By Cocer Peptides 
Watanni 1 da suka gabata
DUKKANIN LABARI DA BAYANIN KYAUTATAWA DA AKE BAYAR A WANNAN SHAFIN KAWAI DOMIN WATSA BAYANI NE DA MANUFOFIN ILIMI.
Kayayyakin da aka bayar akan wannan gidan yanar gizon an yi niyya ne kawai don binciken in vitro. Binciken in vitro (Latin: *a cikin gilashi*, ma'ana a cikin gilashin gilashi) ana gudanar da shi a wajen jikin mutum. Waɗannan samfuran ba magunguna ba ne, Hukumar Abinci da Magunguna ta Amurka (FDA) ba ta amince da su ba, kuma dole ne a yi amfani da su don hanawa, magani, ko warkar da kowane yanayi na likita, cuta, ko cuta. Doka ta haramta shigar da waɗannan samfuran cikin jikin mutum ko dabba ta kowace hanya.
A fagen ilimin rayuwa, tsufa ya kasance babban batun bincike koyaushe. Yayin da bincike kan hanyoyin tsufa ke ci gaba da zurfafawa, rawar nicotinamide adenine dinucleotide (NAD +) a cikin tsarin rigakafin tsufa ya sami ƙarin hankali. A matsayin coenzyme da ke cikin mahimman hanyoyin ilimin lissafin jiki a cikin sel, an gano NAD + yana da alaƙa da tsarin tsufa.
Hoto 1 Ayyukan Halittu na NAD. NAD tana daidaita ma'aunin makamashi, amsa damuwa, da homeostasis ta salula ta hanyar sirtuins, PARPs, da enzymes redox daban-daban.
Bayanin Ayyukan Jiki na NAD+
NAD + coenzyme ne wanda ke yaɗuwa a cikin sel, yana shiga cikin mahimman hanyoyin ilimin lissafi daban-daban. Ya kasance da farko a cikin nau'i biyu a cikin sel: nau'in oxidized (NAD+) da sigar da aka rage (NADH), wanda zai iya canzawa. Wannan ma'auni mai ƙarfi yana da mahimmanci don kiyaye metabolism na salon salula na al'ada da aiki.
1. Metabolism na makamashi: NAD + yana taka muhimmiyar rawa a cikin numfashi na salula. A cikin hanyoyin metabolism na makamashi kamar glycolysis, tricarboxylic acid sake zagayowar, da oxidative phosphorylation, NAD + yana aiki azaman mai karɓar lantarki, yana karɓar electrons da aka saki yayin iskar oxygenation na abubuwan rayuwa don samar da NADH. Daga baya, NADH yana tura electrons zuwa sarkar numfashi na mitochondrial, inda oxidative phosphorylation ke haifar da adenosine triphosphate (ATP), yana samar da makamashi ga tantanin halitta. Wannan tsari yana tabbatar da cewa sel na iya ci gaba da samun isasshen kuzari don kula da ayyukansu na yau da kullun, kamar haɓakar tantanin halitta, rarrabawa, da gyarawa.
A lokacin glycolysis, 3-phosphoglycerate yana canja wurin atom ɗin hydrogen zuwa NAD + a ƙarƙashin aikin 3-phosphoglycerate dehydrogenase, yana haifar da NADH da 1,3-diphosphoglycerate. Daga baya, NADH yana tura electrons zuwa oxygen ta hanyar sarkar numfashi a cikin mitochondria, a ƙarshe yana samar da ruwa da haɗin haɗin ATP. Wannan yana nuna cewa NAD + wani abu ne mai mahimmanci na metabolism na makamashin salula, kuma canje-canje a cikin maida hankalinsa kai tsaye yana shafar ingancin samar da makamashi.
