%253DGlucose%2Brestriction%2Bextends%2BCaenorhabditis%2Belegans%2Blife%2Bspan%2Bby%2Binducing%2Bmitochondrial%2Brespiration%2Band%2Bincreasing%2Boxidative%2Bstress.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cmet.2007.08.011%26rft_id%253Dinfo%253Apmid%252F17908557%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [59]: /lookup/external-ref?access_num=10.1016/j.cmet.2007.08.011&link_type=DOI [60]: /lookup/external-ref?access_num=17908557&link_type=MED&atom=%2Fsci%2F371%2F6528%2F462.atom [61]: /lookup/external-ref?access_num=000249929000007&link_type=ISI [62]: #xref-ref-15-1 "View reference 15 in text" [63]: 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/314002
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Friedrich Becker,K. Lenhard Rudolph. Targeting enzyme aging[J]. Science,2021.
APA	Friedrich Becker,&K. Lenhard Rudolph.(2021).Targeting enzyme aging.Science.
MLA	Friedrich Becker,et al."Targeting enzyme aging".Science (2021).