2. Gyaran DNA: NAD + wani yanki ne na dangin poly (ADP-ribose) polymerase (PARP). Bayan PARP ta gane kuma ta ɗaure zuwa wuraren DNA da suka lalace, tana amfani da NAD + a matsayin maɗaukaki don canja wurin ƙungiyoyin ADP-ribose zuwa kanta ko wasu sunadaran, suna kafa sarƙoƙin poly(ADP-ribose) (PAR). Waɗannan sarƙoƙi na PAR na iya ɗaukar da kunna jerin sunadaran da ke cikin gyaran DNA, kamar DNA ligase da DNA polymerase, don haka fara aikin gyaran DNA. Lokacin da kwayoyin halitta suka fallasa ga lalacewar DNA ta hanyar abubuwa irin su ultraviolet radiation ko sinadarai, tsarin PARP-NAD + da sauri yana amsawa don gyara DNA da aka lalata da kuma kula da kwanciyar hankali. Idan matakan NAD + ba su isa ba, an hana ayyukan PARP, wanda ke haifar da rage ƙarfin gyaran DNA, ƙara yawan rashin zaman lafiyar kwayoyin halitta, da haɓaka tsufa na salula da kuma fara cuta.
3. Canjin sunadaran bayan fassarorin: NAD + kuma tana shiga cikin halayen halayen sunadarai na dangin sirtuin. Sirtuins aji ne na NAD +-dogara deacetylases waɗanda zasu iya cire gyare-gyaren acetyl daga ragowar lysine akan sunadaran. Wannan gyare-gyaren deacetylation yana daidaita ayyuka, kwanciyar hankali, da kuma tsarin subcellular sunadaran sunadaran da yawa, ta haka yana tasiri metabolism na salon salula, amsa damuwa, tsufa, da sauran tsarin ilimin lissafi. Alal misali, SIRT1 na iya tsara ayyukan abubuwan da aka rubuta kamar p53 da FOXO ta hanyar gyare-gyaren deacetylation, ta haka yana tasiri tsarin kwayar halitta, apoptosis, da matakan damuwa na antioxidant. Lokacin da sel ke cikin damuwa, SIRT1 deacetylates p53 ta hanyar cinye NAD +, ta haka yana hana ayyukan rubutun p53, rage abin da ya faru na apoptosis, da haɓaka ƙarfin rayuwa ta salula.
Canje-canje a Matakan NAD+ Lokacin Tsufa
Nazarin ya nuna cewa tare da shekaru, matakan NAD + a hankali suna raguwa a cikin kyallen takarda da ƙwayoyin jiki da yawa. An lura da wannan raguwa a cikin nau'o'in nau'i daban-daban, ciki har da dabbobi masu shayarwa, nematodes, da kwari masu 'ya'yan itace, suna nuna cewa rage matakan NAD + na iya zama abin kiyayewa a cikin tsarin tsufa.
1. Canje-canje na ƙayyadaddun ƙwayar cuta: Girma da kuma hanyoyin da ke haifar da raguwar matakin NAD + tare da shekaru na iya bambanta a cikin kyallen takarda daban-daban. A cikin tsokar kwarangwal, tsufa yana tare da raguwar ayyukan enzymes masu mahimmanci a cikin hanyar NAD + biosynthetic, wanda ke haifar da raguwar NAD + kira. Magana da ayyukan NAD + suna cinye enzymes kamar CD38 yana ƙaruwa, haɓaka NAD + lalata kuma a ƙarshe yana haifar da raguwa mai yawa a cikin matakan NAD + a cikin ƙwayar kwarangwal. A cikin hanta, ban da sauye-sauyen da aka ambata a cikin haɓakawa da hanyoyin lalacewa, tsufa na iya shafar hanyoyin sufuri na NAD +, wanda ke haifar da rashin daidaituwa a cikin rarrabawar NAD + na intracellular kuma yana ƙara rage tasirin sa.
2. Ƙungiya tare da cututtukan da suka shafi shekaru: Rage matakan NAD + suna da dangantaka da farawa da ci gaba da cututtuka daban-daban na shekaru. A cikin cututtukan zuciya da jijiyoyin jini, raguwar matakan NAD + na myocardial wanda ke haifar da tsufa yana haifar da rikicewar metabolism na makamashi, ƙara yawan damuwa na oxidative, da apoptosis na sel myocardial, don haka yana ƙara tabarbarewar aikin zuciya. A cikin cututtukan neurodegenerative irin su cutar Alzheimer da cutar Parkinson, raguwa a cikin matakan NAD + neuronal yana rinjayar gyaran DNA da homeostasis na gina jiki, inganta haɓakar sunadarai na neurotoxic da mutuwar neuronal. Cututtuka masu narkewa kamar su ciwon sukari kuma suna da alaƙa da raguwar matakan NAD +, kamar yadda ƙarancin NAD + yana lalata ƙwayar insulin da kuma ji na insulin, wanda ke haifar da ƙayyadaddun tsarin glucose na jini.
Hanyoyin da suka rage matakan NAD+ suna inganta tsufa
1. **Rashin lafiyar makamashi ***: NAD+ yana taka muhimmiyar rawa a cikin metabolism na makamashin salula. Yayin da shekaru ke ƙaruwa, raguwar matakan NAD + yana haifar da lalacewar hanyoyin metabolism na makamashi da rage yawan samar da ATP. Wannan ba wai kawai yana rinjayar ayyukan ilimin halittar jiki na al'ada ba amma har ma yana haifar da jerin martani na ramuwa, kamar yaɗawar mitochondrial mai wuce kima da ƙarancin aiki. Mitochondria sune gidajen wutar lantarki; lokacin da NAD + bai isa ba, aikin sarkar numfashi na mitochondrial ya lalace, yana haifar da haɓaka samar da nau'in oxygen mai amsawa (ROS) yayin jigilar lantarki. ROS mai yawa zai iya kai hari ga DNA na mitochondrial, sunadarai, da lipids, yana kara rushe tsarin mitochondrial da aiki, haifar da mummunan zagayowar da ke hanzarta tsufa na salula.
Hoto 2 Hanyoyin da aka tsara na yadda tsufa ke shafar metabolism na NAD. Tsufa yana rushe ma'auni tsakanin haɗin NAD da lalata, yana haifar da rage matakan NAD a cikin kyallen takarda daban-daban.
2. Tarin lalacewar DNA: A matsayin ma'auni na PARP, rage matakan NAD + yana raunana karfin gyaran DNA. Lokacin da ba za a iya gyara lalacewar DNA da kyau a cikin lokaci ba, yana haifar da rashin zaman lafiya na kwayoyin halitta, yana tara adadi mai yawa na maye gurbi da rashin daidaituwa na chromosomal. Wadannan lalacewar kwayoyin halitta suna tsoma baki tare da ayyuka na ilimin lissafi na salon salula na yau da kullum, suna shafar yaduwar kwayar halitta, bambanta, da apoptosis, don haka inganta tsufa na salula. Lalacewar DNA kuma tana kunna hanyoyin siginar da ke da alaƙa da tsufa a cikin sel, kamar hanyoyin p53-p21 da p16INK4a-Rb, yana ƙara haifar da faruwar tsufa na salula.
3. Dysregulation na hanyoyin siginar da ke da alaƙa: NAD +-dogaran sirtuin sunadaran iyali suna taka muhimmiyar rawa wajen daidaita hanyoyin siginar da ke da alaƙa. Yayin da matakan NAD+ ke raguwa, an hana ayyukan sirtuin, wanda ke haifar da raguwar gyare-gyaren deacetylation na sunadaran da ake niyya a ƙasa. Rage aikin SIRT1 yana haifar da p53 kasancewa a cikin yanayin da ba a iya jurewa ba, yana haɓaka aikin rubutun p53, yana haifar da kama sake zagayowar tantanin halitta da apoptosis; a lokaci guda, raunin deacetylation na FOXO factor transcription ta SIRT1 yana rinjayar juriya na damuwa na ƙwayar cuta da tsarin rayuwa. Bugu da ƙari, sauye-sauye a cikin ayyukan wasu dangin sirtuin kamar SIRT3 da SIRT6 kuma suna tasiri aikin mitochondrial, kwanciyar hankali na genomic, da martani mai kumburi, tare da haifar da ci gaba na salon salula.
Dabarun rigakafin tsufa don haɓaka matakan NAD+
Ganin dangantakar da ke tsakanin rage matakan NAD + da tsufa, dabarun jinkirta tsufa ta hanyar haɓaka matakan NAD + sun zama wurin bincike.
1. Haɓakawa NAD+ Precursors: Ƙara NAD+ precursors hanya ce ta gama gari don ƙara matakan NAD+. Abubuwan NAD+ na gama gari sun haɗa da nicotinamide (NAM), nicotinamide mononucleotide (NMN), da nicotinamide riboside (NR). Ana iya jujjuya waɗannan maɓuɓɓugan zuwa NAD + ta takamaiman hanyoyin rayuwa a cikin sel, don haka haɓaka matakan sa.
Nicotinamide (NAM): NAM wani nau'i ne na bitamin B3 wanda za'a iya canza shi zuwa nicotinamide mononucleotide (NMN) ta hanyar aikin nicotinamide phosphoribosyltransferase (NAMPT), wanda ake amfani dashi don haɗa NAD +. Babban adadin kari na NAM na iya mayar da martani ya hana ayyukan NAMPT, yana iyakance ikonsa na ƙara matakan NAD+. Yin amfani da dogon lokaci mai girma na NAM na iya haifar da sakamako masu illa kamar zubar da fata, amma a cikin allurai masu dacewa, NAM na iya haɓaka matakan NAD + na ciki yadda ya kamata, inganta ƙarfin makamashi, da haɓaka ayyukan gyaran DNA.
Nicotinamide mononucleotide (NMN): NMN shine mafarin kai tsaye a cikin hanyar NAD + biosynthetic. Nazarin ya nuna cewa NMN na baka yana shiga cikin hanzari kuma ya canza zuwa NAD +, yana haɓaka matakan NAD + sosai a cikin kyallen takarda daban-daban. A cikin gwaje-gwajen dabba, ƙarin NMN ya nuna ci gaba mai mahimmanci a cikin rikice-rikice na rayuwa da suka shafi shekaru, rashin lafiyar zuciya, da cututtuka na neurodegenerative. Misali, a cikin tsofaffin beraye, ƙarin NMN ya inganta ƙarfin locomotor, haɓaka haɓakar insulin, rage sauye-sauyen cututtukan cututtukan da ke da alaƙa da shekaru a cikin zuciya, da haɓaka aikin fahimi. Bugu da ƙari, an nuna NMN don inganta mitochondrial biogenesis, haɓaka aikin mitochondrial, da kuma rage lalacewa mai haifar da damuwa.
Nicotinamide riboside (NR): NR wani ingantaccen NAD + precursor ne wanda za'a iya canza shi zuwa NMN ta hanyar phosphorylation ta nicotinamide riboside kinase (NRK), wanda ake amfani dashi don haɗa NAD +. Kamar NMN, kari tare da NR na iya ƙara matakan NAD + na ciki, inganta aikin rayuwa, da jinkirta tsufa. A cikin berayen da suka tsufa, ƙarin NR na iya sake fasalin hanyoyin amsawa na rayuwa da damuwa, haɓaka ƙarfin ɗaurin chromatin na jigon agogon circadian BMAL1, maido da rhythms na numfashi na mitochondrial da ayyukan circadian, kuma a wani ɓangare na mayar da yanayin yanayin ƙwararrun beraye zuwa na ƙananan beraye.
Hoto 3 Samfurin da ke nuna hanyar NAD+ da hanyar ceto da nicotinamide riboside (NR) zuwa NAD+.
2. Tsarin NAD+ enzymes na rayuwa:
Kunna NAD + synthase: NAMPT shine ƙarancin ƙarancin enzyme a cikin hanyar NAD + biosynthetic, kuma ƙara yawan aiki na iya haɓaka haɗin NAD +. Wasu mahadi na halitta, irin su resveratrol da apigenin, an samo su don kunna NAMPT, don haka haɓaka samar da NAD +. Resveratrol wani fili ne na polyphenolic da ake samu a cikin fatun innabi, jan giya, da sauran tsirrai. Yana iya daidaita maganganun NAMPT a kaikaice ta kunna hanyar siginar SIRT1-PGC-1α, ta haka yana haɓaka matakan NAD +. Maganin resveratrol yana inganta metabolism na makamashi, yana rage lalacewar danniya, kuma yana kara tsawon rayuwa a cikin tsofaffin beraye.
Hana NAD + enzymes masu cinyewa: CD38 shine babban NAD + mai amfani da enzyme wanda maganganunsa da ayyukansa ya karu da shekaru, yana haɓaka lalata NAD +. Hana ayyukan CD38 yana rage yawan amfani da NAD+ kuma yana kiyaye matakan NAD+ na cikin salula. Wasu ƙananan mahadi, irin su 78c da apigenin, an ruwaito su hana ayyukan CD38. Yin amfani da masu hana CD38 na iya ƙara yawan matakan NAD + da inganta rashin lafiyar jiki da suka shafi shekaru, kamar haɓaka aikin zuciya da inganta cututtuka na rayuwa.
3. Tsarin rayuwa: Abubuwan salon rayuwa kuma suna tasiri sosai matakan NAD+.
Motsa jiki: motsa jiki na yau da kullun yana motsa hanyar NAD + biosynthetic kuma yana haɓaka matakan NAD +. Dukansu motsa jiki na motsa jiki da horarwa mai ƙarfi na iya ƙara yawan magana da aiki na NAMPT a cikin ƙwayar kwarangwal, inganta haɓakar NAD +. Motsa jiki kuma na iya daidaita maganganun NAD + kwayoyin da ke da alaƙa da metabolism, haɓaka aikin mitochondrial, da haɓaka ƙarfin antioxidant na salula. A cikin tsofaffin tsofaffi, motsa jiki na matsakaici na iya ƙara yawan abun ciki na NAD + a cikin tsokoki, inganta ƙarfin tsoka da aikin motsa jiki, da rage jinkirin tsarin tsufa.
Ƙuntatawa na abinci: Ƙuntatawa na abinci, kamar ƙuntatawa na kalori (CR) da azumi na wucin gadi (IF), an gane su azaman ingantattun dabarun rage tsufa. Waɗannan tsarin abincin abincin suna yin tasirin rigakafin tsufa ta hanyar daidaita tsarin NAD +. CR da IF suna kunna sunadaran dangin sirtuin kamar SIRT1, haɓaka haɗin NAD + da amfani. Ƙuntatawa na abinci na iya rage yawan damuwa na oxidative, inganta aikin rayuwa, da rage haɗarin cututtuka masu alaka da shekaru. A cikin gwaje-gwajen dabba, ƙuntatawa na kalori na dogon lokaci na iya haɓaka matakan NAD + da haɓaka rayuwar jinsuna da yawa.
Tasirin Tsufa na Ƙarfafa matakan NAD+
1. Abubuwan rigakafin tsufa a cikin gwaje-gwajen dabba: Yawancin gwaje-gwajen dabba sun tabbatar da cewa haɓaka matakan NAD + na iya rage saurin tsarin tsufa da haɓaka haɓakar ilimin ilimin halittar jiki da ke da alaƙa da shekaru.
Ingantattun Ayyukan Metabolic: A cikin tsofaffin beraye, haɓakawa tare da NMN ko NR na iya haɓaka haɓakar insulin, daidaita matakan glucose na jini, da haɓaka rikice-rikice na metabolism na lipid. NAD + precursor supplementation na iya ƙara fatty acid oxidation a cikin adipose nama, rage tara mai, da rage haɗarin cututtukan da ke da alaƙa da kiba. Haɓaka matakan NAD + kuma na iya haɓaka aikin hanta na rayuwa, haɓaka iyawar hanta na detoxification don magunguna da gubobi, da kiyaye aikin hanta na al'ada.
Kariya na Ayyukan Cardiovascular: A lokacin tsarin tsufa, tsarin zuciya na zuciya yana jurewa tsarin tsari da sauye-sauye na aiki, irin su hypertrophy na myocardial da rage karfin jini. Haɓakawa tare da masu haɓaka NAD + na iya haɓaka ƙanƙanwar zuciya da aikin shakatawa, rage fibrosis na zuciya, da rage lalacewar danniya. A cikin nau'in dabba, haɓakawa tare da NMN ko NR na iya rage karfin jini, inganta aikin endothelial na jijiyoyin jini, da kuma rage haɗarin cututtukan zuciya. A cikin nau'ikan infarction na myocardial, haɓaka matakan NAD + na iya haɓaka rayuwa da gyare-gyare, rage girman infarct, da haɓaka aikin zuciya.
Tasirin Neuroprotective: A cikin samfuran cututtukan neurodegenerative, haɓaka matakan NAD + yana nuna mahimman tasirin neuroprotective. Nazarin ya nuna cewa haɓakawa tare da NMN ko NR na iya inganta aikin fahimi, rage ƙwayar cutar neuroinflammation, da rage haɗuwa da sunadaran neurotoxic. A cikin nau'ikan linzamin kwamfuta na cutar Alzheimer, haɓakawa tare da abubuwan NAD + na iya rage samar da β-amyloid, hana wuce gona da iri na phosphorylation na furotin tau, kare neurons daga lalacewa, kuma ta haka inganta ƙwarewar koyo da ƙwaƙwalwar ajiya.
Tsawon rayuwa: A cikin kwayoyin halitta daban-daban, an nuna haɓaka matakan NAD + don tsawaita rayuwa. A cikin nematodes da kwari na 'ya'yan itace, haɓaka matakan NAD + ta hanyar sarrafa kwayoyin halitta ko ƙari tare da abubuwan da suka gabata na NAD + na iya ƙara tsawon rayuwarsu. A cikin gwaje-gwajen linzamin kwamfuta, kari na dogon lokaci tare da NMN ko NR kuma ya nuna yanayin zuwa tsawon rayuwa, kodayake wannan tasirin na iya bambanta a cikin karatu daban-daban. Gabaɗaya, waɗannan binciken suna nuna ingantaccen tasirin haɓaka matakan NAD + akan tsawon rayuwa.
Kammalawa
A matsayin mahimmin coenzyme a cikin sel, NAD + yana taka muhimmiyar rawa a cikin mahimman hanyoyin ilimin halittar jiki kamar metabolism na makamashi, gyaran DNA, da gyaran bayan fassarorin sunadaran. Yayin da shekaru ke ƙaruwa, raguwa a cikin matakan NAD + yana da alaƙa da tsarin tsufa da kuma farawa da ci gaba na cututtuka daban-daban na shekaru. Dabarun don haɓaka matakan NAD +, kamar haɓaka NAD + precursors, daidaita NAD + enzymes na rayuwa, da ayyukan rayuwa, sun nuna tasirin rigakafin tsufa a cikin gwaje-gwajen dabbobi, gami da ingantaccen aikin rayuwa, kariya ga tsarin zuciya da jijiyoyin jini, da tsawan rayuwa.
Sources
[1] Chubanava S, Trebak J T. Motsa jiki na yau da kullum yana kare kariya daga raguwar da ke da alaka da tsufa a cikin abun ciki na tsoka na NAD [J]. Gwajin Gerontology, 2023,173:112109.DOI:10.1016/j.exger.2023.112109.
[2] Soma M, Lalam S K. Matsayin nicotinamide mononucleotide (NMN) a cikin anti-tsufa, tsawon rai, da yuwuwar sa don magance yanayi na yau da kullun[J]. Rahoton Halittar Halitta, 2022,49 (10): 9737-9748.DOI: 10.1007/s11033-022-07459-1.
[3] Curry A, Farin D, Cen Y. Kananan Ma'aikatan Kwayoyin Halitta masu Targeting NAD(+) Biosynthetic Enzymes[J]. Chemistry Magani na Yanzu, 2022,29(10):1718-1738.DOI:10.2174/0929867328666210531144629.
[4] Yuan Y, Liang B, Liu X, et al. Niyya NAD +: shine dabarun gama gari don jinkirta tsufa na zuciya?[J]. Gano Mutuwar Cell, 2022,8. https://api.semanticscholar.org/CorpusID:248393418
[5] Levine DC, Hong H, Weidemann BJ, et al. NAD(+) Yana Sarrafa Sake Shirye-shiryen Circadian ta hanyar Canjawar Nukiliya ta PER2 zuwa Counter Aging[J]. Kwayoyin Halitta, 2020,78(5):835-849.DOI:10.1016/j.molcel.2020.04.010.
[6] Fang EF, Hou Y, Lautrup S, et al. NAD (+) haɓaka yana dawo da mitophagy kuma yana iyakance haɓakar tsufa a cikin ciwon Werner [J]. Sadarwar yanayi, 2019,10 (1): 5284.DOI: 10.1038/s41467-019-13172-8.
[7] Yaku K, Okabe K, Nakagawa T. NAD metabolism: Abubuwan da ke faruwa a cikin tsufa da tsawon rai [J]. Binciken Nazarin Tsufa, 2018,47:1-17.DOI:10.1016/j.arr.2018.05.006.
[8] Chaturvedi P, Tyagi S C. NAD (+) : Babban dan wasa a cikin gyaran zuciya da skeletal tsoka da kuma tsufa [J]. Jaridar Kwayoyin Halitta, 2018,233 (3): 1895-1896.DOI: 10.1002/jcp.26014.
Samfura akwai don amfani da bincike kawai:
